PROG: 1 UNIQUE IDENTIFIER NIH/00632 PROTOCOL ID NUMBERS NINDS 93 N-30 PROTOCOL TITLE The Efficacy of Oral Levocarnitine (L-Carnitine) Therapy on Zidovudine-Induced Myopathy: A Double-Blind, Placebo-Controlled Trial. VERSION NUMBER & DATE (940520) TRIAL CATEGORY Neurologic Manifestations TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Dulakas M PROTOCOL CHAIRS CO-CHAIR Cupler E GENERAL DESCRIPTION PURPOSE: To evaluate the effects of levocarnitine (L-carnitine) on zidovudine (AZT)-induced myopathy in patients currently receiving AZT therapy for HIV infection. GENERAL DESCRIPTION RATIONALE: Some HIV-infected patients receiving AZT therapy develop a medication-induced muscle disease called myopathy. Current recommendations usually are to decrease or discontinue AZT therapy, but since AZT is the most effective treatment of HIV infection currently available, a therapy for the side effect of muscle disease would be highly beneficial. GENERAL DESCRIPTION METHODOLOGY: Patients who are receiving AZT and experiencing myopathy are randomized to receive either oral L-carnitine or placebo thrice daily for 6 months. Patients will undergo two muscle biopsies in addition to EMG and nerve conduction studies, blood studies, and muscle strength and function assessments. A total of five clinic visits (visits for screening, for the initial biopsy, and at months 2, 4, and 6) will be required. Patients will also need to complete questionnaires at home every 2 weeks. At the end of 6 months, patients on the placebo arm may receive 6 months of L-carnitine on an optional basis, provided benefit was shown. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940520) DISEASE STUDIED Myopathy. DISEASES STATUS Patients have the following symptoms and conditions: 1. Current AZT therapy for HIV infection and intending to remain on AZT therapy for the duration of the study. 2. Biopsy-proven AZT-induced myopathy. Clinical signs of AZT-induced myopathy may include muscle weakness, muscle shrinkage, fatigue, decreased endurance, muscle pain, abnormal elevation of creatine kinase, or evidence of muscle disease by EMG. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled PROTOCOL DETAILS STUDY INTENT: Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: OPEN patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Minimum of 6 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Current AZT therapy for HIV infection. 2. Diagnosis of AZT-induced myopathy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Prior AZT. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: AZT. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. SUBSTANCE IDENTIFICATION Drug 1 DRG-0211 Levocarnitine MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Drug or placebo thrice daily for at least 6 months SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral OTHER TREATMENT INFO. TREATMENT DURATION: 6 months. SUPPORTING AGENCY National Institute of Neurological Disorders & Stroke. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Carnitine/*THERAPEUTIC USE MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Muscles/DRUG EFFECTS/*PATHOLOGY MESH HEADING Muscular Diseases/*CHEMICALLY INDUCED/ COMPLICATIONS/PATHOLOGY MESH HEADING Zidovudine/ADVERSE EFFECTS CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 940520 ENTRY MONTH 9406 MARYLAND National Institute of Neurological Disorders & Stroke 9000 Rockville Pike / Bldg 10 Room 4N248 Bethesda, MD 20892 Contact: Dr Edward Cupler (301) 402-1931 OPEN / USA Accrual 940520. 2 UNIQUE IDENTIFIER NIH/00600 PROTOCOL ID NUMBERS NIAID WIHS PROTOCOL TITLE Women's Interagency HIV Study (WIHS). VERSION NUMBER & DATE (940621) TRIAL CATEGORY Epidemiology GENERAL DESCRIPTION PURPOSE: To define, in women, the following: the spectrum and course of HIV infection; the pattern and rate of change of immunologic markers in women and the relationship of these changes to other immunologic and virologic parameters and to the clinical manifestations of HIV; and the various factors that may influence HIV disease progression. Methodology: Study visits are scheduled for every 6 months. GENERAL DESCRIPTION METHODOLOGY: Study visits are scheduled for every 6 months. PROTOCOL PHASE Epidemiology OPEN/CLOSED INDICATOR Open: Pending first patient enrolled (940930) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Participants must meet the following criteria: o HIV-infected women OR o HIV-uninfected women who are at high risk for HIV because of multiple sexual partners, injection of drugs, or has a sex partner who is at high risk, either through multiple sex partners or injection of drugs. ELIGIBILITY HIV Seropositive. HIV Seronegative. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Prospective PROTOCOL DETAILS STUDY INTENT: Epidemiology. PROTOCOL DETAILS PROJECTED ACCRUAL: 2500 patients. (2000 HIV-positive women; 500 HIV-seronegative women). PROTOCOL DETAILS STUDY DURATION: 4 years (until July 1997). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 6 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Participants meet the following criteria: 1. HIV infected women OR uninfected women who are at high risk for HIV. 2. Willing to be retested for HIV infection for this study. 3. Able to complete interview in English or Spanish. 4. Able to travel to and from site clinic and participate in a baseline visit as an outpatient. 5. Willing to have blood drawn. NOTE: Patients must be 18 years of age for enrollment at certain sites. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: Non-applicable percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: Non-applicable g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: Non-applicable cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: Non-applicable platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CD4/CD8 RATION: Non-applicable. PATIENT INCLUSION CRIT. BILIRUBIN: Non-applicable mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): Non-applicable. PATIENT INCLUSION CRIT. SGPT(ALT): Non-applicable. PATIENT INCLUSION CRIT. CREATININE: Non-applicable. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: Non-applicable ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: Non-applicable. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. SEX: MALE SUPPORTING AGENCY NIAID Epidemiology Branch. MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/*EPIDEMIOLOGY/ETIOLOGY MESH HEADING Human MESH HEADING Middle Age LAST REVISION DATE 940930 ENTRY MONTH 9410 CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 940303 ACTU: 1201. CALIFORNIA University of California / San Francisco Box 1352 / 400 Parnassus Avenue / AC-16 San Francisco, CA 94143-0422 Contact: Rose Katsis (415) 476-9356 OPEN 940303. DISTRICT OF COLUMBIA Georgetown University Medical Center 110 Kober-Cogan Bldg / 3800 Reservoir Road N.W. Washington, DC 20007 Contact: Barbara Lewis (202) 784-2687 OPEN 940303. ILLINOIS Chicago Consortium 1835 West Harrison / CCSN Room 1245 Chicago, IL 60612 Contact: Kathleen Weber (312) 572-3715 Contact: Dr Mardge Cohen OPEN 940303. NEW YORK Bronx - Lebanon Hospital Center 1309 Fulton Avenue / 4th Floor Bronx, NY 10456 Contact: Sara Back (718) 901-8980 OPEN 940303. NEW YORK SUNY at Brooklyn 450 Clarkson Avenue Brooklyn, NY 11203 Contact: Susan Holman (718) 270-1819 OPEN 940303. 3 UNIQUE IDENTIFIER NIH/00615 PROTOCOL ID NUMBERS NIAID VEU 018 PROTOCOL TITLE A Phase I Safety and Immunogenicity Trial of UBI Microparticulate Monovalent HIV-1 MN Peptide Immunogen in HIV-1 Seronegative Human Subjects. VERSION NUMBER & DATE (940912) TRIAL CATEGORY Vaccines TRIAL CATEGORY HIV Negative PROTOCOL CHAIRS CHAIR Lambert J GENERAL DESCRIPTION PURPOSE: To evaluate the safety and immunogenicity of a new microparticulate formulation of an HIV-1 MN PND peptide for oral administration in healthy, HIV-1 seronegative adult volunteers at low risk for infection. GENERAL DESCRIPTION RATIONALE: Vaccine formulations of synthetic peptides adsorbed to alum may not provide other requisite characteristics of an effective HIV vaccine, such as induction of mucosal immunity, production of cytotoxic T cells, and ease of administration. An oral microparticulate vaccine containing a prototype synthetic peptide has been developed. The microparticles can be degraded over time, inducing both secretory and systemic immune responses. GENERAL DESCRIPTION METHODOLOGY: Twelve volunteers per dose regimen will receive oral microparticulate multivalent HIV-1 peptide vaccine at months 0, 1, and 6, either as 1 mg daily for 3 days or 3 mg in a single dose. Additionally, four volunteers per regimen will receive placebo. Volunteers are followed for 1 year. They will be contacted once or twice yearly for 5 years to check on health status. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Healthy. DISEASES STATUS Subjects have the following conditions: 1. Normal history and physical exam. 2. HIV negative by ELISA within 8 weeks of study entry. 3. Absolute CD4 count >= 400 cells/mm3. 4. Normal urine dipstick with esterase and nitrite. 5. Lower or intermediate risk sexual behavior. ELIGIBILITY HIV Seronegative. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled PROTOCOL DETAILS STUDY INTENT: Vaccine prophylaxis, Immunology, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 32 patients. (16 vaccinees at each of two participating sites) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 52 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 26/32 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Subjects must have: 1. Normal history and physical exam. 2. HIV negativity by ELISA within 8 weeks of study entry. 3. Absolute CD4 count >= 400 cells/mm3. 4. Normal urine dipstick with esterase and nitrite. 5. Lower or intermediate risk sexual behavior. NOTE: No more than 10 percent of subjects may be over 50 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: >= 34 percent. (women); >= 38 percent (men). PATIENT INCLUSION CRIT. PLATELET COUNT: 150000 - 550000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 400 cells/mm3. ( 400 - 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. SGPT(ALT): <= 1.5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 1.6 mg/dl. PATIENT INCLUSION CRIT. OTHER: WBC >= 3500 cells/mm3 with normal differential. Total lymphocytes >= 800 cells/mm3. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Subjects with the following prior conditions are excluded: 1. History of immunodeficiency, chronic illness, or autoimmune disease. 2. History of anaphylaxis or other serious reactions to vaccines. 3. History of inflammatory gastrointestinal disease, celiac disease, or intestinal malignancy. 4. History of acute gastroenteritis within the past month or gastrointestinal surgery within the past year. 5. History of cancer unless there has been surgical excision with reasonable assurance of cure. 6. History of serious allergic reaction. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Identifiable higher risk behavior for HIV infection, including the following: 1. History of injection drug use within the past 12 months. 2. Higher risk sexual behavior as defined by the AVEG. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Blood products or immunoglobulin within the past 6 months. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. History of immunosuppressive medications. 2. Live attenuated vaccines within 60 days prior to study entry (NOTE: Medically indicated subunit or killed vaccines, e.g., influenza or pneumococcal, are not exclusionary, but should not be given within 2 weeks of HIV immunization). 3. Experimental agents within 30 days prior to study entry. 4. Prior HIV vaccines. PATIENT EXCLUSION CRIT. COMPLICATIONS: Subjects with the following symptoms or conditions are excluded: 1. Positive hepatitis B surface antigen. 2. Medical or psychiatric condition (such as psychosis or suicidal tendencies) or occupational responsibilities that preclude study compliance. 3. Active syphilis. NOTE: Subjects whose serology is documented to be a false positive or due to a remote (> 6 months) treated infection are eligible. 4. Active tuberculosis. NOTE: Subjects with a positive PPD and normal chest x-ray showing no evidence of TB and not requiring isoniazid therapy are eligible. PATIENT EXCLUSION CRIT. AVAILABILITY: Unavailable for 52 weeks of follow-up. SUBSTANCE IDENTIFICATION Drug 1 DRG-0212 Microparticulate Monovalent HIV-1 Peptide Vaccine MANUFACTURERS Drug 1: United Biomedical Inc 25 Davids Drive Hauppauge, NY 11788 Contact: Dr Bruce Forrest (516) 273-2828. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1 mg daily for 3 days OR 3 mg in a single dose (or placebo) at months 0, 1, and 6 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 1 mg vials SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (VEU), United Biomedical Inc. MESH HEADING Administration, Oral MESH HEADING Adult MESH HEADING Female MESH HEADING HIV Infections/*PREVENTION & CONTROL MESH HEADING HIV-1/*IMMUNOLOGY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Vaccines, Synthetic/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/IMMUNOLOGY CAS REGISTRY NUMBER 0 (Vaccines, Synthetic) LAST REVISION DATE 941207 ENTRY MONTH 9407 MARYLAND Johns Hopkins University / Center for Immunization Research Hampton House / 624 North Broadway Baltimore, MD 21205 Contact: Dr Jack Lambert (410) 955-7283 OPEN 940629. NEW YORK University of Rochester Medical Center Box 689 / 575 Elmwood Avenue Rochester, NY 14642 Contact: Unspecified (716) 275-5744 Contact: (716) 275-6561 OPEN 940629. 4 UNIQUE IDENTIFIER NIH/00635 PROTOCOL ID NUMBERS NIAID VEU 016A PROTOCOL TITLE A Phase I, Multicenter, Randomized, Double-Blind, Placebo-Controlled HIV-1 Vaccine Trial to Evaluate the Safety and Immunogenicity of MN Recombinant Soluble gp120/HIV-1 (rsgp120/HIV-1) (Genentech) in Combination With QS21 Adjuvant and/or Alum in Healthy Adults. VERSION NUMBER & DATE (940610) TRIAL CATEGORY Vaccines TRIAL CATEGORY HIV Negative PROTOCOL CHAIRS CHAIR McElrath J GENERAL DESCRIPTION PURPOSE: To extend the evaluation of safety and immunogenicity of MN recombinant soluble gp120/HIV-1 (MN rsgp120/HIV-1) in combination with QS21 with or without alum and on two different vaccination schedules. GENERAL DESCRIPTION RATIONALE: Recent animal studies indicate that immunizing with MN rsgp120/HIV-1 in combination with QS21 on a 0, 1, 2 month schedule results in a more rapid rise in binding and neutralizing antibody response than on a 0, 1, 6 month schedule. Such an effect may be particularly desirable in vaccine delivery. This study compares these two delivery schedules using the unadjuvanted vaccine formulation rsgp120/HIV-1 with or without addition of alum. GENERAL DESCRIPTION METHODOLOGY: Healthy volunteers (20 per group) receive MN rsgp120/HIV-1 (300 or 0 mcg) in combination with QS21 (100 mcg), either with or without alum, at 0, 1, and 2 months or 0, 1, and 6 months. For both vaccination schedules, an additional five volunteers receive only vehicle with alum. The 0 mcg antigen groups are included primarily as negative controls. Subjects may be contacted for follow-up on health status once or twice yearly for at least 5 years. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Healthy. DISEASES STATUS Subjects have the following conditions: 1. Normal history and physical exam, with no significant abnormalities. 2. Negative for HIV by ELISA within 8 weeks of immunization. 3. Absolute CD4 count >= 400 cells/mm3. 4. Normal urine dipstick with esterase and nitrite. ELIGIBILITY HIV Seronegative. OTHER PROTOCOL NUMBERS IND BB5045 STUDY DESIGN Randomized; Double-Blind; Multicenter; Placebo-Controlled; Drug Tolerance; Dose Comparison PROTOCOL DETAILS STUDY INTENT: Drug safety, Vaccine prophylaxis, Immunology. PROTOCOL DETAILS PROJECTED ACCRUAL: VEU 017 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Approximately 12 months, with possible follow-up once or twice yearly for at least 5 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 110/VEU 017 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 5 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Subjects must have: 1. Normal history and physical exam. 2. HIV negative by ELISA within 8 weeks of immunization. 3. Absolute CD4 count >= 400 cells/mm3. 4. Normal urine dipstick with esterase and nitrite. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: >= 34 percent. (women); >= 38 percent (men). PATIENT INCLUSION CRIT. PLATELET COUNT: 150000 - 550000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 400 cells/mm3. ( 400 - 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. SGPT(ALT): <= 1.5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 1.6 mg/dl. PATIENT INCLUSION CRIT. OTHER: WBC >= 3500 cells/mm3 with normal differential. Total lymphocytes >= 800 cells/mm3. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Subjects with the following prior conditions are excluded: 1. History of immunodeficiency, autoimmune disease, or use of immunosuppressive medications. 2. History of anaphylaxis or other serious adverse reactions to vaccines. 3. History of allergy to thimersol. 4. History of serious allergic reaction to any substance, requiring hospitalization or emergent medical care (e.g., Steven-Johnson syndrome, bronchospasm, or hypotension). 5. Prior psychiatric condition (such as history of suicide attempts or past psychosis) that precludes compliance. 6. History of cancer unless there has been surgical excision that is considered to have achieved cure. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Subjects are NOT excluded on the basis of HIV risk behaviors, but AVOIDANCE of any activity that may expose subject to HIV (e.g., unprotected sex or needle sharing) is STRONGLY RECOMMENDED. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Receipt of blood products or immunoglobulin within the past 6 months. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Live attenuated vaccines within 60 days prior to study entry. (NOTE: Medically indicated subunit or killed vaccines, such as influenza or pneumococcal, are allowed but should be given at least 2 weeks prior to HIV immunizations.) 2. Experimental agents within 30 days prior to study entry. 3. Prior HIV vaccines. PATIENT EXCLUSION CRIT. COMPLICATIONS: Subjects with the following symptoms or conditions are excluded: 1. Hepatitis B surface antigen. 2. Medical or psychiatric condition (such as recent suicidal ideation or present psychosis) that precludes compliance. 3. Occupational responsibilities that preclude compliance. 4. Active syphilis. NOTE: Subjects with serology documented to be false positive or due to a remote (> 6 months) treated infection are eligible. 5. Active tuberculosis. NOTE: Subjects with a positive PPD and normal chest x-ray showing no evidence of TB and not requiring isoniazid therapy are eligible. PATIENT EXCLUSION CRIT. AVAILABILITY: Unavailable for 18 months of follow-up. SUBSTANCE IDENTIFICATION Drug 1 DRG-0153 rgp120/HIV-1MN SUBSTANCE IDENTIFICATION Drug 2 DRG-0178 QS-21 SUBSTANCE IDENTIFICATION Drug 3 DRG-0172 Aluminum hydroxide MANUFACTURERS Drug 1: Genentech Incorporated 460 Point San Bruno Boulevard South San Francisco, CA 94080 Contact: Professional Services (800) 821-8590. MANUFACTURERS Drug 2: Genentech Incorporated 460 Point San Bruno Boulevard South San Francisco, CA 94080 Contact: Professional Services (800) 821-8590. MANUFACTURERS Drug 3: Genentech Incorporated 460 Point San Bruno Boulevard South San Francisco, CA 94080 Contact: Professional Services (800) 821-8590. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 0 or 300 mcg at months 0, 1, and 2 or months 0, 1, and Drug 2: 0 or 100 mcg at months 0, 1, and 2 or months 0, 1, and Drug 3: Administered with vaccine in selected subject cohorts amonths 0, 1, and 2 or months 0, 1, and 6 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intramuscular. Drug 2: Intramuscular. Drug 3: Intramuscular OTHER TREATMENT INFO. END POINT: Safety, immunogenicity. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (VEU). MESH HEADING Adjuvants, Immunologic MESH HEADING Adult MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Envelope Protein gp120/*IMMUNOLOGY MESH HEADING HIV Infections/*PREVENTION & CONTROL MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Vaccines, Synthetic CAS REGISTRY NUMBER 0 (HIV Envelope Protein gp120) CAS REGISTRY NUMBER 0 (Adjuvants, Immunologic) CAS REGISTRY NUMBER 0 (Vaccines, Synthetic) LAST REVISION DATE 941207 ENTRY MONTH 9406 MARYLAND Johns Hopkins University / Center for Immunization Research Hampton House Rm 125 / 624 North Broadway Baltimore, MD 21205 Contact: Karen Charron (410) 955-7283 OPEN 940504 ACTU: 6002. MISSOURI St Louis University School of Medicine / Sec Inf Dis 1402 South Grand Boulevard St Louis, MO 63104 Contact: Dr Robert B Belshe (314) 577-8648 Contact: Heidi Israel (314) 577-8649 OPEN 940602 ACTU: 6007. NEW YORK University of Rochester Medical Center Box 689 / Room 36209 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Dr Michael Keefer (716) 275-0810 OPEN 940602 ACTU: 6005. 5 UNIQUE IDENTIFIER NIH/00490 PROTOCOL ID NUMBERS NIAID VEU 014 PROTOCOL TITLE A Multicenter, Randomized, Placebo-Controlled, Double-Blind Trial to Evaluate the Safety and Immunogenicity of a Recombinant Vaccinia-HIV-1 IIIB Env/Gag/Pol Vaccine (TBC-3B). VERSION NUMBER & DATE (940601) TRIAL CATEGORY Vaccines TRIAL CATEGORY HIV Negative PROTOCOL CHAIRS CHAIR Keefer M GENERAL DESCRIPTION PURPOSE: To evaluate, in healthy HIV-1 seronegative vaccinia-immune and vaccinia-naive volunteers, the safety and immunogenicity of an HIV-1 candidate vaccine (TBC-3B) consisting of a live recombinant vaccinia virus expressing the env, gag, and pol genes of HIV-1 IIIB strain. To evaluate the potential of boosting with one of a variety of HIV-1 recombinant subunit, peptide, or pseudovirion vaccines, if available, to augment the immune responses of the vaccinees. GENERAL DESCRIPTION RATIONALE: Antigenic drift, defined as the genetic variation of the HIV-1 envelope gene that results in antigenic variation during natural infection, may confound attempts to achieve protective immunity using a vaccine based solely on HIV-1 envelope proteins. Inclusion of conserved core and polymerase proteins along with envelope protein in a candidate vaccine may address some of the problems with antigenic variability. A prime-boost immunization approach using a novel priming immunogen expressing env, gag, and pol genes of the HIV-1 IIIB strain will be attempted in this study. GENERAL DESCRIPTION METHODOLOGY: In Part I, vaccinia-immune volunteers are randomized to one of two regimens. Group A receives priming with TBC-3B on days 1 and 56, followed by boosting on day 224 (8 months) with one of the following: TBC-3B, an alternative immunogen such as pseudovirion particles or a recombinant HIV-1 subunit or peptide vaccine, or placebo. Group B receives priming with control vaccine (DryVax), followed by boosting with an appropriate placebo. At least 50 percent of subjects in Part I will be observed for a minimum of 8 weeks before subsequent volunteers are enrolled in Part II. In Part II, vaccinia-naive volunteers are randomized to one of three regimens. Group C receives TBC-3B on day 0 and saline placebo on day 56. Group D receives TBC-3B on days 0 and 56. Both Group C and D receive boosting with TBC-3B or an alternative immunogen on day 224. Group E receives control vaccine (DryVax) on days 0 and 56, followed by appropriate placebo on day 224. Per 06/10/94 addendum, volunteers will be contacted once or twice per year for at least 5 years to check on health status. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940427) DISEASE STUDIED Healthy. DISEASES STATUS Subjects have the following conditions: 1. Negative for HIV-1 by ELISA and Western blot within 6 weeks prior to immunization. 2. Normal history and physical exam. 3. History of smallpox vaccination at least 5 years prior to study entry (Part I) OR no prior smallpox vaccination (Part II). 4. Absolute CD4 count >= 400 cells/mm3. 5. Normal urinalysis. ELIGIBILITY HIV Seronegative. OTHER PROTOCOL NUMBERS IND BB4930 STUDY DESIGN Multicenter; Randomized; Placebo-Controlled; Double-Blind PROTOCOL DETAILS STUDY INTENT: Immunology, Drug safety, Vaccine prophylaxis. PROTOCOL DETAILS PROJECTED ACCRUAL: 50 patients. (18 patients in Part I; 32 patients in Part II) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 18 months, with follow-up once or twice yearly for at least 5 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 18/50 (941109). PROTOCOL DETAILS STUDY DURATION: 1.5 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 4 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Subjects must have: 1. Negative ELISA and Western blot for HIV-1 within 6 weeks prior to immunization. 2. Normal history and physical exam. 3. History of smallpox vaccination at least 5 years prior to study entry (Part I) OR no prior smallpox vaccination (Part II). 4. Absolute CD4 count >= 400 cells/mm3. 5. Normal urinalysis. NOTE: No more than 10 percent of volunteers in both Parts I and II may be over 50 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: >= 34 percent. (women); >= 38 percent (men). PATIENT INCLUSION CRIT. PLATELET COUNT: 150000 - 550000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 400 cells/mm3. ( 400 - 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. SGPT(ALT): <= 1.5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 1.6 mg/dl. PATIENT INCLUSION CRIT. OTHER: Total lymphocytes >= 800 cells/mm3. WBC >= 3500 cells/mm3 with normal differential. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Subjects with the following prior conditions are excluded: 1. History of immunodeficiency, chronic illness, autoimmune disease, or use of immunosuppressive medications. 2. History of anaphylaxis or other serious adverse reactions to vaccines. 3. Eczema within the past year. 4. History of serious allergic reaction to any substance, requiring hospitalization or emergent medical care (e.g., Steven-Johnson syndrome, bronchospasm, or hypotension). 5. Prior psychiatric condition (such as history of suicide attempts or past psychosis) that precludes compliance. 6. History of cancer unless there has been surgical excision that is considered to have achieved cure. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: It is STRONGLY RECOMMENDED that any activity that might expose subject to HIV (unprotected sex or needle sharing) be avoided. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Receipt of blood products or immunoglobulins within the past 6 months. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior HIV vaccines. 2. Live attenuated vaccines within the past 60 days. NOTE: Medically indicated subunit or killed vaccines (e.g., influenza, pneumococcal) do not exclude but should be administered at least 2 weeks prior to HIV immunizations. 3. Experimental agents within the past 30 days. PATIENT EXCLUSION CRIT. COMPLICATIONS: Subjects with the following symptoms or conditions are excluded: 1. Positive hepatitis B surface antigen. 2. Medical or psychiatric condition (such as recent suicidal ideation or present psychosis) that precludes compliance. 3. Occupational responsibilities that preclude compliance. 4. Active syphilis. NOTE: Subjects with serology documented to be a false positive or due to a remote (> 6 months) treated infection are eligible. 5. Active tuberculosis. NOTE: Subjects with a positive PPD and a normal chest x-ray showing no evidence of TB and not requiring isoniazid therapy are eligible. 6. Eczema. 7. Household contact with persons meeting any of the following criteria: pregnancy, less than 12 months of age, eczema, immunodeficiency disease, or use of immunosuppressive medications. PATIENT EXCLUSION CRIT. AVAILABILITY: Unavailable for 18 months of follow-up. SUBSTANCE IDENTIFICATION Drug 1 DRG-0089 Smallpox vaccine SUBSTANCE IDENTIFICATION Drug 2 DRG-0206 TBC-3B Vaccine TRADE NAME OF SUBSTANCE Drug 1‰ DryVax MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Therion Biologics Corporation 76 Rogers Street Cambridge, MA 02142 Contact: Dr Dennis Panicali (617) 876-7779 Contact: Gail Mazzara (617) 876-7779. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Groups B and E: Administered on days 0 and 56, followedby boost with same control vaccine or placebo on day 224. Drug 2: Groups A and D: Administered on days 0 and 56, with boousing the candidate vaccine, other immunogen, or placebo on dayGroup C: Administered on day 0, with placebo given on day 56, followed by boost using the candidate vaccine, other immunogen,placebo on day 224 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Scarification using bifurcated needle. Drug 2: Scarification using bifurcated needle SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (VEU). MESH HEADING Adult MESH HEADING Female MESH HEADING HIV Infections/*PREVENTION & CONTROL MESH HEADING HIV-1/*IMMUNOLOGY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Smallpox Vaccine MESH HEADING Vaccines, Synthetic MESH HEADING Vaccinia Virus/*IMMUNOLOGY MESH HEADING Viral Vaccines CAS REGISTRY NUMBER 0 (Vaccines, Synthetic) CAS REGISTRY NUMBER 0 (Smallpox Vaccine) CAS REGISTRY NUMBER 0 (Viral Vaccines) LAST REVISION DATE 940427 ENTRY MONTH 9404 MARYLAND Johns Hopkins University / Center for Immunization Research Hampton House Rm 125 / 624 North Broadway Baltimore, MD 21205 Contact: Karen Charron (410) 955-7283 OPEN 941110 ACTU: 6002. MISSOURI St Louis University School of Medicine / Sec Inf Dis 1402 South Grand Boulevard St Louis, MO 63104 Contact: Dr Robert B Belshe (314) 577-8648 Contact: Heidi Israel (314) 577-8649 OPEN 940411 ACTU: 6007. NEW YORK University of Rochester Medical Center Box 689 / Room 36209 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Dr Michael Keefer (716) 275-0810 OPEN 940328 ACTU: 6005. 6 UNIQUE IDENTIFIER NIH/00512 PROTOCOL ID NUMBERS NIAID VEU 013B PROTOCOL TITLE A Phase I, Multicenter, Clinical Trial to Evaluate the Safety and Immunogenicity of Vaccinia-Derived MN HIV-1 Recombinant Envelope Glycoprotein (rgp160) of Human Immunodeficiency Virus in Combination With Recombinant Vaccinia-HIV-1 LAV Envelope Vaccine (HIVAC-1e): Part B. VERSION NUMBER & DATE (930210) TRIAL CATEGORY Vaccines TRIAL CATEGORY HIV Negative PROTOCOL CHAIRS CHAIR Gorse G GENERAL DESCRIPTION PURPOSE: To determine in healthy volunteers the safety and immunogenicity of two immunizations of MN rgp160 vaccine (Immuno-AG) in combination with a live recombinant vaccinia virus LAV HIV-1 gp160 vaccine (HIVAC-1e) versus DryVax (the standard smallpox vaccine that was used for many years) control in combination with placebo. GENERAL DESCRIPTION RATIONALE: A gp160 vaccine derived from the MN strain, the most prevalent strain of HIV-1 in the United States, has been developed. A previous study showed that a combination vaccine strategy, consisting of priming with HIVAC-1e followed by boosting with a gp160 subunit vaccine, resulted in humoral and cellular immune responses of greater and longer duration than either vaccine alone. Thus, a live vector/subunit boost approach using the MN rgp160 vaccine merits investigation. GENERAL DESCRIPTION METHODOLOGY: Volunteers are randomized to receive either HIVAC-1e on days 0 and 56 followed by immunization with MN rgp160 vaccine on days 224 and 364, or DryVax control on days 0 and 56 followed by placebo on days 224 and 364. Ten volunteers are entered on the MN rgp160 vaccine arm and two volunteers on the placebo arm. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Pending first patient enrolled (940615) DISEASE STUDIED Healthy. DISEASES STATUS Subjects have the following conditions: 1. Normal history and physical exam. 2. Negative for HIV by ELISA within 6 weeks prior to immunization. 3. Negative for HIV by Western blot (i.e., no reactivity at gp160, gp120, and gp41). Exceptions may be made if patients have a p24 band on Western blot and other tests are negative. 4. CD4 count >= 400 cells/mm3. 5. No history of smallpox vaccination. 6. Normal urine dipstick with esterase and nitrate. 7. No history of immunodeficiency, chronic illness, autoimmune disease, or use of immunosuppresssive medications. ELIGIBILITY HIV Seronegative. OTHER PROTOCOL NUMBERS IND BB4949 STUDY DESIGN Multicenter; Randomized; Placebo-Controlled PROTOCOL DETAILS STUDY INTENT: Vaccine prophylaxis, Drug safety, Immunology. PROTOCOL DETAILS PROJECTED ACCRUAL: 16 patients. PROTOCOL DETAILS STUDY DURATION: 18 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Subjects must have: 1. Normal history and physical exam. 2. Negative test for HIV by ELISA within 6 weeks prior to immunization. 3. Negative test for HIV by Western blot. 4. CD4 count >= 400 cells/mm3. 5. No history of smallpox vaccination. 6. Normal urine dipstick with esterase and nitrate. 7. No history of immunodeficiency, chronic illness, autoimmune disease, or use of immunosuppresssive medications. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: >= 34 percent. (women); >= 38 percent (men). PATIENT INCLUSION CRIT. PLATELET COUNT: 150000 - 550000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 400 cells/mm3. ( 400 - 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. SGPT(ALT): <= 1.5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 1.6 mg/dl. PATIENT INCLUSION CRIT. OTHER: White blood cell count >= 3500 cells/mm3 with normal differential. Total lymphocyte count >= 800 cells/mm3. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Subjects with the following prior conditions are excluded: 1. History of anaphylaxis or other serious adverse reactions to vaccines. 2. Eczema within the past year. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Higher risk behavior for HIV infection as determined by screening questionnaire, including: 1. History of injection drug use within 12 months prior to study entry. 2. Higher or intermediate risk sexual behavior. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Blood products or immunoglobulin within the past 6 months. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior HIV vaccines. 2. Live attenuated vaccines within the past 60 days. NOTE: Medically indicated subunit or killed vaccines (e.g., influenza, pneumococcal) do not exclude but should be administered at least 2 weeks prior to HIV immunizations. 3. Experimental agents within the past 30 days. PATIENT EXCLUSION CRIT. COMPLICATIONS: Subjects with the following conditions are excluded: 1. Positive for hepatitis B surface antigen. 2. Medical or psychiatric condition or occupational responsibilities that preclude compliance. 3. Active syphilis (NOTE: If serology is documented to be a false positive or due to a remote (> 6 months) infection, subject is eligible). 4. Active tuberculosis (NOTE: Subjects with a positive PPD and normal x-ray showing no evidence of TB and who do not require INH therapy are eligible). 5. Eczema. 6. Household contact with persons meeting any of the following criteria: pregnancy, < 12 months of age, eczema, or immunodeficiency disease or use of immunosuppressive medications. PATIENT EXCLUSION CRIT. AVAILABILITY: Unavailable for 18 months of follow-up. SUBSTANCE IDENTIFICATION Drug 1 DRG-0162 gp160 Vaccine (Immuno-AG) SUBSTANCE IDENTIFICATION Drug 2 DRG-0059 HIVAC-1e SUBSTANCE IDENTIFICATION Drug 3 DRG-0089 Smallpox vaccine TRADE NAME OF SUBSTANCE Drug 3‰ DryVax MANUFACTURERS Drug 1: Immuno-US Incorporated / Media Information Office c/o Cooney/Waters Group / 99 Park Avenue / Suite 25 New York, NY 10016 Contact: Sherri Michelstein (212) 557-7111. MANUFACTURERS Drug 2: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Jennifer Jackson (203) 284-6172. MANUFACTURERS Drug 3: Wyeth-Ayerst Research PO Box 8299 Philadelphia, PA 19101 Contact: Dr Gary Horwith (610) 341-5770. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mcg (or placebo) on days 224 and 364. Drug 2: Administered on days 0 and 56. Drug 3: Administered on days 0 and 56 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intramuscular injection. Drug 2: Scarification using bifurcated needle. Drug 3: Scarification using bifurcated needle OTHER TREATMENT INFO. END POINT: Vaccine safety, immunogenicity. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (VEU). MESH HEADING Adult MESH HEADING Female MESH HEADING Gene Products, env/*IMMUNOLOGY MESH HEADING HIV Infections/*PREVENTION & CONTROL MESH HEADING HIV-1/*IMMUNOLOGY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Protein Precursors/*IMMUNOLOGY MESH HEADING Smallpox Vaccine MESH HEADING Vaccines, Synthetic MESH HEADING Vaccinia Virus/*IMMUNOLOGY MESH HEADING Viral Vaccines CAS REGISTRY NUMBER 0 (HIV envelope protein gp160) CAS REGISTRY NUMBER 0 (Vaccines, Synthetic) CAS REGISTRY NUMBER 0 (Smallpox Vaccine) CAS REGISTRY NUMBER 0 (Viral Vaccines) LAST REVISION DATE 940615 ENTRY MONTH 9304 MISSOURI St Louis University School of Medicine / Sec Inf Dis 1402 South Grand Boulevard St Louis, MO 63104 Contact: Dr Robert B Belshe (314) 577-8648 Contact: Heidi Israel (314) 577-8649 OPEN 930420 ACTU: 6007. 7 UNIQUE IDENTIFIER NIH/00519 PROTOCOL ID NUMBERS NIAID DATRI 008 PROTOCOL TITLE A Pilot Study of Methodology to Rapidly Evaluate Drugs for Bactericidal Activity, Tolerance, and Pharmacokinetics in the Treatment of Pulmonary Tuberculosis Using Isoniazid and Levofloxacin. VERSION NUMBER & DATE 3 (940819) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the methodology for rapidly determining the early bactericidal activity (EBA), tolerance, and pharmacokinetics of isoniazid and levofloxacin in the treatment of pulmonary tuberculosis (TB). GENERAL DESCRIPTION RATIONALE: Traditionally, in trials for treatment of TB, a new drug is administered in combination with two or more other antituberculous agents of known effectiveness over a long period of time. In this setting, it is difficult to determine the effect of any single drug or dose level. Development of new agents for the treatment of TB may be accelerated by a methodology in which a new agent could be evaluated for activity by administering it as a single agent over a short time period. This study utilizes a method to measure the amount of bacteria present each day in the lungs. GENERAL DESCRIPTION METHODOLOGY: An initial cohort of patients receive isoniazid (with pyridoxine) daily for 5 days. Sputum samples are collected daily for determination of the EBA (decline in colony-forming units/ml sputum). If the methodology is validated, additional patients are randomized to receive one of two doses of levofloxacin daily for 5 days, with determination of EBA. All patients are hospitalized for 2 days of baseline evaluation and 5 days of treatment. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Tuberculosis. DISEASES STATUS Patients have the following symptoms and conditions: 1. Presumptive active pulmonary TB as evidenced by a sputum smear positive for acid-fast bacilli (AFB) AND a chest radiograph and other clinical signs and symptoms compatible with active pulmonary TB. 2. Either HIV positive or HIV negative. 3. No clinical evidence of central nervous system or miliary tuberculosis. ELIGIBILITY AIDS. HIV Seronegative / OTHER. OTHER PROTOCOL NUMBERS IND 42,061 STUDY DESIGN Pilot Study; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug tolerance, Pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 44 patients. (At least 24 patients in the isoniazid pilot; at least 20 patients in the levofloxacin portion of the study). PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 7 days. PROTOCOL DETAILS ACTUAL ACCRUAL: 17/44 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 9 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Presumptive active pulmonary TB. 2. No clinical evidence of central nervous system or miliary tuberculosis. NOTE: Both HIV-positive and HIV-negative patients are eligible. NOTE: Pregnant women may be enrolled in the isoniazid cohort only. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. (men); >= 8.0 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 60 ml/min. (levofloxacin cohort); >= 40 ml/min (isoniazid cohort). PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 5 x ULN. Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. WEIGHT: 40 kg. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed in all patients: Antacids if administered more than 2 hours before or after study drug. Allowed in isoniazid patients: Anticonvulsant therapy if blood levels are monitored. Allowed in levofloxacin patients: 1. Acceptable medications other than antacids if administered at least 2 hours before or 1 hour after study drug. 2. Anticonvulsant therapy, theophylline, or warfarin if doses are monitored. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of treatment-limiting intolerance or known hypersensitivity to isoniazid (in patients receiving isoniazid) or to quinolones (in patients receiving levofloxacin). 2. Vomiting or diarrhea >= grade 2 at screening or within 2 days prior to screening. 3. History of drug-resistant TB (in patients receiving isoniazid). [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. WEIGHT: < 40 kg. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Known risk factors for multi-drug resistant (MDR) TB, including: o Domicile, shelter, or prison exposure to a known case of MDR TB within the past 6 months. o Residence in a specific domicile, shelter, or prison cell block within 6 months of a known outbreak of MDR TB. o Hospitalization, within the past 6 months, on a medical service PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Any prior treatment or prophylaxis for TB if enrolling on the isoniazid cohort. 2. Any anti-TB drug within the past 12 weeks, including standard drugs against TB as well as clofazimine, rifabutin, and all quinolones and aminoglycosides. 3. Corticosteroids, pentoxifylline, colony-stimulating factors, interferons, or interleukins within the past 12 weeks. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. All standard TB therapies. 2. Clofazimine. 3. Rifabutin. 4. Quinolones. 5. Aminoglycosides. 6. Corticosteroids. 7. Pentoxifylline. 8. Colony-stimulating factors. 9. Interferons. 10. Interleukins. 11. Disulfiram (patients receiving isoniazid). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active or suspected MAI infection. 2. Active or suspected hepatitis. 3. Any other serious acute infection, diabetes, chronic obstructive pulmonary disease, malignancy requiring chemotherapy, or major organ dysfunction. 4. Extreme illness or toxic appearance. 5. Pregnancy (if entering the levofloxacin portion of the study). SUBSTANCE IDENTIFICATION Drug 1 DRG-0123 Isoniazid SUBSTANCE IDENTIFICATION Drug 2 DRG-0125 Pyridoxine SUBSTANCE IDENTIFICATION Drug 3 DRG-0129 Levofloxacin MANUFACTURERS Drug 1: Barr Laboratories Incorporated 2 Quaker Road PO Box D-2900 Pomona, NY 10970 Contact: Unspecified (914) 362-1100. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Ortho Pharmaceutical Corporation Route 202 / PO Box 300 Raritan, NJ 08869-0602 Contact: Dr Vincent Ahonkha (908) 704-4991. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 300 mg daily for 5 days. Drug 2: 50 mg daily for 5 days (with isoniazid). Drug 3: 500 or 750 mg daily for 5 days SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 300 mg. Drug 2: 50 mg. Drug 3: 500 or 750 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 300 mg tablets. Drug 2: Oral, 50 mg tablets. Drug 3: Oral, 125 and 500 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 5 days. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Significant toxicity. 2. Significant clinical deterioration or disease progression. 3. Further participation deemed detrimental to patient's health or well-being. 4. Production of sputum inadequate to complete laboratory evaluations. 5. Inability to continue study drug. 6. Indication for systemic cytotoxic therapy for a newly diagnosed malignancy. 7. Major protocol violation. 8. At the request of the patient. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (DATRI). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Colony Count, Microbial MESH HEADING Drug Evaluation MESH HEADING Female MESH HEADING Human MESH HEADING Isoniazid/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Ofloxacin/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/PHARMACOKINETICS/*THERAPEUTIC USE MESH HEADING Opportunistic Infections/COMPLICATIONS/*DRUG THERAPY/MICROBIOLOGY MESH HEADING Pyridoxine/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE MESH HEADING Sputum/*MICROBIOLOGY MESH HEADING Tuberculosis, Pulmonary/COMPLICATIONS/*DRUG THERAPY/MICROBIOLOGY CAS REGISTRY NUMBER 54-85-3 (Isoniazid) CAS REGISTRY NUMBER 65-23-6 (Pyridoxine) CAS REGISTRY NUMBER 82419-36-1 (Ofloxacin) LAST REVISION DATE 941207 ENTRY MONTH 9308 ALABAMA University of Alabama at Birmingham 619 South 19th Street Birmingham, AL 35233-6505 Contact: Penny Phillips (205) 975-5748 Contact: FAX (205) 934-1721 OPEN 931222. CALIFORNIA UCLA School of Medicine 10833 LeConte Ave Los Angeles, CA 90024-1793 Contact: Dr David Hardy (310) 206-5427 OPEN 940218. CALIFORNIA Harbor UCLA Medical Center 1124 West Carson / N-24 Torrance, CA 90502 Contact: Sally Kruger (310) 222-3848 OPEN 931006. FLORIDA University of Miami / Jackson Memorial Hospital 1611 NW 12th Avenue Miami, FL 33101 Contact: Portia James (305) 585-7223 OPEN 940615. FLORIDA Broward General Medical Center 1600 South Andrews Avenue Ft. Lauderdale, FL 33316 Contact: Tim Palmer-Pattison (305) 467-3006 Contact: (305) 355-5560 OPEN 930818. ILLINOIS University of Illinois 833 S Wood Street M/C 886 Chicago, IL 60622 Contact: Dr Jenny Colombo (312) 996-2133 OPEN 940629. LOUISIANA Tulane U School of Medicine \ General Clinical Research Ctr 1430 Tulane Avenue New Orleans, LA 70112-2699 Contact: Dana Wineski (504) 585-4020 OPEN 930818. 8 UNIQUE IDENTIFIER NIH/00501 PROTOCOL ID NUMBERS NIAID DATRI 007 PROTOCOL TITLE The Effect of Therapy on the Tissue Burden of Disseminated MAC Infection as Measured by Quantitative Bone Marrow Culture and Correlation With Quantitative Blood Culture in HIV-Infected Patients. VERSION NUMBER & DATE 4 (940119) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To assess the feasibility of using culture and staining techniques to quantify tissue Mycobacterium avium Complex (MAC) burden in bone marrow. To correlate and compare changes in MAC bone marrow burden with quantitative MAC blood culture results at baseline and after 4 and 8 weeks of treatment. GENERAL DESCRIPTION RATIONALE: MAC is easiest to detect in the blood, although doctors generally believe that MAC in blood is just spill-over from infection of other parts of the body. Traditionally, studies of potential treatments for MAC focus only on MAC changes in the blood. This study compares MAC changes in blood to those in bone marrow, which is another tissue where MAC is often found. GENERAL DESCRIPTION METHODOLOGY: Patients receive both clarithromycin and ethambutol for 48 weeks; those who become intolerant to the study drugs may receive suggested substitute drugs (azithromycin and rifabutin). Patients receive a bone marrow biopsy at baseline and at either 4 or 8 weeks. Patients are evaluated at weeks 1, 2, 4, 6, 8, 12, 24, 36, and 48. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by a clinical history compatible with HIV disease or by ELISA confirmed by Western blot, positive HIV culture, positive HIV antigen, plasma viremia, or a second antibody test positive by a method other than ELISA. 2. Confirmed MAC bacteremia. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 41,772 STUDY DESIGN Open Label; Randomized; Pilot Study; Drug Combination PROTOCOL DETAILS STUDY INTENT: Combination pharmacokinetics, Combination drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 24 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 48 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 14/24 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 8 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Confirmed MAC bacteremia. 3. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 3.0 mg/dl. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Any antiretroviral therapy that is approved or is available through an FDA-sanctioned treatment IND or treatment protocol. 2. Primary or secondary PCP prophylaxis with TMP/SMX, dapsone, or aerosolized pentamidine, as well as approved therapies for other AIDS-related opportunistic infections not otherwise excluded. 3. Erythromycin, interferon-alpha, and supportive care for any therapy-related toxicities as necessary. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of treatment-limiting intolerance or hypersensitivity to the study drugs or other macrolides. 2. Changes on chest radiograph within 7 days prior to study entry, that are consistent with acute Pneumocystis carinii pneumonia, pulmonary tuberculosis, or other acute respiratory infection. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Clarithromycin, azithromycin, or ethambutol for more than 10 consecutive days within the 8 weeks prior to study entry OR between the time an initial AFB positive blood sample was collected and study entry. 2. Cytokines (other than erythropoietin and interferon-alpha) within 8 weeks prior to study entry. 3. Steroids within 8 weeks prior to study entry. 4. Cytotoxic chemotherapy within 8 weeks prior to study entry. 5. Acute therapy for an AIDS-related opportunistic infection or malignancy, or other acute medical illness or infection within 4 weeks prior to study entry. 6. Rifabutin monotherapy if initiated for MAC prophylaxis between the time an initial AFB positive blood sample was collected and study entry. 7. Aminoglycosides, quinolones, clofazimine, or rifamycins IF ADMINISTERED IN ANY COMBINATION within 7 days prior to study entry OR between the time an initial AFB positive blood sample was collected and study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. MAC inhibitors, including aminoglycosides, quinolones, clofazimine, azithromycin (except when administered as a substitute drug), and rifamycins, during the first 24 weeks of the study. 2. Immunomodulators (including colony-stimulating cytokines such as GM-CSF and G-CSF) other than those that are specifically allowed. 3. Steroids in excess of physiologic replacement doses. 4. Cytotoxic chemotherapy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0099 Clarithromycin SUBSTANCE IDENTIFICATION Drug 2 DRG-0111 Ethambutol TRADE NAME OF SUBSTANCE Drug 1‰ Biaxin TRADE NAME OF SUBSTANCE Drug 2‰ Myambutol MANUFACTURERS Drug 1: Abbott Laboratories One Abbott Park Road Abbott Park, IL 60064 Contact: Dr J Carl Craft (708) 937-8147. MANUFACTURERS Drug 2: Lederle Laboratories North Middletown Road Pearl River, NY 10965 Contact: Dr Amy Baim (914) 732-2147 Contact: Dr John Riefler (914) 732-2035. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 500 mg BID for 48 weeks. Drug 2: 15 mg/kg (to a maximum of 1200 mg) daily for 48 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 1000 mg. Drug 2: 15 mg/kg (to a maximum of 1200 mg) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 500 mg tablets. Drug 2: Oral, 100 and 400 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 48 weeks. OTHER TREATMENT INFO. END POINT: Quantitative changes in blood and bone marrow MAC load after 4 and 8 weeks. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Development of an AIDS-related opportunistic infection or malignancy, or other medical condition requiring the use of non-permitted or contraindicated medications. 2. Drug-related, dose-limiting toxicity. 3. Physician-documented clinical failure after 8 weeks of study therapy. 4. Physician-documented significant clinical deterioration at any time. 5. Failure to achieve at least a one log decrease in total colony-forming units (CFU) of MAC from a blood sample at week 8 of study. 6. Desire of patient to withdraw from study. OTHER TREATMENT INFO. MODIFICATION: For reduced color differentiation or significant loss of visual acuity: Discontinue ethambutol permanently unless another cause has been identified. For severe or life threatening nausea, vomiting, diarrhea, or other adverse reactions or for bilirubin > 2.5 x ULN or LFTs > 5 x ULN: Hold study drugs for up to 3 days until symptoms resolve, then restart study therapies (at initial doses) in a step-wise manner, allowing 48-72 hours between the start of each drug. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (DATRI). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Clarithromycin/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Ethambutol/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 74-55-5 (Ethambutol) CAS REGISTRY NUMBER 81103-11-9 (Clarithromycin) LAST REVISION DATE 941207 ENTRY MONTH 9307 ARIZONA University of Arizona / Section of Infectious Diseases 1501 North Campbell Avenue Tucson, AZ 85724 Contact: Joel Gray (602) 626-2533 OPEN 930804. MARYLAND University of Maryland 22 South Greene Street P O Box 243 Baltimore, MD 21201 Contact: Troylynn Maupin (410) 328-3588 OPEN 931222. NEW JERSEY University of Med and Dentistry of New Jersey / Cooper 401 Haddon Avenue / Dept of Medicine Room 277 Camden, NJ 08103 Contact: Barbara McCall (609) 963-3833 OPEN 930630. NEW YORK SUNY at Stony Brook Health Sciences Center / Div Infect Dis HSC T 15 Room 080 Stony Brook, NY 11794-8153 Contact: Ruth Ann Burk (516) 444-1658 OPEN 930901. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 931006 ACTU: 7401. OREGON The Research and Education Group 2701 NW Vaughn / Suite 770 Portland, OR 97210 Contact: Sue Peterson (503) 795-6639 Contact: FAX (503) 274-4892 OPEN 930630. 9 UNIQUE IDENTIFIER NIH/00453 PROTOCOL ID NUMBERS NIAID DATRI 002 PROTOCOL TITLE Pilot Study to Evaluate the Efficacy of Zidovudine in Preventing CD4+ Lymphocyte Decline in Patients With Primary HIV Infection. (One treatment arm receives placebo.) VERSION NUMBER & DATE 4 (940803) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the safety and efficacy of early treatment with zidovudine for preventing a decline in CD4+ lymphocyte counts in patients with primary HIV infection. To determine the natural history of virologic and immunologic changes in primary HIV infection. GENERAL DESCRIPTION RATIONALE: Previous studies indicate that intervention with zidovudine during primary HIV infection could reduce the initial viral burden and subsequent decline in immune functions, and could prolong not only the time to development of AIDS but also the time to initiation of chronic antiretroviral therapy. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either zidovudine (1000 mg) or placebo daily for 24 weeks. Patients are followed until development of an AIDS-related opportunistic infection or malignancy. After week 24, patients meeting standard prescribing criteria may start FDA-approved anti-HIV therapies. After study week 48, patients may co-enroll on another clinical trial to receive experimental therapy. PROTOCOL PHASE Phase I / Pilot Study OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: Asymptomatic or symptomatic primary HIV infection, plus one of the following two criteria- 1) p24 antigenemia documented within 1 month prior to study entry and either HIV enzyme immunoassay (IA) negative or HIV IA positive with Western blot negative/indeterminate, within 1 month prior to study entry. 2) Documented seroconversion within 1 month prior to study entry and Western blot negative/indeterminate. ELIGIBILITY ASYM. ARC. OTHER PROTOCOL NUMBERS IND 28,972 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Pilot Study; 2-Arm PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 80 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Patients receive treatment on study for 24 weeks. Following treatment, patients continue to be followed until development of an AIDS-related opportunistic infection or malignancy. PROTOCOL DETAILS ACTUAL ACCRUAL: 17/80 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 9 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Asymptomatic or symptomatic primary HIV infection, plus one of the following two criteria- a) p24 antigenemia documented within 1 month prior to study entry and either HIV enzyme immunoassay (IA) negative or HIV IA positive with Western blot negative/indeterminate, within 1 month prior to study entry. b) Documented seroconversion within 1 month prior to study entry and Western blot negative/indeterminate. 2. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. (men); >= 8.0 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 2.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 10 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 2.0 mg/dl. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception during the study and for 90 days after. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Medications for nausea, vomiting, analgesia, or anxiety. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Chronic steroid use. 2. Immunomodulators. 3. Myelosuppressive agents. 4. Other antiretroviral agents or experimental therapies (NOTE: FDA-approved therapies permitted in patients who qualify after week 24; experimental therapies permitted after study week 48). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following condition are excluded: poor venous access. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg (or placebo) 5x daily for 24 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 1000 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg capsules OTHER TREATMENT INFO. TREATMENT DURATION: 24 weeks. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Acute medical conditions that necessitate use of excluded medications. 2. Unacceptable toxicity. OTHER TREATMENT INFO. MODIFICATION: Dose reductions, with or without dose interruption, are permitted. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (DATRI), Burroughs Wellcome. MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY/IMMUNOLOGY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zidovudine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 941207 ENTRY MONTH 9301 CALIFORNIA Cedars-Sinai Medical Center 8700 Beverly Boulevard / Becker 226 Los Angeles, CA 90048 Contact: Cyndi Frank (310) 855-3755 Contact: Eric Daar (310) 855-3896 OPEN 930203. CALIFORNIA Veterans Administration Medical Center Palo Alto 3801 Miranda Ave / Suite 119 Palo Alto, CA 94304 Contact: Larry Mole (415) 493-5000 X 469OPEN 921230. FLORIDA Broward General Medical Center 1600 South Andrews Avenue Ft. Lauderdale, FL 33316 Contact: Tim Palmer-Pattison (305) 467-3006 Contact: (305) 355-5560 OPEN 930428. ILLINOIS University of Illinois / Section of Infectious Diseases 840 South Wood Street / Room 908 Chicago, IL 60612 Contact: Dr Luis Moriera (312) 996-7870 Contact: Beeper (312) 996-7000 X 730OPEN 930901. MARYLAND Johns Hopkins University School of Medicine 600 North Wolfe Street / Marburg B-186 Baltimore, MD 21287-2080 Contact: Judy Shahan (410) 955-8708 OPEN 930721. NEW YORK Bellevue Hospital / NYU 462 East 27th Street New York, NY 10016 Contact: Richard Hutt (212) 561-3906 OPEN 930818. RHODE ISLAND Miriam Hospital / Brown University 164 Summit Avenue Providence, RI 02906 Contact: Dr Josiah Rich (401) 331-8500 X 715OPEN 930127. 10 UNIQUE IDENTIFIER NIH/00470 PROTOCOL ID NUMBERS NIAID CPCRA 022 PROTOCOL TITLE The Efficacy of a Standardized Acupuncture Regimen and Amitriptyline Compared With Placebo as a Treatment for Pain Caused by Peripheral Neuropathy in HIV-Infected Patients. VERSION NUMBER & DATE 4 (941027) TRIAL CATEGORY Neurologic Manifestations PROTOCOL CHAIRS CHAIR Shlay J PROTOCOL CHAIRS CO-CHAIR Flaws B GENERAL DESCRIPTION PURPOSE: To evaluate the separate and combined efficacy of a standardized acupuncture regimen and amitriptyline on the relief of pain due to peripheral neuropathy and on the quality of life of HIV-infected patients. GENERAL DESCRIPTION RATIONALE: Both amitriptyline, an antidepressant, and acupuncture, a Chinese medical approach that uses needles to relieve pain, have been used successfully to reduce pain in some people. It is not known how effectively these approaches relieve or reduce pain in patients with peripheral neuropathy secondary to HIV infection. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either standardized point acupuncture or alternate point acupuncture treatment twice weekly for the first 6 weeks, then once weekly for the next 8 weeks, plus either oral amitriptyline or placebo daily for the entire 14 weeks. Acupuncture points are located on the lower leg. Patients are evaluated at weeks 6 and 14 and are asked to keep a daily pain diary. OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Peripheral neuropathy. DISEASES STATUS Patients have the following symptoms and conditions: 1. Working diagnosis of HIV infection, based on medical history, clinical signs and symptoms, or results of laboratory tests. 2. Lower extremity peripheral neuropathy secondary to HIV infection. 3. Pain for at least 2 weeks prior to study entry. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS IND 41,279 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Multicenter; 4-Arm PROTOCOL DETAILS STUDY INTENT: Combination modality therapy, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 260 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 16 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 80/260 (941207). PROTOCOL DETAILS STUDY DURATION: 3.5 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 5 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Lower extremity peripheral neuropathy secondary to HIV infection. 3. Pain for at least 2 weeks prior to study entry. 4. Life expectancy of at least 6 months. NOTE: Co-enrollment in other experimental protocols is permitted as long as dual participation is allowed in those protocols. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Required: Acupuncture. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Antiretroviral therapy. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antiretroviral therapy. 2. Nonsystemic treatment of Kaposi's sarcoma. 3. Maintenance with an existing regimen of analgesic medication or herbal treatment. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded (not applicable for patients at sites using an acupuncture only study design): 1. History of cardiac disease. 2. History of seizure disorder. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 2 weeks prior to study entry: 1. MAO inhibitors. 2. Tricyclic antidepressants. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Active treatment for an acute opportunistic infection or malignancy (nonsystemic treatment of Kaposi's sarcoma is permitted). 2. Other tricyclic antidepressants. 3. MAO inhibitors. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known allergy to amitriptyline (not applicable for patients at sites using an acupuncture only study design). 2. EKG indicating malignant arrhythmia or cardiac conduction disturbances (not applicable for patients at sites using an acupuncture only study design). 3. Prison incarceration. SUBSTANCE IDENTIFICATION Drug 1 DRG-0169 Amitriptyline hydrochloride MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 25 mg (or placebo) daily as initial dose, with escalatiq 2-3 days until 75 mg daily is reached, continuing for 14 weekthen tapering to discontinuation SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 25 mg initial dose, with escalation q 2-3 days up to 75mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 25 mg capsules OTHER TREATMENT INFO. TREATMENT DURATION: 14 weeks. OTHER TREATMENT INFO. END POINT: Primary: Change in pain intensity after 6 and 14 weeks of treatment. Secondary: Change in quality of life and neurological status during treatment, change in pain intensity during a 4-week follow-up period, treatment failure. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Acute illness (e.g., opportunistic infection requiring treatment). 2. Extreme pain that necessitates discontinuation. OTHER TREATMENT INFO. MODIFICATION: Patients unable to tolerate 75 mg/day amitriptyline may have dose reduced to 50 or 25 mg/day or, if necessary, to 25 mg every 2-3 days. For adverse effects caused by acupuncture: Hold acupuncture until the primary physician permits resumption. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (CPCRA). MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Acupuncture Therapy MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Amitriptyline/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Pain/*THERAPY MESH HEADING Peripheral Nervous System Diseases/ *COMPLICATIONS CAS REGISTRY NUMBER 50-48-6 (Amitriptyline) LAST REVISION DATE 941207 ENTRY MONTH 9304 CALIFORNIA Community Consortium of San Francisco 3180 18th Street Suite 201 San Francisco, CA 94110 Contact: Thomas Mitchell (415) 476-9554 OPEN 930427. COLORADO Denver / CPCRA 605 Bannock Street Denver, CO 80204-4507 Contact: Jack Rouff (303) 436-7184 Contact: (303) 436-7224 OPEN 930427. NEW YORK Harlem AIDS Treatment Group Harlem Hospital / Women's Pavilion Room 126 New York, NY 10037 Contact: Joshua Standig (212) 939-2951 OPEN 930420. NEW YORK Clinical Directors Network of Region II 5601 2nd Avenue #3 Brooklyn, NY 11220 Contact: Linda Podhurst (212) 255-3841 OPEN 930511. OREGON The Research and Education Group 2701 NW Vaughn / Suite 770 Portland, OR 97210 Contact: Joyce St Arnaud (503) 229-8428 OPEN 930427. 11 UNIQUE IDENTIFIER NIH/00441 PROTOCOL ID NUMBERS NIAID CPCRA 006 PROTOCOL TITLE A Randomized, Comparative, Prospective Study of Daily Trimethoprim / Sulfamethoxazole (TMS) and Thrice Weekly TMS for Prophylaxis Against PCP in HIV-Infected Patients. VERSION NUMBER & DATE 3 (940701) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR El-Sadr W PROTOCOL CHAIRS CO-CHAIR Luskin-Hawk R GENERAL DESCRIPTION PURPOSE: To compare the safety and efficacy of two dosage regimens (daily and thrice weekly) of trimethoprim / sulfamethoxazole (TMP/SMX; TMS) in the prevention of Pneumocystis carinii pneumonia (PCP) in high-risk HIV-infected patients. GENERAL DESCRIPTION RATIONALE: Previous tests have shown that TMP / SMX given daily is effective in preventing recurrence of PCP and may be effective in preventing PCP in patients who have never developed it. Because TMP / SMX can cause side effects, this study will attempt to determine the safest and most effective dose of this combination. GENERAL DESCRIPTION METHODOLOGY: Patients receive TMP / SMX orally on a daily or thrice weekly basis. Patients are clinically evaluated every 4 months. Patients on daily TMP / SMX who develop a drug-related toxicity may be switched to thrice-weekly TMP / SMX. Duration of follow-up is 12 months. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Pneumocystis carinii pneumonia ( PCP ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Working diagnosis of HIV infection based on patient's medical history, behavioral history, clinical signs and symptoms, and results of laboratory tests. 2. CD4 count <= 200 cells/mm3 or <= 15 percent of total lymphocyte count OR a history of prior PCP. 3. No active pneumocystosis. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Multicenter; Prospective; Randomized; Comparative; 2-Arm; Open Label PROTOCOL DETAILS STUDY INTENT: Drug prophylaxis, Drug safety, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 2500 patients. (1250 on each of two treatment arms) PROTOCOL DETAILS ACTUAL ACCRUAL: 1897/2500 (941207). PROTOCOL DETAILS STUDY DURATION: Approximately 37 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 19 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CD4 count <= 200 cells/mm3 OR a history of prior PCP. 3. No active pneumocystosis. Patients or their guardians must sign informed consent. Pregnant patients are eligible at the clinician's discretion. Patients who do not meet required laboratory values may be eligible at the discretion of the clinician. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. Patients with no prior episodes of Pneumocystis carinii pneumonia must have a CD4 count <= 200 cells/mm3 ( 0 - 100 - 200 ) or <= 15 percent of total lymphocyte count. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Other PCP prophylaxis or medication with anti-PCP activity. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: Known treatment-limiting reaction to sulfonamides or trimethoprim. SUBSTANCE IDENTIFICATION Drug 1 DRG-0031 Sulfamethoxazole SUBSTANCE IDENTIFICATION Drug 2 DRG-0030 Trimethoprim MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Arm I: 1 DS tablet daily. Arm II: 1 DS tablet 3 times weekly (MWF). Drug 2: Arm I: 1 (double strength) DS tablet daily. Arm II: 1 Dtablet 3 times weekly (MWF) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Oral OTHER TREATMENT INFO. END POINT: Primary: Occurrence/recurrence of morphologically or histologically confirmed or probable PCP. Secondary: Development of confirmed or probable toxoplasmosis, development of confirmed or probable extrapulmonary pneumocystosis, drug intolerance/toxicity, and death. OTHER TREATMENT INFO. DISCONTINUE: Treatment is temporarily discontinued for the following reasons: 1. Toxicity. 2. Pregnancy. 3. Acute opportunistic or bacterial infection. 4. Opportunistic malignancy. Treatment is permanently discontinued for the following reasons: 1. Severe toxicity that precludes further treatment. 2. Development of illness requiring > 4 weeks of medication with potential anti-PCP activity or that may interact with study drug. 3. Continuation of therapy not considered in the best interest of patient. 4. Refusal of patient to continue study therapy. OTHER TREATMENT INFO. MODIFICATION: Patients on daily TMP / SMX may be temporarily or permanently reduced to thrice weekly TMP / SMX if toxicity occurs. If toxicity necessitates interruption of study therapy for more than 4 weeks, the clinician will determine whether study drug may be resumed or permanently discontinued. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (CPCRA), Burroughs Wellcome. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Pneumonia, Pneumocystis carinii/COMPLICATIONS/ *PREVENTION & CONTROL MESH HEADING Trimethoprim-Sulfamethoxazole Combination/ ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/ *THERAPEUTIC USE CAS REGISTRY NUMBER 8064-90-2 (Trimethoprim-Sulfamethoxazole Combination) LAST REVISION DATE 941207 ENTRY MONTH 9210 CALIFORNIA Community Consortium of San Francisco 3180 18th Street Suite 201 San Francisco, CA 94110 Contact: Thomas Mitchell (415) 476-9554 OPEN 920924. COLORADO Denver / CPCRA 605 Bannock Street Denver, CO 80204-4507 Contact: Jack Rouff (303) 436-7184 Contact: (303) 436-7224 OPEN 920731. DISTRICT OF COLUMBIA Washington Regional AIDS Program 50 Irving St N W / Room ID-151B Washington, DC 20422 Contact: John Scott (202) 745-8695 OPEN 921001. DELEWARE Delaware / CPCRA 501 West 14th Street Wilmington, DE 19899 Contact: Arlene Bincsik (302) 428-2538 OPEN 930112. GEORGIA Atlanta AIDS Research Consortium Incorporated 131 Ponce deLeon Suite 220 Atlanta, GA 30308 Contact: Amy Morris (404) 876-2317 OPEN 930127. ILLINOIS Chicago CPCRA 711 West North Avenue Suite 201 Chicago, IL 60610 Contact: Jeffrey Zurlinden (312) 266-0227 OPEN 930203. LOUISIANA Louisiana Community AIDS Research Program 1430 Tulane Avenue New Orleans, LA 70112 Contact: Ermelle Martinez Laurent (504) 584-1971 OPEN 921021. MICHIGAN Comprehensive AIDS Alliance of Detroit 4160 John R / Harper Hospital Prof Bldg / Suite 202 Detroit, MI 48201 Contact: Constance Rowley (313) 993-0934 OPEN 920723. MICHIGAN Henry Ford Hospital 2799 West Grand Boulevard Detroit, MI 48202 Contact: Diane Mastro-Polak (313) 876-7664 OPEN 920910. NEW JERSEY North Jersey Community Research Initiative 657 King Boulevard Newark, NJ 07102 Contact: Victoria Taylor (201) 648-0350 OPEN 921029. NEW YORK Harlem AIDS Treatment Group Harlem Hospital / Women's Pavilion Room 126 New York, NY 10037 Contact: Joshua Standig (212) 939-2951 OPEN 920709. NEW YORK Bronx-Lebanon Hospital Center 1309 Fulton Avenue Bronx, NY 10456 Contact: Cathy Pollard (718) 293-2593 Contact: (718) 901-8916 OPEN 920918. NEW YORK Addiction Research And Treatment Corporation 22 Chapel Street Brooklyn, NY 11201 Contact: Dr Robert Sawyer (718) 260-2917 OPEN 920924. NEW YORK Addiction Research and Treatment Corporation 22 Chapel Street Brooklyn, NY 11201 Contact: Robert C Sawyer (718) 260-2917 OPEN 920924. NEW YORK Clinical Directors Network of Region II 5601 2nd Avenue #3 Brooklyn, NY 11220 Contact: Linda Podhurst (212) 255-3841 OPEN 921009. OREGON The Research and Education Group 2701 NW Vaughn / Suite 770 Portland, OR 97210 Contact: Joyce St Arnaud (503) 229-8428 OPEN 940908. OREGON The Research and Education Group 2701 Northwest Vaughn / Suite 770 Portland, OR 97210-9951 Contact: Robert Forrest, Admin Director (503) 229-8428 Contact: Fax (503) 227-0902 OPEN 941123. 12 UNIQUE IDENTIFIER NIH/00235 PROTOCOL ID NUMBERS NIAID CPCRA 004 PROTOCOL TITLE Prophylaxis Against Tuberculosis (TB) in Patients With Human Immunodeficiency Virus (HIV) Infection and Confirmed Latent Tuberculous Infection. VERSION NUMBER & DATE 4 (940630) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Gordin F PROTOCOL CHAIRS CO-CHAIR Brown LS GENERAL DESCRIPTION PURPOSE: To evaluate and compare the effectiveness of a 2-month regimen of rifampin and pyrazinamide versus a 1-year course of isoniazid (INH) to prevent the development of tuberculosis in patients who are coinfected with HIV and latent Mycobacterium tuberculosis (MTb). GENERAL DESCRIPTION RATIONALE: Current guidelines recommend 6 to 12 months of treatment with INH for purified protein derivative (PPD)-positive individuals. Problems with this treatment include compliance, adverse reaction, and the possibility of not preventing disease due to INH-resistant organisms. Studies suggest that two or three months of rifampin and pyrazinamide may be more effective than longer courses of INH. A two month prevention course should help to increase compliance. In addition, the use of two drugs (rifampin and pyrazinamide) may help overcome problems with drug resistance. GENERAL DESCRIPTION METHODOLOGY: After baseline screening, patients are randomized to one of two treatment arms and are evaluated by means of clinic visits monthly for the first three months, then every three months for the first year (there are additional clinic visits for INH patients). Patients are then evaluated every six months. One group of patients takes INH, 300 mg/day, and vitamin B6, 50 mg/day, for 12 months. The other group of patients takes rifampin 450 or 600 mg/day (dose depends on patients' weight) plus pyrazinamide 20 mg/kg/day (maximum 3,000 mg/day) in 3-4 divided doses for 60 days. PROTOCOL PHASE Unspecified OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Tuberculosis. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection evidenced by documented positive serology for HIV, OR documented history of any opportunistic infection or malignancy indicative of AIDS by CDC definition, OR a working diagnosis of HIV infection based on the patient's medical history, behavioral history, clinical signs and symptoms, and results of other laboratory tests. 2. Positive PPD (purified protein derivative) skin test WITHOUT evidence of active clinical tuberculosis. (A positive PPD skin test is defined as >= 5 mm induration to 5 TU of PPD using the Mantoux method; the optimal time for reading the reaction is between 48 and 72 hours after application, although a positive reaction read beyond 72 hours is allowed.) OR Documented history of a positive PPD skin test without subsequent treatment or prophylaxis for more than one month with any antituberculous medication. ELIGIBILITY AIDS. ASYM. ARC. OTHER PROTOCOL NUMBERS TB/PPD+. IND 37,315 STUDY DESIGN Prospective; Multicenter; Randomized; Open Label; 2-Arm; Comparative PROTOCOL DETAILS STUDY INTENT: Comparative drug therapy, Combination drug therapy, Drug prophylaxis, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 2000 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 2 - 6 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 1089/2000 (941207). PROTOCOL DETAILS STUDY DURATION: Possibly 6 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 24 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Signed informed consent. 3. Reasonably good health at time of study entry. 4. Perceived life expectancy of at least six months. Allowed: Participation in other clinical trials as long as there is no potential activity of other study drugs against Mycobacterium tuberculosis (MTb), additive toxicities between study agents, or known possible drug interactions between study drugs. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 8 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. ULN = upper limit of normal. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophil count > 750 cells/mm3. Alkaline phosphatase <= 5 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Abstinence or effective method of birth control / contraception including oral contraceptives during the study. Not pregnant. Negative pregnancy test within 30 days of study entry. OTHER PATIENT INCL. CH. RISK BEHAVIOR: Willing and able, in the clinician's opinion, to comply with the treatment and clinical management issues. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Treatment with quinolones, fluoroquinolones, aminoglycosides, or other agents with known or potential activity against M. tuberculosis. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Antiretroviral treatment. Pneumocystis carinii pneumonia prophylaxis. Treatment for acute opportunistic infection/malignancy. Aminoglycosides, quinolones or fluoroquinolones such as ciprofloxacin or ofloxacin for < 14 days for treatment of intercurrent infection. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients may not have: 1. Current active tuberculosis. 2. Acute hepatitis. 3. Peripheral neuropathy of grade 3 or grade 4. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: No abstinence or no agreement to use effective method of birth control / contraception during the study. Pregnant. Positive pregnancy test within 30 days of study entry. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: History of treatment for > 2 months with agents that have known or potential antituberculous activity other than those specifically allowed. Agents with potential or known antituberculous activity include the following: 1. Aminoglycosides such as amikacin 2. Aminosalicylic acid salts 3. Capreomycin 4. Ciprofloxacin 5. Clofazimine 6. Cycloserine 7. Ethambutol 8. Ethionamide 9. Isoniazid 10. Kanamycin 11. Ofloxacin 12. Pyrazinamide 13. Quinolones or fluoroquinolones 14. Rifabutin 15. Rifampin 16. Streptomycin 17. Thiacetazone. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Quinolones, fluoroquinolones, or aminoglycosides with antituberulous activity (may be used for up to 14 days for treatment of intercurrent infection). Other agents with known or potential antituberculosis activity should be avoided, including the following: 1. Aminosalicylic acid salts 2. Capreomycin 3. Clofazimine 4. Cycloserine 5. Ethambutol 6. Ethionamide 7. Isoniazid 8. Kanamycin 9. Pyrazinamide 10. Rifabutin 11. Rifampin 12. Streptomycin 13. Thiacetazone. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following conditions or symptoms are excluded: 1. Current active tuberculosis (confirmed or suspected). 2. Sensitivity or intolerance to study medication. 3. Acute hepatitis. 4. Evidence of peripheral neuropathy, i.e., signs or symptoms of paresis, paresthesias, neuromotor abnormalities, or neurosensory deficits of grade 3 or worse. 5. Inability to have concomitant medications changed to avoid serious interaction with study drug. SUBSTANCE IDENTIFICATION Drug 1 DRG-0109 Rifampin SUBSTANCE IDENTIFICATION Drug 2 DRG-0124 Pyrazinamide SUBSTANCE IDENTIFICATION Drug 3 DRG-0123 Isoniazid SUBSTANCE IDENTIFICATION Drug 4 DRG-0125 Pyridoxine TRADE NAME OF SUBSTANCE Drug 1‰ Rifadin MANUFACTURERS Drug 1: Marion Merrell Dow Medical Information / PO Box 9627 Kansas City, MO 64134-0627 Contact: Medical Information (800) 633-1610. MANUFACTURERS Drug 2: Lederle Laboratories North Middletown Road Pearl River, NY 10965 Contact: Dr Amy Baim (914) 732-2147 Contact: Dr John Riefler (914) 732-2035. MANUFACTURERS Drug 3: Barr Laboratories Incorporated 2 Quaker Road PO Box D-2900 Pomona, NY 10970 Contact: Harold Cohen (914) 362-1100 X 2823. MANUFACTURERS Drug 4: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 450 mg (if 25-49 kg) or 600 mg (if 50 kg or greater) daily x 60 days. Drug 2: 20 mg/kg (maximum 3000 mg) daily in 3-4 divided doses fdays. Drug 3: 300 mg daily for 12 months. Drug 4: 50 mg daily for 12 months SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 450 or 600 mg. Drug 2: 20 mg/kg. Drug 3: 300 mg. Drug 4: 50 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 150 and 300 mg capsules. Drug 2: Oral, 500 mg tablets. Drug 3: Oral, 300 mg tablets. Drug 4: Oral, 50 mg tablets OTHER TREATMENT INFO. END POINT: Primary end point: Time to development of confirmed active pulmonary or extrapulmonary tuberculosis, supported by more inclusive analyses using probable tuberculosis with confirmed tuberculosis. Secondary end point: Combined end point of death and confirmed or probable active tuberculosis, toxicity from treatment, and laboratory findings. OTHER TREATMENT INFO. DISCONTINUE: Patients will be removed from the study for the following reasons: 1. Grade 4 toxicity at the discretion of the primary physician. 2. Development of any confirmed or probable active pulmonary or extrapulmonary tuberculosis. 3. Development of severe clinical hepatitis due to study drug. 4. Development of Mycobacterium avium infection requiring continuous, chronic, or recurrent treatment with agents active in the treatment of tuberculosis at the discretion of the investigator. 5. Persistent or recurring serious study drug toxicity despite temporary drug discontinuation. 6. Pregnancy (ONLY if on the rifampin/pyrazinamide arm). OTHER TREATMENT INFO. MODIFICATION: For grade 2 toxicities, study drugs may be temporarily withheld at the investigator's discretion. For grade 3 toxicity that is possibly related to study drug, withhold study drug. Depending on the nature and severity of the toxicity, the degree to which it resolved, and/or the emergence of alternative explanations for the toxicity or the patient's deterioration, the study drug may be restarted at the discretion of the primary physician. For any grade 4 toxicity, the study drug will be temporarily withheld and may be permanently stopped at the discretion of the primary physician. Study drug will be temporarily withheld for: 1. Development of mild to moderate toxicity. 2. Development of moderate clinical hepatitis due to study drug (rechallenge of study drug will occur at the discretion of the investigator). 3. Development of clinical hepatitis due to reasons other than study drug. 4. Treatment for acute opportunistic infection or malignancy requiring temporary cessation of study medication at the investigator's discretion. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (CPCRA). MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antitubercular Agents/ADMINISTRATION & DOSAGE/ *THERAPEUTIC USE MESH HEADING Drug Evaluation MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Isoniazid/ADMINISTRATION & DOSAGE/THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Multicenter Studies MESH HEADING Opportunistic Infections/COMPLICATIONS/ PREVENTION & CONTROL MESH HEADING Pyrazinamide/ADMINISTRATION & DOSAGE/ THERAPEUTIC USE MESH HEADING Pyridoxine/ADMINISTRATION & DOSAGE/ THERAPEUTIC USE MESH HEADING Rifampin/ADMINISTRATION & DOSAGE/*THERAPEUTIC USE MESH HEADING Tuberculosis/COMPLICATIONS/*PREVENTION & CONTROL CAS REGISTRY NUMBER 0 (Antitubercular Agents) CAS REGISTRY NUMBER 13292-46-1 (Rifampin) CAS REGISTRY NUMBER 54-85-3 (Isoniazid) CAS REGISTRY NUMBER 65-23-6 (Pyridoxine) CAS REGISTRY NUMBER 98-96-4 (Pyrazinamide) LAST REVISION DATE 941207 ENTRY MONTH 9111 CALIFORNIA Community Consortium of San Francisco 3180 18th Street Suite 201 San Francisco, CA 94110 Contact: Thomas Mitchell (415) 476-9554 OPEN 911202. COLORADO Denver / CPCRA 605 Bannock Street Denver, CO 80204-4507 Contact: Jack Rouff (303) 436-7184 Contact: (303) 436-7224 OPEN 911202. CONNECTICUT Hill Health Corporation 400-428 Columbus Avenue New Haven, CT 06519 Contact: Adrienne Joy Burns (203) 776-9594 OPEN 911202. DISTRICT OF COLUMBIA Washington Regional AIDS Program 50 Irving St N W / Room ID-151B Washington, DC 20422 Contact: John Scott (202) 745-8695 OPEN 911202. DELEWARE Delaware / CPCRA 501 West 14th Street Wilmington, DE 19899 Contact: Arlene Bincsik (302) 428-2538 OPEN 911202. GEORGIA Atlanta AIDS Research Consortium Incorporated 131 Ponce deLeon Suite 220 Atlanta, GA 30308 Contact: Amy Morris (404) 876-2317 OPEN 930203. ILLINOIS Chicago Department of Health / Speciality STD Clinic 1306 South Michigan Avenue Chicago, IL 60605 Contact: James R. Dickes (312) 747-0120 OPEN 930414. ILLINOIS Chicago CPCRA 711 West North Avenue Suite 201 Chicago, IL 60610 Contact: Jeffrey Zurlinden (312) 266-0227 OPEN 911202. LOUISIANA Louisiana Community AIDS Research Program 1430 Tulane Avenue New Orleans, LA 70112 Contact: Ermelle Martinez Laurent (504) 584-1971 OPEN 911202. MASSACHUSETTS Boston Department of Health and Hospitals 1010 Massachusetts Avenue / Second Floor Boston, MA 02118 Contact: Dr Hermide Pierre Mercier (617) 534-5916 OPEN 930513. MARYLAND Brazil / Johns Hopkins University 615 North Wolfe Street / Room 5515 Baltimore, MD 21205 Contact: Dr Mauro Schecter (410) 955-6964 OPEN 930408. MARYLAND Johns Hopkins University / School of Hygiene & Public Hlth 615 North Wolfe Street / Room 5515 Baltimore, MD 21205-2179 Contact: Jacqueline S. Coberly (410) 955-7767 Contact: (410) 955-6964 OPEN 930423. MICHIGAN Comprehensive AIDS Alliance of Detroit 4160 John R / Harper Hospital Prof Bldg / Suite 202 Detroit, MI 48201 Contact: Constance Rowley (313) 993-0934 OPEN 911202. MICHIGAN Henry Ford Hospital 2799 West Grand Boulevard Detroit, MI 48202 Contact: Diane Mastro-Polak (313) 876-7664 OPEN 920210. NEW JERSEY Community Research Initiative of North Jersey 393 Central Avenue Newark, NJ 07102 Contact: William Orr (201) 648-0350 Contact: Vicki Taylor Contact: Dr George Perez OPEN 911202. NEW JERSEY Saint Michaels Medical Center 267 Martin Luther King Boulevard / c/o OCRE / mailstop 73B Newark, NJ 07102 Contact: Sung Poblete (201) 877-2960 OPEN 930408. NEW JERSEY North Jersey Community Research Initiative 657 King Boulevard Newark, NJ 07102 Contact: Victoria Taylor (201) 648-0350 OPEN 920706. NEW JERSEY W C Lattimore Comprehensive Pulmonary Disease Clinic Martland Building / GA 43 / 65 Bergen Street Newark, NJ 07103 Contact: Sandi Barnes (201) 982-6232 OPEN 930420. NEW YORK Beth Israel Medical Center / MMTP / Tb Interim Clinic / Third Floor / 103 East 125th Street New York, NY 10035 Contact: Sara Back (212) 427-9541 X 206OPEN 930408. NEW YORK Harlem AIDS Treatment Group Harlem Hospital / Women's Pavilion Room 126 New York, NY 10037 Contact: Joshua Standig (212) 939-2951 OPEN 911202. NEW YORK Bronx-Lebanon Hospital Center 1309 Fulton Avenue Bronx, NY 10456 Contact: Cathy Pollard (718) 293-2593 Contact: (718) 901-8916 OPEN 920511. NEW YORK Addiction Research And Treatment Corporation 22 Chapel Street Brooklyn, NY 11201 Contact: Dr Robert Sawyer (718) 260-2917 OPEN 911202. NEW YORK Clinical Directors Network of Region II 5601 2nd Avenue #3 Brooklyn, NY 11220 Contact: Linda Podhurst (212) 255-3841 OPEN 911202. 13 UNIQUE IDENTIFIER NIH/00626 PROTOCOL ID NUMBERS NIAID ACTG 281 PROTOCOL TITLE HPMPC ( Cidofovir ) Peripheral CMV Retinitis Trial Protocol. VERSION NUMBER & DATE 1 (940316) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate short-term and long-term safety and efficacy of intravenous cidofovir (HPMPC) for treatment of small peripheral cytomegalovirus (CMV) retinitis lesions. To provide data on the relative safety and efficacy of 3 mg/kg versus 5 mg/kg HPMPC as maintenance regimens. Methodology: In Stage 1, up to 30 patients are randomized to either observation with deferral of treatment until the retinitis progresses (observation group), or to intravenous HPMPC at 5 mg/kg for two consecutive weekly induction doses, followed by 3 mg/kg every other week for maintenance. In Stage 2, up to 70 patients are randomized to observation or to HPMPC at 5 mg/kg for two consecutive weekly induction doses followed by either 3 or 5 mg/kg every other week for maintenance, for a total of three treatment groups. Concomitant saline hydration and probenecid are administered to patients receiving HPMPC. GENERAL DESCRIPTION METHODOLOGY: In Stage 1, up to 30 patients are randomized to either observation with deferral of treatment until the retinitis progresses (observation group), or to intravenous HPMPC at 5 mg/kg for two consecutive weekly induction doses, followed by 3 mg/kg every other week for maintenance. In Stage 2, up to 70 patients are randomized to observation or to HPMPC at 5 mg/kg for two consecutive weekly induction doses followed by either 3 or 5 mg/kg every other week for maintenance, for a total of three treatment groups. Concomitant saline hydration and probenecid are administered to patients receiving HPMPC. OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Cytomegalovirus retinitis ( CMV retinitis ). DISEASES STATUS Patients have the following symptoms and conditions: 1. AIDS by CDC criteria. 2. CMV retinitis as determined by a SOCA-certified ophthalmologist, with small lesions involving < 25 percent of the total area of the retina and confined to the periphery of the retina, located at least 1500 microns from the margin of the optic disc and 3000 microns from the center of the fovea (entirely in zones 2 or 3). 3. At least one lesion whose size is one-quarter disc area or greater that can be photographed. 4. Visual acuity in an affected eye of three or more lines on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart at 1 meter distance (Snellen equivalent 8/200). 5. NO retinal detachment in the affected eye(s). 6. NO extraocular CMV disease. 7. NO media opacity that precludes visualization of the fundus of both eyes. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS FDA 231A. GS-93-105 STUDY DESIGN 2-Stage; Randomized PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 90 patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS by CDC criteria. 2. CMV retinitis as determined by a SOCA-certified ophthalmologist, with lesion size, location, and severity as specified in the Disease Status field. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.5 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 3.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. < 1+ proteinuria on urinalysis. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception during the study and for 90 days after. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prophylaxis with anti-CMV agents. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Oral trimethoprim/sulfamethoxazole. 2. Aerosolized pentamidine. 3. Dapsone. 4. Fluconazole. 5. Ketoconazole. 6. Itraconazole. 7. Rifabutin. 8. Filgrastim (G-CSF). 9. Antiretroviral agents. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of renal disease or renal dialysis. 2. History of clinically significant cardiac disease, including symptoms of ischemia, congestive heart failure, or arrhythmia. 3. History of clinically significant probenecid allergy. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Drug or alcohol abuse sufficient to hinder compliance with study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior therapy for CMV disease with ganciclovir, foscarnet, CMV hyperimmune immunoglobulin, or other investigational agents with anti-CMV activity. 2. Therapy with nephrotoxic drugs within the past 7 days, including amphotericin B, aminoglycoside antibiotics, vidarabine, and intravenous pentamidine. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Ongoing therapy for CMV disease with ganciclovir, foscarnet, CMV hyperimmune immunoglobulin, or other investigational agents with anti-CMV activity. 2. Therapy with nephrotoxic drugs, including amphotericin B, aminoglycoside antibiotics, vidarabine, and intravenous pentamidine. SUBSTANCE IDENTIFICATION Drug 1 DRG-0145 HPMPC SUBSTANCE IDENTIFICATION Drug 2 DRG-0053 Probenecid TRADE NAME OF SUBSTANCE Drug 1‰ GS-0504 MANUFACTURERS Drug 1: Gilead Sciences Incorporated 353 Lakeside Drive Foster City, CA 94404 Contact: Dr Robert Stagg (415) 572-6566. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 5 mg/kg for two consecutive weekly induction doses, followed by 3 or 5 mg/kg every other week for maintenance. Drug 2: Administered concurrently with HPMPC SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Gilead Sciences Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Cytomegalovirus Infections/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Cytosine/ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Organophosphorus Compounds/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Retinitis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 113852-37-2 (1-(3-hydroxy-2-phosphonylmethoxypropyl)cytos- ine) LAST REVISION DATE 941207 ENTRY MONTH 9405 MARYLAND Johns Hopkins University / SOCA 615 North Wolfe Street Room 5010 Baltimore, MD 21205 Contact: Janet Holbrook (410) 955-8175 Contact: (410) 955-0930 OPEN 940506. 14 UNIQUE IDENTIFIER NIH/00643 PROTOCOL ID NUMBERS NIAID ACTG 277 PROTOCOL TITLE A Randomized, Comparative Study of Daily Dapsone and Daily Atovaquone for Prophylaxis Against PCP in HIV-Infected Patients Who Are Intolerant of Trimethoprim and/or Sulfonamides. VERSION NUMBER & DATE 2 (940701) TRIAL CATEGORY Opportunistic Infections PROTOCOL CHAIRS CHAIR El-Sadr W PROTOCOL CHAIRS CO-CHAIR Luskin-Hawk R, Murphy R GENERAL DESCRIPTION PURPOSE: To compare the efficacy and safety of dapsone versus atovaquone in preventing or delaying the onset of histologically proven or probable pneumocystis carinii pneumonia in HIV-infected patients with CD4 counts <= 200 cells/mm3 or <= 15 percent of the total lymphocyte count who are intolerant to trimethoprim and/or sulfonamides. GENERAL DESCRIPTION RATIONALE: Trimethoprim/sulfamethoxazole (TMP/SMX), which is effective for secondary PCP prophylaxis, is associated with allergic manifestations and side effects that limit its use. Patients who are intolerant of TMP/SMX require an effective alternative. Dapsone and atovaquone have both shown promise as PCP prophylactic agents. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either dapsone or atovaquone daily, with follow-up at the clinic every 4 months. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Pneumocystis carinii pneumonia ( PCP ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Working diagnosis of HIV infection based on medical history, behavioral history, clinical signs and symptoms, or laboratory test results. 2. CD4 count <= 200 cells/mm3 or <= 15 percent of total lymphyocyte count at any time in the past OR a history of PCP. 3. History of intolerance of trimethoprim and/or sulfonamides that required permanent discontinuation. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS CPCRA 034. IND 45,799 STUDY DESIGN Randomized; Comparative; Multicenter; 2-Arm; Drug Comparison; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug prophylaxis, Drug safety, Drug efficacy, Comparative drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 700 patients. (350 patients per treatment arm) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: At least 20 months. PROTOCOL DETAILS ACTUAL ACCRUAL: 269/700 (941207). PROTOCOL DETAILS STUDY DURATION: 32 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 74 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Working diagnosis of HIV infection. 2. CD4 count <= 200 cells/mm3 or <= 15 percent of total lymphyocyte count at any time in the past OR a history of PCP. 3. History of intolerance of trimethoprim and/or sulfonamides that required permanent discontinuation. NOTE: Pregnant patients are eligible at the clinician's discretion. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 200 cells/mm3. OR <= fifteen percent of the total lymphocyte count at any time in the past. ( 0 - 100 - 200 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. Adequate G6PD (normal or elevated). PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior PCP prophylaxis. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Strongly recommended: Pyrimethamine (50 mg) and folinic acid (15 mg) weekly in patients receiving dapsone who have CD4 count < 100 cells/mm3 and are toxoplasmosis seropositive. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: Known treatment-limiting reaction to dapsone or atovaquone. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: PCP prophylaxis (other than study drug) or any medication with potential anti-PCP activity. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Active pneumocystosis. SUBSTANCE IDENTIFICATION Drug 1 DRG-0036 Dapsone SUBSTANCE IDENTIFICATION Drug 2 DRG-0084 Atovaquone MANUFACTURERS Drug 1: Jacobus Pharmaceutical Company PO Box 5290 / 37 Cleveland Lane Princeton, NJ 08540 Contact: Dr David Jacobus (609) 921-7447 Contact: Dr Neil Lewis (609) 921-7447. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 100 mg daily. Drug 2: 1500 mg daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 100 mg. Drug 2: 1500 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 25 and 100 mg tablets. Drug 2: Oral, 750 mg/5 ml foil sachets OTHER TREATMENT INFO. TREATMENT DURATION: At least 20 months. OTHER TREATMENT INFO. END POINT: Primary: Occurrence/recurrence of morphologically or histologically proven PCP or probable PCP. Secondary: Toxicity; incidence of PCP, extrapulmonary pneumocystosis, and death; development of toxoplasmosis; death. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity to the assigned study drug, with inability of patient to switch over to the alternate regimen. 2. Development of toxoplasmosis. 3. Patient has reached a switchpoint but has exhausted switchover alternatives. 4. Deemed in the best interest of patient to discontinue study therapy. 5. Refusal of patient to continue therapy. 6. Termination of the study. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Dapsone/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Naphthoquinones/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Pneumonia, Pneumocystis carinii/COMPLICATIONS/ *PREVENTION & CONTROL CAS REGISTRY NUMBER 80-08-0 (Dapsone) CAS REGISTRY NUMBER 94015-53-9 (atovaquone) LAST REVISION DATE 941207 ENTRY MONTH 9410 ALABAMA University of Alabama at Birmingham 908 20th Street S / 1917 Research Clinic Room 135 Birmingham, AL 35294-2041 Contact: Susan Duncan (205) 934-3690 OPEN 941201 ACTU: 5801. ALABAMA Dr John Dunkel 101-A Bob Wallace Avenue Huntsville, AL 35801 Contact: Dr John Dunkel (205) 533-6558 OPEN 941020. CALIFORNIA Children's Hospital of Los Angeles / Children's AIDS Center 4650 Sunset Blvd / Mail Stop #54 Los Angeles, CA 90027 Contact: Antonieta Sosa (213) 669-2180 OPEN 941110 ACTU: 9916. CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 941116 ACTU: 1201. CALIFORNIA USC Univ Hosp & Ambulatory Health Care Center 2020 Zonal Avenue / Room 309 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 941116 ACTU: 1204. CALIFORNIA University of California San Diego 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 941103 ACTU: 0701. CALIFORNIA AIDS Community Research Consortium 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harris (415) 364-5653 OPEN 941017 ACTU: 0505. CALIFORNIA Santa Clara Valley Med Ctr / ACRC 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harriss (415) 364-5653 OPEN 941017 ACTU: 0506. CALIFORNIA San Francisco General Hospital / UCSF 995 Potrero Avenue / Building 80 Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 941103 ACTU: 0801. CALIFORNIA General Hospital / AIDS Clinical Trials Unit 995 Potrero Avenue / Bldg 80 / Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 846OPEN 941205 ACTU: 0808. CALIFORNIA UCSF / AIDS Clinic Ambulatory Care Center 995 Potrero Avenue San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 941104 ACTU: 0802. CALIFORNIA Community Consortium of San Francisco 3180 18th Street Suite 201 San Francisco, CA 94110 Contact: Thomas Mitchell (415) 476-9554 OPEN 941019. CALIFORNIA Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Contact: Virginia Tallman (415) 723-2804 Contact: Dr Rami Ramachandran (415) 723-6231 OPEN 941014 ACTU: 0501. CALIFORNIA Merrit-Peralta Medical Ctr/Adult Immunology Clinic U of CA 450 30th Street Oakland, CA 94609 Contact: Bruce Ross (510) 273-8200 Contact: David Greenberg OPEN 941123 ACTU: 0804. COLORADO Denver / CPCRA 605 Bannock Street Denver, CO 80204-4507 Contact: Jack Rouff (303) 436-7184 Contact: (303) 436-7224 OPEN 941031. COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 941003 ACTU: 6101. COLORADO Rose Med Ctr / Univ of Colorado Hlth Sci Ctr / Colorado ACTU Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 941024 ACTU: 6104. COLORADO Kaiser Permanente Franklin Med Cntr / Univ Col Hlth Sci Cntr 4200 East Ninth Avenue / Colorado ACTU / Campus Box B-163 Denver, CO 80262 Contact: Graham Ray (303) 270-8551 Contact: FAX (303) 270-6102 OPEN 941003 ACTU: 6103. COLORADO Denver Department of Health and Hospitals / Univ of CO Colorado ACTU / Campus Box B 163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 941003 ACTU: 6102. DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 941123 ACTU: 5701. DISTRICT OF COLUMBIA HIV Center - DC General Hospital / Georgetown Univ Med Ctr Kober-Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 Contact: Fax (202) 687-6476 OPEN 941122 ACTU: 5703. DISTRICT OF COLUMBIA Whitman-Walker Clinic / Georgetown Univ Medical Center Kober-Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 Contact: Fax (202) 687-6476 OPEN 941207 ACTU: 5702. DISTRICT OF COLUMBIA Washington Regional AIDS Program 50 Irving St N W / Room ID-151B Washington, DC 20422 Contact: John Scott (202) 745-8695 OPEN 941011. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 941006 ACTU: 0901. GEORGIA AIDS Research Consortium of Atlanta 131 Ponce deLeon Suite 220 Atlanta, GA 30308 Contact: Amy Morris (404) 577-2311 OPEN 941123. HAWAII Hawaii Aids Clinical Trails Unit Leahi Hospital / Young Bldg / 3675 Kilauea Avenue / 6th Flr Honolulu, HI 96816 Contact: Debra M Ogata Arakaki (808) 737-2751 OPEN 941117 ACTU: 5201. ILLINOIS Chicago CPCRA 711 West North Avenue Suite 201 Chicago, IL 60610 Contact: Jeffrey Zurlinden (312) 266-0227 OPEN 941017. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 940923 ACTU: 2701. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 941104 ACTU: 2702. ILLINOIS Cook County Hospital Passavant Pavilion / Room 823 / 303 East Superior Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 941205 ACTU: 2705. ILLINOIS Louis A Weiss Memorial Hospital / Northwestern Univ Med Schl 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941017 ACTU: 2708. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 941007 ACTU: 2601. LOUISIANA Louisiana Community AIDS Research Program Tulane University Medical Center / 1430 Tulane Avenue, HC28 New Orleans, LA 70112 Contact: Janice Walker (504) 584-1971 Contact: Fax (504) 584-1972 OPEN 941123. MASSACHUSETTS Massachusetts General Hospital / Harvard 55 Fruit Street Gray 5 Boston, MA 02114 Contact: Ellen Godfrey (617) 726-5598 OPEN 941205 ACTU: 0101. MASSACHUSETTS Beth Israel Hospital 330 Brookline Avenue Boston, MA 02115 Contact: Sheila Hussey (617) 735-4103 OPEN 941123 ACTU: 0102. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 941018 ACTU: 0201. MARYLAND State of Maryland Div of Corrections c/o Johns Hopkins Hosp 1830 East Monument Street / Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 941115 ACTU: 0202. MICHIGAN Henry Ford Hospital 2799 West Grand Boulevard Detroit, MI 48202 Contact: Diane Mastro-Polak (313) 876-7664 OPEN 941121. MINNESOTA St Paul-Ramsey Medical Center 640 Jackson Street St Paul, MN 55101 Contact: Ray Nelson (612) 221-1280 OPEN 941031 ACTU: 1503. MINNESOTA Hennepin County Med Clinic / Univ of Minnesota Hosp Clinic 420 Delaware Street SE / Room G255 Mayo Building Minneapolis, MN 55415 Contact: Renee St Jacques (612) 373-1810 OPEN 941014 ACTU: 1502. MINNESOTA University of Minnesota Hospital and Clinic PO Box 437 / UMHC / Harvard Street & East River Road Minneapolis, MN 55455 Contact: Nancy Reed (612) 625-1462 OPEN 941014 ACTU: 1501. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 941003 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 941003 ACTU: 2102. NORTH CAROLINA Moses H Cone Memorial Hospital / University North Carolina 1200 North Elm Street Greensboro, NC 27401 Contact: Pam Mentley (910) 574-7888 OPEN 941017 ACTU: 3203. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 940923 ACTU: 3201. NORTH CAROLINA Wake County Department of Health Hosp South Room 0207 Box 3284 Durham, NC 27710 Contact: Kelley Rayle (919) 250-1035 OPEN 941103 ACTU: 3206. NORTH CAROLINA Carolinas Medical Center / Department of Internal Medicine 1000 Blythe Blvd AHEC Room 507 Charlotte, NC 28203 Contact: Joan Connell (704) 355-5292 Contact: (704) 355-3165 OPEN 941007 ACTU: 3204. NEBRASKA University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-5130 Contact: Frances Tennant (402) 559-5750 OPEN 941104 ACTU: 1505. NEW JERSEY North Jersey Community Research Initiative 657 King Boulevard Newark, NJ 07102 Contact: Victoria Taylor (201) 648-0350 OPEN 941031. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 941017 ACTU: 1802. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 941003 ACTU: 0401. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 941031 ACTU: 1801. NEW YORK Harlem AIDS Treatment Group / Harlem Hospital Center Womens Pavilion Room 126 / 506 Lenox Avenue New York, NY 10037 Contact: Luis Fuentes (212) 649-4343 OPEN 941026. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 941007 ACTU: 1902. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 941007 ACTU: 1901. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 941116 ACTU: 1903. NEW YORK Bronx Veterans Administration Medical Center 130 West Kingsbridge Road Bronx, NY 10468 Contact: Nancy Ostrow (718) 584-9000 X 667Contact: (718) 584-9000 X 667OPEN 941201 ACTU: 1804. NEW YORK Adirondack Medical Center at Saranac Lake 47 New Scotland Avenue Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 941005 ACTU: 7403. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 941005 ACTU: 7401. NEW YORK Mid-Hudson Care Center / Albany Med College / Div Med Oncol 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 941005 ACTU: 7402. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 941123 ACTU: 1103. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 941003 ACTU: 1102. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 941031 ACTU: 1101. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 941013 ACTU: 2301. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 940930 ACTU: 2501. OREGON The Research and Education Group 2701 NW Vaughn / Suite 770 Portland, OR 97210 Contact: Joyce St Arnaud (503) 229-8428 OPEN 941101. PENNSYLVANIA University of Pennsylvania / Div of Infectious Diseases 549 Johnson Pavillion / 6073 / 36th and Hamilton Walk Philadelphia, PA 19104-6073 Contact: Debora Dunbar (215) 349-8092 OPEN 941018 ACTU: 6201. PENNSYLVANIA Thomas Jefferson Unversity 1015 Chestnut Street Philadelphia, PA 19107 Contact: Lyle Jew (215) 955-7785 OPEN 941104 ACTU: 6202. SOUTH CAROLINA Medical University of SC / Infect Diseases Division 807 CSB 171 Ashley Avenue Charleston, SC 29425 Contact: Denise Taylor (803) 782-6174 OPEN 941024 ACTU: 3205. 15 UNIQUE IDENTIFIER NIH/00671 PROTOCOL ID NUMBERS NIAID ACTG 275 PROTOCOL TITLE A Phase II Randomized, Double-Blind, Placebo-Controlled Trial of the Virologic Effect of Two Different Nucleoside Treatment Strategies (Zidovudine Versus Zidovudine in Combination With Didanosine) for HIV Infection in Subjects With CD4+ Counts >= 550 Cells/mm3. VERSION NUMBER & DATE 1 (940922) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Erice A PROTOCOL CHAIRS CO-CHAIR Balfour H, Carey J, Henr GENERAL DESCRIPTION PURPOSE: To determine the effects of zidovudine (AZT) alone and in combination with didanosine (ddI) on viral load in the lymphoid tissue and blood of antiretroviral-naive, HIV-infected patients with CD4 counts >= 550 cells/mm3. GENERAL DESCRIPTION RATIONALE: Recent studies have shown that during the asymptomatic phase (clinical latency) of HIV infection, there is an extraordinarily large number of infected CD4+ lymphocytes and macrophages throughout the lymphoid system, both in latent and productive states. These findings support the belief that early intervention therapy with reverse transcriptase inhibitors could prolong the clinical latency period. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive AZT alone, AZT plus ddI, or no therapy (placebo) daily for 48 weeks. Patients are followed at weeks 2, 4, and 8, and then every 8 weeks thereafter until week 48. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Pending first patient enrolled (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA confirmed by a) Western blot, positive HIV antigen, or positive HIV culture; or b) a second antibody test other than ELISA. 2. CD4 count >= 550 cells/mm3 within 30 days prior to study entry. 3. Asymptomatic by CDC criteria. ELIGIBILITY ASYM. OTHER PROTOCOL NUMBERS IND 35,208 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Multicenter; 3-Arm; Drug Combination PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Combination and single drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 105 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 50 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 3 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. CD4 count >= 550 cells/mm3. 3. No ARC or AIDS conditions by CDC criteria. 4. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 12 g/dl. (men); >= 11.0 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 550 cells/mm3. ( 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 75 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 80. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. Alkaline phosphatase <= 5 x ULN. Total serum amylase <= 1.5 x ULN (if serum amylase > 1.5 x ULN, then lipase <= 1.5 x ULN or pancreatic amylase <= 1.5 x ULN is acceptable). PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: 1. Radiation therapy to local lesion only. 2. Acupuncture. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antibiotics for bacterial infections as clinically indicated. 2. Recombinant erythropoietin (EPO) and G-CSF as clinically indicated for grade 3 or worse anemia and neutropenia, respectively. 3. Antipyretics. 4. Analgesics. 5. Allergy medications. 6. Oral contraceptives. 7. Nonprescription medications such as vitamins or herbal therapies. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of chronic diarrhea, defined as more than four loose or watery stools on average daily for the past month. 2. History of grade 2 or worse peripheral neuropathy. 3. History of pancreatitis. 4. Bacterial infection requiring antibiotics within 14 days prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse or alcoholism. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within 2 weeks prior to study entry: Transfusion. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy except to local lesion. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Prior HIV therapy with antiretrovirals or systemic immunomodulators. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other antiretrovirals or systemic immunomodulators. 2. Systemic corticosteroids. 3. Systemic cytotoxic chemotherapy. 4. Intravenous pentamidine. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Presence of factors predisposing to pancreatitis such as active alcoholism. 2. Other medical conditions that would interfere with study compliance. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0016 Didanosine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir TRADE NAME OF SUBSTANCE Drug 2‰ Videx MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Colin McLaren (203) 284-6942. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg (or placebo) TID for 48 weeks. Drug 2: 200 mg (or placebo) BID for 48 weeks (125 mg BID if les60 kg body weight) SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 600 mg. Drug 2: 400 mg (250 mg if less than 60 kg body weight) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg capsules. Drug 2: Oral; 25, 50, and 100 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 48 weeks. OTHER TREATMENT INFO. END POINT: Virologic and immunologic parameters. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Decrease in CD4 count to <= 50 percent of baseline on repeat testing. 3. Development of AIDS-indicator conditions. 4. Pregnancy. 5. Further participation considered detrimental to patient's health or well-being. 6. Requirement for medications not allowed on this study. 7. Patient noncompliance or refusal of further treatment. OTHER TREATMENT INFO. MODIFICATION: For grade 3 drug-related toxicity other than myositis, hyperamylasemia, anemia, neutropenia, or peripheral neuropathy: Hold study drugs until toxicity resolves to grade 2 or better, then resume at 50 percent dose. For grade 4 toxicity other than myositis, hyperamylasemia, anemia, or neutropenia: Hold study drugs until toxicity resolves to grade 3 or better, then resume at reduced dose following consultation with an ACTG physician, patient, study chair, and patient's personal physician. For grade 2 or 3 peripheral neuropathy: Hold study drugs until toxicity resolves to grade 1 or better, then resume AZT at full dose and ddI at 50 percent dose. For grade 3 or 4 myositis, hyperamylasemia, anemia, or neutropenia: Depending on specific toxicity, hold one or both study drugs until toxicity resolves to acceptable levels, then resume at full or reduced dose. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Didanosine/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zidovudine/*THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 941207 ENTRY MONTH 9412 MINNESOTA University of Minnesota Hospital and Clinic PO Box 437 / UMHC / Harvard Street & East River Road Minneapolis, MN 55455 Contact: Nancy Reed (612) 625-1462 OPEN 941118 ACTU: 1501. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 941123 ACTU: 2501. PENNSYLVANIA Thomas Jefferson Unversity 1015 Chestnut Street Philadelphia, PA 19107 Contact: Lyle Jew (215) 955-7785 OPEN 941205 ACTU: 6202. 16 UNIQUE IDENTIFIER NIH/00657 PROTOCOL ID NUMBERS NIAID ACTG 269 PROTOCOL TITLE Phase II Evaluation of Low-Dose Oral Etoposide for the Treatment of Relapsed or Progressed AIDS-Related Kaposi's Sarcoma After Systemic Chemotherapy. VERSION NUMBER & DATE 1 (940819) TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Von Roenn JH PROTOCOL CHAIRS CO-CHAIR Paredes J GENERAL DESCRIPTION PURPOSE: To assess the toxicity, tumor response rate, and effect on quality of life of daily low-dose etoposide administered for 7 consecutive days every other week in patients with AIDS-related Kaposi's sarcoma that has relapsed or progressed after systemic chemotherapy. GENERAL DESCRIPTION RATIONALE: Etoposide may be at least as, or even more, effective and less myelotoxic when given in low doses over prolonged periods of time. GENERAL DESCRIPTION METHODOLOGY: Patients receive low-dose (50 mg) oral etoposide on days 1 through 7 of every 2-week cycle. Patients who achieve a complete or partial response after two cycles and have no toxicity greater than grade 2 may have their dose escalated to 100 mg for subsequent cycles. If there are no responses to therapy among the first 14 evaluable patients, the study will close; if there is at least one objective response to therapy among the first 14 evaluable patients, enrollment will continue until all 41 patients are enrolled. Patients continue therapy until maximal tumor response (either stable disease or complete response) is achieved or disease progression occurs. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Pending first patient enrolled (941207) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA confirmed by Western blot. 2. Biopsy-proven Kaposi's sarcoma that has relapsed or progressed following non-investigational systemic chemotherapy with at least two agents. 3. Mucocutaneous lesions (15 or more) and/or symptomatic mucosal lesions and/or visceral Kaposi's sarcoma (symptomatic lymphadema qualifies patients in the absence of these three conditions). 4. NO active acute opportunistic infections requiring treatment with myelosuppressive antibiotics (maintenance for OIs is permitted). ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 34,080 STUDY DESIGN Open Label; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 41 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: At least two cycles. PROTOCOL DETAILS STUDY DURATION: Indefinite. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 6 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Kaposi's sarcoma that has relapsed or progressed. 3. Mucocutaneous lesions (15 or more) and/or symptomatic mucosal lesions and/or visceral Kaposi's sarcoma (symptomatic lymphadema qualifies patients in the absence of these three conditions). 4. NO active acute opportunistic infections requiring treatment with myelosuppressive antibiotics (maintenance for OIs is permitted). 5. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 2.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase < 5 x ULN. Absolute neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 12 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Maintenance therapy for opportunistic infections. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: Neuropsychiatric history. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 11 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Continued alcohol consumption or continued intravenous drug use that would impair ability to comply with study requirements. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Radiation therapy within 7 days prior to study entry. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior etoposide. 2. Any other anti-KS drugs within 14 days prior to study entry. 3. Any investigational drug other than antiretrovirals within 14 days prior to study entry. 4. Any prior investigational agent, if given as the ONLY prior treatment for KS. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Other active malignancies except basal cell carcinoma of the skin, or carcinoma in situ of the cervix. 2. Grade 3 or worse peripheral neuropathy. 3. Altered mental status that would prevent informed consent or prevent study compliance. SUBSTANCE IDENTIFICATION Drug 1 DRG-0081 Etoposide MANUFACTURERS Drug 1: Bristol-Myers Squibb Company PO Box 4500 Princeton, NJ 08543-4500 Contact: Sharon Duncan (609) 897-2126. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 50 mg daily on days 1 through 7 every 2 weeks for a minimum of 2 cycles, with escalation to 100 mg in subsequent cyif patient achieves partial or complete response with no toxicigrade 2 SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 50 or 100 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 50 mg capsules OTHER TREATMENT INFO. END POINT: Complete and partial response rates. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Development of opportunistic infection that precludes further treatment on study. 3. Development of other malignancies requiring radiation or systemic therapy. 4. Granulocytes < 1000 cells/mm3 or platelets < 75000 cells/mm3 persisting for more than 2 weeks after study therapy is held for hematologic toxicity. 5. Progressive disease after two cycles. 6. Considered to have reached maximal tumor response. 7. Study drug is held for more than 21 days. 8. Pregnancy. 9. Patient noncompliance or desire of patient to withdraw. 10. Further study therapy deemed detrimental to patient's health. OTHER TREATMENT INFO. MODIFICATION: For grade 3 or 4 hematologic toxicity: Hold study drug until toxicity resolves to grade 1, then resume at 50 mg daily on days 1 through 4 every 2 weeks (in patients on the 50 mg dose) or at 50 mg daily on days 1 through 7 every 2 weeks (in patients on the 100 mg dose). If grade 3 or 4 hematologic toxicity recurs, discontinue study drug permanently. For grade 3 nonhematologic toxicity: Hold study drug until toxicity resolves to grade 1 or better, then resume at reduced dose. For recurrent grade 3 or any occurrence of grade 4 nonhematologic toxicity, discontinue study drug permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Bristol-Myers Squibb Company. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Etoposide/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 33419-42-0 (Etoposide) LAST REVISION DATE 941207 ENTRY MONTH 9410 COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 941123 ACTU: 6101. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 941102 ACTU: 0901. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941101 ACTU: 2701. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 941004 ACTU: 2101. NEW YORK St Clare's Hospital and Health Center 415 West 51st Street New York, NY 10019 Contact: Phyllis Ristau (212) 459-8449 OPEN 941031 ACTU: 2204. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 941116 ACTU: 1102. 17 UNIQUE IDENTIFIER NIH/00681 PROTOCOL ID NUMBERS NIAID ACTG 268 PROTOCOL TITLE Gradual Initiation of Trimethoprim/Sulfamethoxazole as Primary Pneumocystis carinii Pneumonia Prophylaxis. VERSION NUMBER & DATE 1 (941013) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Para MF PROTOCOL CHAIRS CO-CHAIR Dohn MN, Frame P GENERAL DESCRIPTION PURPOSE: To determine whether gradual initiation of trimethoprim/sulfamethoxazole (TMP/SMX) reduces the incidence of treatment-limiting adverse reactions compared to the routine initiation of the drugs for Pneumocystis carinii pneumonia (PCP) prophylaxis in HIV-infected patients. GENERAL DESCRIPTION RATIONALE: Although a number of clinical trials have demonstrated the superiority of TMP/SMX for PCP prophylaxis, the incidence of adverse reactions to this medication is high. In a pilot study in which patients were initiated with TMP/SMX prophylaxis by gradually increasing the dose over 2 weeks, no significant adverse reactions have occurred. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either gradually increasing doses of TMP/SMX suspension or routine daily initiation of TMP/SMX double strength (DS) tablets for 2 weeks. All patients will then be switched over to receive open-label TMP/SMX DS tablets daily for 10 weeks. PROTOCOL PHASE Phase IV OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Pneumocystis carinii pneumonia ( PCP ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA, Western blot, HIV serum p24 antigen, or a positive HIV culture. 2. CD4 count <= 250 cells/mm3 OR history or presence of thrush regardless of CD4 count. 3. NO history of confirmed or probable pneumocystosis. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND 46,533 STUDY DESIGN Randomized; Double-Blind; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug prophylaxis, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 370 patients. (185 patients on each of two treatment arms) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 3 months. PROTOCOL DETAILS ACTUAL ACCRUAL: 3/370 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 6 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CD4 count <= 250 cells/mm3 OR history or presence of thrush. 3. NO history of confirmed or probable pneumocystosis. NOTE: Pregnant women are not excluded, but safety issues should be discussed with patient prior to enrollment. NOTE: This study is appropriate for prisoner participation. NOTE: Coenrollment in ongoing ACTG antiretroviral studies is permitted provided no new study drugs are added to the patient's drug regimen for 4 weeks before or after initiation of TMP/SMX. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.2 g/dl. (men); >= 8.5 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 250 cells/mm3. OR a presence of thrush regardless of CD4 count. ( 0 - 100 - 200 ). PATIENT INCLUSION CRIT. SGOT(AST): <= 10 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.5 x ULN. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not breast-feeding. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior aerosolized pentamidine and dapsone for primary PCP prophylaxis. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed if clinically indicated: Recombinant erythropoietin (rEPO) and G-CSF. Allowed for symptomatic treatment of mild study drug toxicity: 1. Antipyretics and analgesics (ibuprofen). 2. Antihistamines (diphenhydramine HCl). 3. Terfenadine or astemizole (but not allowed with concomitant antifungal or macrolide use). 4. Systemic steroids. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Breast-feeding. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded at any time: Prior TMP/SMX as primary PCP prophylaxis. Excluded within 4 weeks prior to study entry: 1. Initiation of antiretroviral agents. 2. Initiation of anti-infective agents (including TMP/SMX for another indication). Excluded within 2 weeks prior to study entry: 1. Antihistamines. 2. Procysteine. 3. Glutathione. 4. N-acetylcysteine (NAC). 5. Systemic corticosteroids (unless used for replacement purposes). 6. Leucovorin calcium. 7. TMP and sulfa drugs separately. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Procysteine. 2. Glutathione. 3. N-acetylcysteine (NAC). 4. Antihistamines (unless used for symptomatic treatment of study drug toxicity). 5. Systemic corticosteroids (unless used for replacement purposes). 6. Leucovorin calcium (unless used for symptomatic treatment of study drug toxicity). 7. TMP or sulfa drugs outside of the study. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known adverse reactions to sulfa, trimethoprim, or TMP/SMX. 2. Inability to comply with dosing schedule or complete dosing record. SUBSTANCE IDENTIFICATION Drug 1 DRG-0030 Trimethoprim SUBSTANCE IDENTIFICATION Drug 2 DRG-0031 Sulfamethoxazole TRADE NAME OF SUBSTANCE Drug 1‰ Septra (in combination with sulfamethoxazole) TRADE NAME OF SUBSTANCE Drug 2‰ Septra (in combination with trimethoprim) MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Arm I: 8, 16, 40, 80, and 160 mg in suspension daily given as gradually increasing doses for 2 weeks (plus tablet placebo), followed by 160 mg in tablet daily for 10 weeks. Arm II: 160 mg in tablet daily for 2 weeks (plus suspension plafollowed by 160 mg in tablet daily for 10 weeks. Drug 2: Arm I: 40, 80, 200, 400, and 800 mg in suspension dailyas gradually increasing doses for 2 weeks (plus tablet placebo)followed by 800 mg in tablet daily for 10 weeks. Arm II: 800 mg in tablet daily for 2 weeks (plus suspension plafollowed by 800 mg in tablet daily for 10 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: Tablet: 160 mg. Suspension: 8, 16, 40, 80, and 160 mg. Drug 2: Tablet: 800 mg. Suspension: 40, 80, 200, 400, and 800 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 160 mg tablets and 40 mg/5 ml suspension. Drug 2: Oral, 800 mg tablets and 200 mg/5 ml suspension OTHER TREATMENT INFO. TREATMENT DURATION: 12 weeks. OTHER TREATMENT INFO. END POINT: Development of treatment-limiting adverse effects. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Development of an intercurrent illness such as major opportunistic infection, new AIDS-defining illness, generalized debilitation, or mental incapacity that would preclude informed consent. 3. Futher participation deemed detrimental to patient's health or well-being. 4. Patient noncompliance or request of patient to withdraw from treatment. OTHER TREATMENT INFO. MODIFICATION: No dose modification will be allowed. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Burroughs Wellcome. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Pneumonia, Pneumocystis carinii/COMPLICATIONS/ *PREVENTION & CONTROL MESH HEADING Trimethoprim-Sulfamethoxazole Combination/ *ADMINISTRATION & DOSAGE/ADVERSE EFFECTS CAS REGISTRY NUMBER 8064-90-2 (Trimethoprim-Sulfamethoxazole Combination) LAST REVISION DATE 941207 ENTRY MONTH 9412 MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 941123 ACTU: 0201. MARYLAND State of Maryland Div of Corrections c/o Johns Hopkins Hosp 1830 East Monument Street / Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 941123 ACTU: 0202. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 941130 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 941130 ACTU: 2102. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 941130 ACTU: 1102. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 941123 ACTU: 2301. 18 UNIQUE IDENTIFIER NIH/00627 PROTOCOL ID NUMBERS NIAID ACTG 262 PROTOCOL TITLE Methadone Effects on Zidovudine (AZT) Disposition. VERSION NUMBER & DATE 2 (940912) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Jatlow P PROTOCOL CHAIRS CO-CHAIR Rainey P GENERAL DESCRIPTION PURPOSE: To determine whether methadone maintenance alters the pharmacokinetics of zidovudine (AZT). To determine whether any such effect of methadone on disposition of AZT is time dependent and whether a metabolic interaction between AZT and methadone exists. GENERAL DESCRIPTION RATIONALE: Injection drug users represent an increasing proportion of HIV-infected persons. Since daily methadone maintenance is the major chemical treatment for injection drug abuse, it is important to determine the impact of methadone on AZT absorption, distribution, and elimination. GENERAL DESCRIPTION METHODOLOGY: After 6 days of inpatient detoxification with clonidine, patients addicted to opiates are randomized to receive either oral or intravenous AZT for the first dose, followed by determination of plasma and urine pharmacokinetics. On the second day of AZT dosing, the alternate form of administration will be used for the first dose. On both days, all other doses are given orally. Patients then begin methadone maintenance in combination with AZT for 7 days of inpatient treatment, with further pharmacokinetic sampling. After hospitalization for 16 days total, patients continue AZT/methadone treatment on an outpatient basis, and then 2 months later are readmitted as inpatients for 5 days for further pharmacokinetic sampling. Control patients who are not addicted to opiates are hospitalized for 3 days at study entry and are randomized for AZT treatment and pharmacokinetic sampling in the same manner as the first group, although they will not receive methadone treatment. Control patients are readmitted for 2 days after 1 week of AZT treatment and then again after 59 days of AZT treatment. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS All patients have the following symptoms and conditions: 1. HIV infection by ELISA confirmed by Western blot. 2. CD4 count 100 - 500 cells/mm3. 3. No active opportunistic infection or wasting syndrome. Methadone recipients only: Opiate addiction or previous enrollment in a methadone treatment program with eligibility for long-term methadone maintenance and AZT therapy. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND 28,972 STUDY DESIGN Controlled; Open Label; Pharmacokinetic; Drug Combination PROTOCOL DETAILS STUDY INTENT: Combination and single pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 15 patients. (10 methadone-treated patients; 5 control patients) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Approximately 65 days. PROTOCOL DETAILS ACTUAL ACCRUAL: 1/15 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. CD4 count 100 - 500 cells/mm3. 3. No active opportunistic infection or wasting syndrome. 4. Opiate addiction or prior enrollment in a methadone treatment program (methadone recipients only). 5. Admission to General Clinical Research Center at Yale-New Haven Hospital for clonidine detoxification (methadone recipients only). [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 100 - 500 cells/mm3. ( 100 - 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: < 2.0 mg/dl. PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 75 ml/min. /1.73 m2. PATIENT INCLUSION CRIT. OTHER: PT < 2 seconds above control. Serum albumin > 2.5 g/dl; no ascites. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Continued active drug or alcohol abuse or dependence that would decrease the probability of study completion. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 4 weeks prior to study entry: 1. Rifampin or its derivatives. 2. Phenytoin. 3. Barbiturates. 4. Cimetidine. 5. Other drugs known to induce or inhibit hepatic microsomal enzymes. Excluded within 14 days prior to study entry: 1. Any other experimental drug. 2. Drugs with known nephrotoxic potential. Excluded within 72 hours prior to study entry: Amiodarone. Anesthetics, general. Azithromycin. Carbamazepine. Ciprofloxacin. Clarithromycin. Dexamethasone. Disulfiram. Erythromycin. Fluoroquinolones. Fluoxetine. Gestodene. Hydrochlorothiazide. Hypoglycemics, oral. Isoniazid. Itraconazole. Ketoconazole. Levomepromazine. MAO inhibitors. Methoxsalen. Nafcillin. Narcotic analgesics. Naringenin. Norethindrone. Omeprazole. Pentazocine. Phenothiazines. Quinidine. Ranitidine. Rifabutin. Sedative Hypnotics. Sulfaphenazole. Tranquilizers (except at discretion of investigator and protocol chair). Tricyclic antidepressants. Troleandomycin. Warfarin. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Amiodarone. Anesthetics, general. Azithromycin. Barbiturates. Carbamazepine. Cimetidine. Ciprofloxacin. Clarithromycin. Dexamethasone. Disulfiram. Erythromycin. Fluoroquinolones. Fluoxetine. Gestodene. Hydrochlorothiazide. Hypoglycemics, oral. Isoniazid. Itraconazole. Ketoconazole. Levomepromazine. MAO inhibitors. Methoxsalen. Nafcillin. Narcotic analgesics. Naringenin. Norethindrone. Omeprazole. Pentazocine. Phenothiazines. Phenytoin. Quinidine. Ranitidine. Rifabutin. Rifampin. Sedative Hypnotics. Sulfaphenazole. Tranquilizers (except at discretion of investigator and protocol chair). Tricyclic antidepressants. Troleandomycin. Warfarin. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Inadequate IV access. 2. Benzodiazepine abuse. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0023 Methadone TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Kathryn Pattishall (919) 315-4440 Contact: Dr Andy Sopchak (919) 315-3891. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Oral dose: 200 mg thrice daily. IV dose: 150 mg over 30 minutes. Drug 2: 30 mg on day 3, 40 mg on day 4, and 50 mg on day 5 and thereafter. (Per 09/12/94 amendment, dose may be increased to 7during the outpatient portion of the study, if indicated.) SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: Oral dose: 600 mg. IV dose: 150 mg. Drug 2: 30, 40, or 50 mg, or, per 09/12/94 amendment, 75 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg capsules or 20 ml vials. Drug 2: Oral, 10 mg/ml stock solution OTHER TREATMENT INFO. TREATMENT DURATION: 59 days. OTHER TREATMENT INFO. END POINT: Pharmacokinetic profile. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Completion of three sets of pharmacokinetic studies. 2. Unacceptable toxicity. 3. Use of any prohibited medications. 4. Decision of patient to withdraw from study. 5. Positive urine drug abuse screen or serum alchol test that reveals drug abuse or decreases likelihood of study completion by patient. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Burroughs Wellcome. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Interactions MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Methadone/*ADVERSE EFFECTS/PHARMACOKINETICS/ THERAPEUTIC USE MESH HEADING Middle Age MESH HEADING Zidovudine/*PHARMACOKINETICS/THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 76-99-3 (Methadone) LAST REVISION DATE 941207 ENTRY MONTH 9406 CONNECTICUT Yale University School of Medicine / Sect of Infectious Dis 135 College Street New Haven, CT 06510-2483 Contact: Laurie Andrews (203) 737-4040 OPEN 940524 ACTU: 6401. 19 UNIQUE IDENTIFIER NIH/00645 PROTOCOL ID NUMBERS NIAID ACTG 261 PROTOCOL TITLE A Phase II Double-Blind Study of Delavirdine Mesylate ( U-90152 ) in Combination With Zidovudine (AZT) and/or Didanosine (ddI) Versus AZT and ddI Combination Therapy. VERSION NUMBER & DATE (940718) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Friedland G PROTOCOL CHAIRS CO-CHAIR Fischl MA, Pollard R GENERAL DESCRIPTION PURPOSE: To determine the safety and anti-HIV activity of delavirdine mesylate (U-90152) in combination with zidovudine (AZT) and/or didanosine (ddI) versus AZT/ddI combination. GENERAL DESCRIPTION RATIONALE: U-90152 has demonstrated anti-HIV activity. Since the combination of this drug with either AZT or ddI has synergistic inhibitory activity against HIV-1 in vitro, and triple therapy appears to have greater inhibitory activity against HIV-1 in vitro than dual therapy, the use of U-90152 in combination with AZT and/or ddI may improve the benefits of these drugs in persons with HIV disease. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive U-90152/AZT/ddI, U-90152/AZT, U-90152/ddI, or AZT/ddI for 48 weeks. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA confirmed by Western blot, HIV antigen, HIV culture, or a second antibody test other than ELISA. 2. CD4 count 100 - 500 cells/mm3 within 60 days prior to study entry. 3. Prior cumulative monotherapy of <= 6 months (may have taken either AZT or ddI, but not both) OR no prior antiretroviral therapy. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND 45,914 STUDY DESIGN Randomized; Multicenter; Double-Blind; 4-Arm; Drug Combination; Comparative PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Combination drug therapy, Comparative drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 471 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 48 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 106/471 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 46 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CD4 count 100 - 500 cells/mm3. 3. Prior cumulative monotherapy of <= 6 months (may have taken either AZT or ddI, but not both) OR no prior antiretroviral therapy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.2 g/dl. (men); >= 8.9 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 100 - 500 cells/mm3. ( 100 - 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. SGOT(AST): <= 3 x ULN. Or <= 5 x ULN if liver function abnormalities have been stable for 1 yea PATIENT INCLUSION CRIT. SGPT(ALT): <= 3 x ULN. Or <= 5 x ULN if liver function abnormalities have been stable for 1 year. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 50 ml/min. (If creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 80. PATIENT INCLUSION CRIT. OTHER: Neutrophils >= 1000 cells/mm3. Serum amylase <= 1.5 x ULN (higher value permitted if both fractionated pancreatic amylase and lipase are < 1.5 x ULN). PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed for cutaneous Kaposi's sarcoma: 1. Localized radiation therapy. 2. Limited intralesional therapy. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: PCP prophylaxis for patients with CD4 count <= 300 cells/mm3. Allowed: 1. Topical antifungal agents. 2. Oral ketoconazole, fluconazole, and itraconazole for candidiasis or disseminated fungal infections. 3. Isoniazid, ethambutol, pyrazinamide, clofazimine, ciprofloxacin, and clarithromycin for acute or maintenance therapy for mycobacterial disease. 4. Acute or maintenance therapy for toxoplasmosis. 5. Acute or maintenance therapy with acyclovir (no more than 1000 mg/day) for herpes simplex virus infection. 6. rEPO and rG-CSF. 7. Antibiotics for bacterial infections (except rifampin and rifabutin). 8. Antipyretics, analgesics, nonsteroidal anti-inflammatory agents, antiemetics, and methadone. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of intolerance to AZT at <= 600 mg/day or ddI at <= 400 mg/day or discontinuation of either drug for toxicity. 2. History of pancreatitis. 3. History of grade 2 or worse peripheral neuropathy. 4. Unexplained temperature >= 38.5 C on any 7 days within the past 30 days. 5. Chronic diarrhea on any 15 days during the past 30 days. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active drug or alcohol use. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior foscarnet as induction or maintenance therapy. 2. Prior U-90152. 3. Prior ddC or d4T. 4. Prior AZT/ddI in combination or taken separately at different times. 5. Prior nonnucleoside reverse transcriptase inhibitors (nevirapine, atevirdine, etc.). 6. HIV-1 vaccine within the past 90 days. 7. Acute treatment for a serious infection or for any opportunistic infection within the past 14 days. Excluded within the past 30 days: 1. Interferon or interleukin. 2. Rifampin. 3. Rifabutin. 4. Terfenadine. 5. Astemizole. 6. Loratadine. 7. Trifluoperazine. 8. Piperazine. 9. Recombinant EPO or G-CSF. 10. Any other investigational drug. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antiretroviral therapies and biologic response modifiers (except for study medications, rEPO, and rG-CSF). 2. Rifampin. 3. Rifabutin. 4. Terfenadine. 5. Astemizole. 6. Loratadine. 7. Trifluoperazine. 8. Piperazine. 9. Systemic corticosteroids for more than 21 consecutive days. 10. Foscarnet. 11. Systemic cytotoxic chemotherapy for a malignancy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Malignancy (other than basal or squamous cell carcinoma of the skin, Stage 1 or 2 cervical intraepithelial neoplasia, or minimal Kaposi's sarcoma). 2. Considered to be unlikely to comply with study requirements. SUBSTANCE IDENTIFICATION Drug 1 DRG-0166 U-90152 SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0016 Didanosine TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir TRADE NAME OF SUBSTANCE Drug 3‰ Videx MANUFACTURERS Drug 1: The Upjohn Company 7000 Portage Road Kalamazoo, MI 49001 Contact: James VanSweden (616) 323-4696. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 3: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Colin McLaren (203) 284-6942. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 400 mg (or placebo) TID for 48 weeks. Drug 2: 200 mg (or placebo) TID for 48 weeks. Drug 3: 200 mg (or placebo) BID for 48 weeks (125 mg or placeboin patients weighing < 60 kg) SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 1200 mg. Drug 2: 600 mg. Drug 3: 400 mg (or 250 mg in patients weighing < 60 kg) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg tablets. Drug 2: Oral, 100 mg capsules. Drug 3: Oral; 25, 50, and 100 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 48 weeks. OTHER TREATMENT INFO. END POINT: Efficacy, toxicity. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Development of a malignancy or progressive Kaposi's sarcoma requiring systemic therapy or radiation therapy. 3. Termination of study by the FDA, NIAID DAIDS, ACTG or pharmaceutical sponsors. 4. Pregnancy or breast-feeding. OTHER TREATMENT INFO. MODIFICATION: Dose interruptions, modifications, and discontinuations will be made for all grade 3 and 4 toxicities considered to be related to study drugs. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Didanosine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zidovudine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 941207 ENTRY MONTH 9409 ALABAMA University of Alabama at Birmingham 908 20th Street S / 1917 Research Clinic Room 135 Birmingham, AL 35294-2041 Contact: Susan Duncan (205) 934-3690 OPEN 941114 ACTU: 5801. CALIFORNIA Olive View Medical Center / Department of Medicine 14445 Olive View Drive / 2B182 Olive View Medical Center Sylmar, CA 91342 Contact: Betsy Manchester (818) 364-3205 OPEN 941012 ACTU: 0602. CALIFORNIA Veterans Admin Hospital at San Diego / UCSD Med Center 9500 Gilman Drive / # 0672 La Jolla, CA 92093 Contact: Candace McIvor (619) 534-7170 OPEN 941110 ACTU: 0702. CALIFORNIA University of California San Diego 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 941110 ACTU: 0701. CALIFORNIA San Francisco General Hospital / UCSF 995 Potrero Avenue / Building 80 Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940919 ACTU: 0801. CALIFORNIA Merrit-Peralta Medical Ctr/Adult Immunology Clinic U of CA 450 30th Street Oakland, CA 94609 Contact: Bruce Ross (510) 273-8200 Contact: David Greenberg OPEN 940919 ACTU: 0804. COLORADO Denver Department of Health and Hospitals / Univ of CO Colorado ACTU / Campus Box B 163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 940921 ACTU: 6102. COLORADO Rose Med Ctr / Univ of Colorado Hlth Sci Ctr / Colorado ACTU Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 941026 ACTU: 6104. COLORADO Kaiser Permanente Franklin Med Cntr / Univ Col Hlth Sci Cntr 4200 East Ninth Avenue / Colorado ACTU / Campus Box B-163 Denver, CO 80262 Contact: Graham Ray (303) 270-8551 Contact: FAX (303) 270-6102 OPEN 940921 ACTU: 6103. CONNECTICUT Yale University School of Medicine / Sect of Infectious Dis 135 College Street New Haven, CT 06510-2483 Contact: Laurie Andrews (203) 737-4040 OPEN 941005 ACTU: 6401. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 940916 ACTU: 0901. HAWAII Hawaii Aids Clinical Trails Unit Leahi Hospital / Young Bldg / 3675 Kilauea Avenue / 6th Flr Honolulu, HI 96816 Contact: Debra M Ogata Arakaki (808) 737-2751 OPEN 940921 ACTU: 5201. LOUISIANA Tulane University School of Medicine / Div of Ped Infect Dis 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 941005 ACTU: 7201. MASSACHUSETTS Massachusetts General Hospital / Harvard 55 Fruit Street Gray 5 Boston, MA 02114 Contact: Ellen Godfrey (617) 726-5598 OPEN 941020 ACTU: 0101. MASSACHUSETTS Beth Israel Hospital 330 Brookline Avenue Boston, MA 02115 Contact: Sheila Hussey (617) 735-4103 OPEN 940913 ACTU: 0102. MASSACHUSETTS Boston City Hospital / AIDS Research Office 818 Harrison Avenue ACC 5th Floor Room 5D11 Boston, MA 02118 Contact: Beverly Byam (617) 534-5160 OPEN 941020 ACTU: 0104. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 941011 ACTU: 0201. MARYLAND State of Maryland Div of Corrections c/o Johns Hopkins Hosp 1830 East Monument Street / Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 941116 ACTU: 0202. MINNESOTA University of Minnesota Hospital and Clinic PO Box 437 / UMHC / Harvard Street & East River Road Minneapolis, MN 55455 Contact: Nancy Reed (612) 625-1462 OPEN 941012 ACTU: 1501. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 941031 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 941031 ACTU: 2102. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 941027 ACTU: 1802. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 941024 ACTU: 0401. NEW YORK Memorial Hospital / Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021 Contact: Gloria Gilbert (212) 639-7169 OPEN 941201 ACTU: 2202. NEW YORK Cornell University Medical Center 525 East 68th Street / Room 2434 New York, NY 10021 Contact: Brenda Greenhill (212) 746-4177 OPEN 941024 ACTU: 2201. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 941017 ACTU: 1801. NEW YORK Harlem Hospital Center 506 Lenox Avenue / Room 3101A New York, NY 10037 Contact: Robin Flam (212) 939-3948 OPEN 941110 ACTU: 7502. NEW YORK North Central Bronx Hospital / Montefiore Family Health Cntr 418 Forchheimer-ID/1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 941205 ACTU: 1906. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 941114 ACTU: 1902. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 941205 ACTU: 1903. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forcheimer - ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 Contact: FAX (718) 597-5814 OPEN 941205 ACTU: 1909. NEW YORK Albert Einstein College of Medicine 418 Forcheimer / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 941205 ACTU: 1904. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 941114 ACTU: 1901. NEW YORK SUNY Health Sciences Center at Brooklyn ACTU Box 77 / 450 Clarkson Avenue Brooklyn, NY 11203-2098 Contact: Donald Smith (718) 270-3372 Contact: (718) 270-3370 OPEN 941003 ACTU: 5901. NEW YORK Adirondack Medical Center at Saranac Lake 47 New Scotland Avenue Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 941005 ACTU: 7403. NEW YORK Mid-Hudson Care Center / Albany Med College / Div Med Oncol 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 941005 ACTU: 7402. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 941005 ACTU: 7401. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 940921 ACTU: 1103. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 941017 ACTU: 1102. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 941017 ACTU: 1101. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 941003 ACTU: 2301. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 941003 ACTU: 2501. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 941017 ACTU: 2401. OTHER University of Puerto Rico / Schl of Med / Inf Dis Sec / ACTU G P O Box 365067 San Juan, PR 00936-5067 Contact: Maritza Cruz-Ortiz (809) 767-9192 Contact: (809) 767-9193 OPEN 941014 ACTU: 5401. PENNSYLVANIA Thomas Jefferson Unversity 1015 Chestnut Street Philadelphia, PA 19107 Contact: Lyle Jew (215) 955-7785 OPEN 941103 ACTU: 6202. 20 UNIQUE IDENTIFIER NIH/00662 PROTOCOL ID NUMBERS NIAID ACTG 260 PROTOCOL TITLE Randomized, Phase I/II, Dose-Ranging, Open-Label Trial of the Anti-HIV Activity of Delavirdine Mesylate (DLV; U-90152S). VERSION NUMBER & DATE 1 (940908) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: PRIMARY: To study the safety and tolerance of delavirdine mesylate (U-90152) monotherapy. To compare the anti-HIV activity of three blood concentration levels of this agent with nucleoside analog monotherapy, either zidovudince (AZT) or didanosine (ddI), based on the reduction of HIV viral burden. SECONDARY: To use pharmacokinetic parameters to assess the relationship between daily drug exposure and antiviral activity and toxicity of the U-90152, AZT, and ddI monotherapy. To assess anti-HIV activity using other disease markers. GENERAL DESCRIPTION RATIONALE: Data suggest that bisheteroarylpiperazines (BHAPs) such as delavirdine mesylate are potent and safe anti-HIV agents and may have different biological behavior than other currently available nonnucleoside RT inhibitors. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive U-90152 at one of three doses (treatment arms I through III) or either AZT or ddI (treatment arm IV). Patients on arm IV who are AZT-naive receive AZT; those who are AZT-experienced receive ddI. Treatment continues for 24 weeks. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV-1 infection by ELISA confirmed by Western blot, HIV antigen, HIV culture, or a second antibody test by a method other than ELISA. 2. CD4 count 200 - 500 cells/mm3 within 45 days prior to study entry. 3. Either no prior antiretroviral therapy or discontinued AZT monotherapy 3 or more weeks prior to study entry. NOTE: Half of patients should be antiretroviral naive. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND 45,914 STUDY DESIGN Randomized; Multicenter; Open Label; 4-Arm; Drug Tolerance; Dose Ranging; Pharmacokinetic; Comparative PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Drug efficacy, Pharmacokinetics, Comparative toxicity, Comparative drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 120 patients. (30 patients on each of four treatment arms) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 24 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 36/120 (941207). PROTOCOL DETAILS STUDY DURATION: 24 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 9 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV-1 infection. 2. CD4 count 200 - 500 cells/mm3. 3. Either no prior antiretroviral therapy or discontinued AZT monotherapy 3 or more weeks prior to study entry. NOTE: Half of patients should be antiretroviral naive. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.2 g/dl. (men); >= 8.9 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 500 cells/mm3. ( 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 3.0 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 3.0 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 75 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 80. PATIENT INCLUSION CRIT. OTHER: Neutrophils >= 1000 cells/mm3. Serum amylase <= 1.5 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior AZT. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. PCP prophylaxis. 2. Topical antifungal agents, clotrimazole troches, nystatin oral suspension, topical ketoconazole, and oral fluconazole. 3. Acyclovir (<= 1000 mg/day) as maintenance therapy for herpes simplex virus. 4. Recombinant erythropoietin and G-CSF. 5. Antibiotics for bacterial infections, unless specifically excluded. 6. Symptomatic treatment such as antipyretics, analgesics, nonsteroidal anti-inflammatory agents, and antiemetics. 7. Antacids. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of pancreatitis (in patients who received prior AZT). 2. History of grade 2 or worse peripheral neuropathy (in patients who received prior AZT). 3. History of hypersensitivity to BHAP compounds (e.g., trifluoperazine - Stelazine, piperazine citrate - Antepar). [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse interfering with compliance. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 30 days prior to study entry: 1. Any investigational medication. 2. Interferon. 3. Interleukin. 4. Rifabutin. 5. Rifampin. 6. Terfenadine. 7. Astemizole. 8. Loratadine. 9. Trifluoperazine. 10. Piperazine citrate. Excluded at any time: 1. Prior ddI, ddC, d4T, or 3TC. 2. Prior foscarnet. 3. Prior BHAP compound or other nonnucleoside RT inhibitor. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Rifabutin. 2. Rifampin. 3. Terfenadine. 4. Astemizole. 5. Loratadine. 6. Trifluoperazine. 7. Piperazine citrate. 8. Any acute or chronic therapy for CMV, MAC, toxoplasmosis, or disseminated fungal infection. 9. Non-study antiretroviral therapies, interferons, biologic response modifiers, and HIV vaccines. 10. Systemic corticosteroids for more than 21 consecutive days. 11. Foscarnet. 12. Systemic cytotoxic chemotherapy for a malignancy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Malignancy other than minimal Kaposi's sarcoma. SUBSTANCE IDENTIFICATION Drug 1 DRG-0166 U-90152 SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0016 Didanosine TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir TRADE NAME OF SUBSTANCE Drug 3‰ Videx MANUFACTURERS Drug 1: The Upjohn Company 7000 Portage Road Kalamazoo, MI 49001 Contact: James VanSweden (616) 323-4696. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 3: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Colin McLaren (203) 284-6942. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200, 300, or 400 mg TID as starting dose, with target trough levels of 3-10, 11-30, or 31-50 micromolars, respectivelDrug 2: 200 mg TID for 24 weeks. Drug 3: 200 mg BID (125 mg BID if < 60 kg body weight) for 24 SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 600, 900, or 1200 mg. Drug 2: 600 mg. Drug 3: 400 mg (250 mg if < 60 kg body weight) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 50 and 100 mg tablets. Drug 2: Oral, 100 mg capsules. Drug 3: Oral; 25, 50, and 100 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 24 weeks. OTHER TREATMENT INFO. END POINT: Toxicity, efficacy. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Indication for systemic cytotoxic therapy for a newly diagnosed malignancy or progressive Kaposi's sarcoma. 2. Further participation deemed detrimental to patient's health or well-being. 3. Development of intercurrent illness such as a major opportunistic infection or new AIDS-defining illness (other than Kaposi's sarcoma) or generalized debilitation or mental incapacity that would preclude informed consent. 4. Pregnancy. 5. Patient non-compliance or desire of patient to withdraw from study. OTHER TREATMENT INFO. MODIFICATION: Dose is held or reduced for specific toxicities. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Didanosine/*ADVERSE EFFECTS/PHARMACOKINETICS/ THERAPEUTIC USE MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zidovudine/*ADVERSE EFFECTS/PHARMACOKINETICS/ THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 941207 ENTRY MONTH 9410 CALIFORNIA Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Contact: Virginia Tallman (415) 723-2804 Contact: Dr Rami Ramachandran (415) 723-6231 OPEN 941017 ACTU: 0501. COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 941013 ACTU: 6101. COLORADO Kaiser Permanente Franklin Med Cntr / Univ Col Hlth Sci Cntr 4200 East Ninth Avenue / Colorado ACTU / Campus Box B-163 Denver, CO 80262 Contact: Graham Ray (303) 270-8551 Contact: FAX (303) 270-6102 OPEN 941013 ACTU: 6103. COLORADO Rose Med Ctr / Univ of Colorado Hlth Sci Ctr / Colorado ACTU Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 941031 ACTU: 6104. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 941021 ACTU: 0901. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941123 ACTU: 2701. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 941115 ACTU: 1103. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 941031 ACTU: 1101. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 941013 ACTU: 2301. 21 UNIQUE IDENTIFIER NIH/00579 PROTOCOL ID NUMBERS NIAID ACTG 259 PROTOCOL TITLE A Phase II Double-Blind Study of Two Doses of SC-49483 in Combination With Zidovudine (AZT) Versus AZT. VERSION NUMBER & DATE 2 (940719) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Fischl MA PROTOCOL CHAIRS CO-CHAIR Saag M GENERAL DESCRIPTION PURPOSE: To determine the safety and anti-HIV activity of two doses of SC-49483 in combination with zidovudine (AZT) versus AZT alone. To determine the influences of viral phenotype on the anti-HIV activity of these treatment regimens. GENERAL DESCRIPTION RATIONALE: SC-49483 has no inherent activity against HIV-1 but is converted in the intestinal wall to SC-48334, which has demonstrated anti-HIV activity. Since SC-49483 causes significantly less gastrointestinal toxicity than SC-48334, the combination of SC-49483 with AZT may improve the benefits of both drugs in patients with HIV infection. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive AZT alone or in combination with one of two doses of SC-49483, administered three times daily. Treatment continues for 16 to 24 weeks. Per 07/19/94 amendment: At the end of 24 weeks, blinded treatment continues for an additional 4 weeks, at which time patients may receive open-label drug on an optional basis for 90 days. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by ELISA confirmed by Western blot, HIV antigen, HIV culture, or a second antibody test by a method other than ELISA. 2. Per 07/19/94 amendment, one of the following: - CD4 count 150 - 350 cells/mm3 within 60 days prior to study entry AND prior AZT for no more than 12 months cumulative (given with or without ddI or ddC). - CD4 count 50 - 350 cells/mm3 within 60 days prior to study entry AND no prior antiretroviral therapy. 3. MT-2 cell assay (to determine synctial vs. nonsynctial viral phenotype) within 60 days prior to study entry. NOTE: Minimal Kaposi's sarcoma is permitted. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND 44,154 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; 3-Arm; Dose Comparison; Drug Tolerance; Multicenter PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Combination and single drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 210 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 16 - 24 weeks. Per amendment, possibly extended for 118 days after the 24th week. PROTOCOL DETAILS ACTUAL ACCRUAL: 164/210 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 37 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. Per 07/19/94 amendment, one of the following: - CD4 count 150 - 350 cells/mm3 within 60 days prior to study entry AND prior AZT for no more than 12 months cumulative (given with or without ddI or ddC). - CD4 count 50 - 350 cells/mm3 within 60 days prior to study entry AND no prior antiretroviral therapy. 3. MT-2 cell assay within 60 days prior to study entry. NOTE: Minimal Kaposi's sarcoma is permitted. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.2 g/dl. (men); >= 8.9 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 50 - 350 cells/mm3. (if no prior antiretroviral therapy). OR 150 - 350 cells/mm3 (if prior antiretroviral therapy). ( 100 - 200 - 300 ). PATIENT INCLUSION CRIT. SGOT(AST): <= 3.0 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 3.0 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 50 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 80. PATIENT INCLUSION CRIT. OTHER: Neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control /contraception during the study and for 60 days after. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Localized radiation therapy and limited intralesional therapy for cutaneous Kaposi's sarcoma. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: PCP prophylaxis (trimethoprim/sulfamethoxazole, dapsone, or aerosolized pentamidine) in patients with CD4 count <= 200 cells/mm3. Allowed: 1. Topical antifungal agents, ketoconazole, fluconazole, and itraconazole for candidiasis or disseminated fungal infections, as medically indicated. 2. Maintenance therapy for Mycobacteria disease with isoniazid, ethambutol, rifampin, pyrazinamide, clofazimine, ciprofloxacin, clarithromycin, or rifabutin. 3. Maintenance therapy for toxoplasmosis with pyrimethamine, sulfadiazine, or clindamycin. 4. Maintenance therapy for herpes simplex virus with acyclovir at <= 1000 mg/day. 5. Recombinant erythropoietin and G-CSF, if indicated. 6. Antibiotics for bacterial infections. 7. Symptomatic treatment such as antipyretics, analgesics, nonsteroidal anti-inflammatory agents, and antiemetics. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of cataracts. 2. History of intolerance to AZT at <= 600 mg/day. 3. Unexplained temperature >= 38.5 degrees C that persists for any 7 days within the 30 days prior to study entry. 4. Chronic diarrhea (defined as >= 3 stools per day) that persists for any 15 days within the 30 days prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 60 days after. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. More than 6 months (more than 12 months per 07/19/94 amendment) cumulative prior therapy with AZT. 2. Prior induction or maintenance therapy with foscarnet. 3. Any investigational drug within 30 days prior to study entry. 4. Prior SC-49483 or SC-48334. 5. Prior ddC, ddI, or stavudine (d4T) as monotherapy. 6. Interferon or interleukin within 30 days prior to study entry. 7. Prior nonnucleoside reverse transcriptase inhibitors (e.g., NVP, ATV). 8. Systemic corticosteroids for > 21 consecutive days. 9. Acute treatment for a serious infection or any opportunistic infection within 14 days prior to study entry. 10. Prior combination therapy with AZT, ddI, and/or ddC within 30 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antiretroviral therapies (other than study drug). 2. Biologic response modifiers. 3. Systemic corticosteroids for > 21 consecutive days. 4. Foscarnet. 5. Systemic cytotoxic chemotherapy for a malignancy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following condition are excluded: Malignancy other than minimal Kaposi's sarcoma. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0193 SC-49483 TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle Park, NC 27709 Contact: Mary Maha Elkins (919) 248-3294. MANUFACTURERS Drug 2: G D Searle & Company 4901 Searle Parkway Skokie, IL 60077 Contact: Susan Smith (708) 982-8975. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg TID for 16-24 weeks. Drug 2: 3 or 5 g (or placebo) TID, with food, for 16-24 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 600 mg. Drug 2: 9 or 15 g SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg capsules. Drug 2: Oral, 1 g capsules OTHER TREATMENT INFO. TREATMENT DURATION: 16 to 24 weeks. Per amendment, possibly extended for 118 days beyond week 24. OTHER TREATMENT INFO. END POINT: Quantitative PBMC HIV-1 microculture titer, changes in plasma HIV RNA by PCR, change in CD4 count, toxicity. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Dose-limiting toxicity. 2. Development of malignancy or progressive Kaposi's sarcoma that requires systemic therapy or radiation therapy. 3. Pregnancy. 4. Decision of the patient to withdraw from study. OTHER TREATMENT INFO. MODIFICATION: Dose is held or reduced for grade 3 or worse toxicities related to study drug. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Burroughs Wellcome, G D Searle & Company. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zidovudine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 941207 ENTRY MONTH 9402 ALABAMA University of Alabama at Birmingham 933 19th Street S/1917 Research Clinic Room 219 Birmingham, AL 35294-2041 Contact: Robin Noles (205) 934-7349 OPEN 940228. CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 940311 ACTU: 1201. CALIFORNIA San Francisco General Hospital / UCSF 995 Potrero Avenue / Building 80 Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940228 ACTU: 0801. CALIFORNIA General Hospital / AIDS Clinical Trials Unit 995 Potrero Avenue / Bldg 80 / Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 846OPEN 940610 ACTU: 0808. CALIFORNIA UCSF / AIDS Clinic Ambulatory Care Center 995 Potrero Avenue San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940311 ACTU: 0802. CALIFORNIA Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Contact: Virginia Tallman (415) 723-2804 Contact: Dr Rami Ramachandran (415) 723-6231 OPEN 941123 ACTU: 0501. CALIFORNIA Merrit-Peralta Medical Ctr/Adult Immunology Clinic U of CA 450 30th Street Oakland, CA 94609 Contact: Bruce Ross (510) 273-8200 Contact: David Greenberg OPEN 940228 ACTU: 0804. COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 941115 ACTU: 6101. CONNECTICUT Yale University School of Medicine / Sect of Infectious Dis 135 College Street New Haven, CT 06510-2483 Contact: Laurie Andrews (203) 737-4040 OPEN 940413 ACTU: 6401. DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 940330 ACTU: 5701. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 940207 ACTU: 0901. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 940207 ACTU: 2701. ILLINOIS Louis A Weiss Memorial Hospital / Northwestern Univ Med Schl 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941017 ACTU: 2708. ILLINOIS Illinois Masonic Med Ctr / Northwestern Univ Med Schl Passavant Pavilion Room 823 / 303 East Superior Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 941024 ACTU: 2707. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940228 ACTU: 2702. ILLINOIS Cook County Hospital Passavant Pavilion / Room 823 / 303 East Superior Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940422 ACTU: 2705. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940214 ACTU: 2601. INDIANA Methodist Hospital Of Indiana 550 North University Boulevard Room 5550 Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940228 ACTU: 2602. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 940208 ACTU: 2101. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 940503 ACTU: 3201. NORTH CAROLINA Wake County Department of Health Hosp South Room 0207 Box 3284 Durham, NC 27710 Contact: Kelley Rayle (919) 250-1035 OPEN 940502 ACTU: 3206. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 940228 ACTU: 1802. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940224 ACTU: 1801. NEW YORK Columbia Presbyterian Medical Center 622 West 168 Street / Harkness Pavilion 5 Room 516 New York, NY 10032-3784 Contact: Mykyelle Wade (212) 305-8507 OPEN 940311 ACTU: 7501. NEW YORK Harlem Hospital Center 506 Lenox Avenue / Room 3101A New York, NY 10037 Contact: Robin Flam (212) 939-3948 OPEN 940422 ACTU: 7502. NEW YORK Montefiore Drug Treatment Center 418 Forchheimer-ID / 1300 Morris Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3639 Contact: (718) 920-5344 OPEN 940207 ACTU: 1905. NEW YORK North Central Bronx Hospital / Montefiore Family Health Cntr 418 Forchheimer-ID/1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940207 ACTU: 1906. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 940210 ACTU: 1902. NEW YORK Comprehensive Health Care Center 418 Forchheimer-ID / 1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940210 ACTU: 1908. NEW YORK Albert Einstein College of Medicine 418 Forcheimer / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940210 ACTU: 1904. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940210 ACTU: 1901. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940210 ACTU: 1903. NEW YORK North Central Bronx Hospital / Samaritan Village Inc 418 Forchheimer ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940207 ACTU: 1907. NEW YORK City Hospital at Elmhurst / Mt Sinai 79-01 Broadway Room D1-29 Elmhurst, NY 11373 Contact: Dinah Reitman (718) 334-3963 OPEN 940323 ACTU: 1803. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 941110 ACTU: 1102. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 940311 ACTU: 2401. 22 UNIQUE IDENTIFIER NIH/00634 PROTOCOL ID NUMBERS NIAID ACTG 252 PROTOCOL TITLE Phase II Trial of Sequential Chemotherapy and Radiotherapy for AIDS-Related Primary Central Nervous System Lymphoma. VERSION NUMBER & DATE (940517) TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Krigel RL PROTOCOL CHAIRS CO-CHAIR Von Roenn J GENERAL DESCRIPTION PURPOSE: To estimate the response rate, overall and disease-free survival, toxicities, factors associated with outcome, and effect on quality of life in patients with AIDS-related primary CNS lymphoma treated with CHOD (cyclophosphamide, doxorubicin, vincristine, and dexamethasone) plus granulocyte-colony stimulating factor (G-CSF) and external beam irradiation. To determine other clinical markers present in this patient population. GENERAL DESCRIPTION RATIONALE: Combined modality therapy may prove of benefit for patients with AIDS-related primary CNS lymphoma. GENERAL DESCRIPTION METHODOLOGY: Patients who upon staging workup are found to be without systemic involvement undergo one cycle of chemotherapy with cyclophosphamide, doxorubicin, vincristine, dexamethasone, and G-CSF. Cyclophosphamide, doxorubicin, and vincristine are administered intravenously on day 1. Dexamethasone is administered intravenously on day 1 and then orally thereafter with gradual discontinuation. G-CSF is administered subcutaneously daily beginning on day 2 and continuing for a total of 10 days or until blood counts have recovered to an acceptable level. Patients with evidence of cancer cells in their cerebrospinal fluid (CSF) will receive chemotherapy with intrathecal cytarabine twice weekly until no further evidence of cancer cells is found in the CSF, then once weekly for 6 weeks, and then monthly for 10 months. Seven to ten days following completion of one cycle of chemotherapy, patients undergo radiotherapy to the brain at a dose of 2.5 Gy daily for 5 days per week for approximately 4 weeks. Total dose to the whole brain and meninges is 30.0 Gy in 12 fractions, and total dose to the primary boost volume is 10.0 Gy in 4 fractions. During therapy, blood is drawn weekly and brain scans are performed every 3-12 weeks. An initial CSF sample will be obtained by lumbar puncture. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Pending first patient enrolled (941207) DISEASE STUDIED Lymphoma, primary CNS. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive confirmed by Western blot. 2. Biopsy proven primary CNS non-Hodgkin's lymphoma, intermediate or high grade histology involving the parenchyma of the brain. 3. No prior cranial radiotherapy or chemotherapy unless given for Kaposi's sarcoma (cranial radiotherapy to other sites is acceptable). 4. Intracranial space-occupying lesion as documented by preoperative CT-head or MRI. 5. No prior history of lymphoma. 6. No clinical evidence of systemic (extracranial) lymphoma (documented by abdominal and chest CT scan and bilateral bone marrow biopsy. 7. No more than 3 weeks post-surgery. NOTE: Patients entering treatment must undergo a lumbar puncture with evaluation of CSF, unless contraindicated. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS ECOG E 1493 STUDY DESIGN Drug Combination; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug tolerance, Combination drug therapy, Combination modality therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 60 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 10 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 3 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Primary CNS lymphoma with NO systemic involvement. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 3.0 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 3.0 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: 0 - 3 (ECOG). PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 16 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior corticosteroids. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: 1. PCP prophylaxis with Bactrim, dapsone, or aerosolized pentamidine. 2. Oral candidiasis prophylaxis with fluconazole, ketoconazole, or clotrimazole oral troches. 3. Antiretroviral agent available by therapy IND. 4. MAI prophylaxis with rifabutin (in patients with CD4 counts < 100 cells/mm3). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. No prior malignancy other than Kaposi's sarcoma, curatively treated carcinoma in situ of the cervix, or squamous cell or basal cell carcinoma of the skin. 2. No new infectious complications within the past 2 weeks that require a change in antibiotics. 3. History of myocardial infarction within the past 3 months. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 15 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Prior chemotherapy other than for Kaposi's sarcoma. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Any investigational agent other than antiretroviral agents available by therapy IND. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Concomitant malignancy other than Kaposi's sarcoma, curatively treated carcinoma in situ of the cervix, or squamous or basal cell carcinoma of the skin. 2. Active uncontrolled infection. 3. Renal failure, active nonmalignant duodenal ulcer, uncontrolled diabetes mellitus, or other serious medical conditions that would preclude aggressive cytotoxic chemotherapy administration. 4. Active heart disease (congestive heart failure or heart block greater than first degree on EKG). SUBSTANCE IDENTIFICATION Drug 1 DRG-0048 Cyclophosphamide SUBSTANCE IDENTIFICATION Drug 2 DRG-0047 Doxorubicin SUBSTANCE IDENTIFICATION Drug 3 DRG-0046 Vincristine SUBSTANCE IDENTIFICATION Drug 4 DRG-0013 Dexamethasone SUBSTANCE IDENTIFICATION Drug 5 DRG-0086 Granulocyte colony-stimulating factor SUBSTANCE IDENTIFICATION Drug 6 DRG-0038 Cytarabine MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. MANUFACTURERS Drug 4: Merck and Company Incorporated Professional Services West Point, PA 19486 Contact: Professional Information (215) 661-7300 Contact: Prof Info / Call Collect (215) 652-3298. MANUFACTURERS Drug 5: Amgen Incorporated 1840 DeHavilland Drive Thousand Oaks, CA 91320-1789 Contact: Mark Davis (805) 499-5725 X 4142. MANUFACTURERS Drug 6: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 750 mg/m2 on day 1. Drug 2: 50 mg/m2 on day 1. Drug 3: 1.4 mg/m2 (maximum 2.0 mg) on day 1. Drug 4: 16 mg IV on day 1, then 16 mg PO or IV daily, with tapeas tolerated. (Dexamethasone is physically incompatible with doxorubicin.). Drug 5: 5 mcg/kg daily beginning on day 2 for a minimum of 10 dand until granulocytes are > 500 cells/mm3 for 2 days. Drug 6: 50 mg via lumbar puncture or Ommaya reservoir, administtwice daily until CSF is negative, then weekly for 6 weeks, themonthly for 10 months (administered only in patients with positCSF cytology) SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 4: 16 mg. Drug 5: 5 mcg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV). Drug 2: Intravenous (IV). Drug 3: Intravenous (IV). Drug 4: Intravenous (IV) and Oral. Drug 5: Subcutaneous. Drug 6: Intrathecal OTHER TREATMENT INFO. END POINT: Response rate, survival, toxicity. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Disease progression. OTHER TREATMENT INFO. MODIFICATION: For bilirubin 2.0 - 3.0 mg/dl: Reduce vincristine and doxorubicin doses by 50 percent. For unacceptable corticosteroid toxicity: Modify or discontinue dexamethasone dose at the discretion of the investigator. For grade 3 major organ toxicity: Reduce G-CSF dose by 50 percent. If grade 3 toxicity persists for 7 days or advances to grade 4 toxicity, discontinue G-CSF permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antineoplastic Agents, Combined/*THERAPEUTIC USE MESH HEADING Brain Neoplasms/*DRUG THERAPY/RADIOTHERAPY MESH HEADING Combined Modality Therapy MESH HEADING Cyclophosphamide/THERAPEUTIC USE MESH HEADING Cytarabine/THERAPEUTIC USE MESH HEADING Dexamethasone/THERAPEUTIC USE MESH HEADING Doxorubicin/THERAPEUTIC USE MESH HEADING Female MESH HEADING Granulocyte Colony-Stimulating Factor/ THERAPEUTIC USE MESH HEADING Human MESH HEADING Lymphoma, High-Grade/*DRUG THERAPY/ RADIOTHERAPY MESH HEADING Lymphoma, Intermediate-Grade/*DRUG THERAPY/ RADIOTHERAPY MESH HEADING Male MESH HEADING Middle Age MESH HEADING Vincristine/THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antineoplastic Agents, Combined) CAS REGISTRY NUMBER 147-94-4 (Cytarabine) CAS REGISTRY NUMBER 23214-92-8 (Doxorubicin) CAS REGISTRY NUMBER 50-02-2 (Dexamethasone) CAS REGISTRY NUMBER 50-18-0 (Cyclophosphamide) CAS REGISTRY NUMBER 57-22-7 (Vincristine) CAS REGISTRY NUMBER 62683-29-8 (Granulocyte Colony-Stimulating Factor) LAST REVISION DATE 941207 ENTRY MONTH 9406 COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 940927 ACTU: 6101. MASSACHUSETTS ECOG Data Management Office 303 Boylston Street Brookline, MA 02146 Contact: Unspecified (PHYSICIANS ONLY) (617) 632-3610 OPEN / USA accrual 940602. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 940912 ACTU: 2101. 23 UNIQUE IDENTIFIER NIH/00572 PROTOCOL ID NUMBERS NIAID ACTG 251 PROTOCOL TITLE Thalidomide for Treatment of Oral and Esophageal Aphthous Ulcers and HIV Viremia in Patients With HIV Infection. VERSION NUMBER & DATE 4 (940829) PROTOCOL CHAIRS CHAIR Jacobson JM GENERAL DESCRIPTION PURPOSE: PRIMARY: To evaluate the effectiveness and safety of thalidomide for treatment of oral and esophageal aphthous ulcers (those unrelated to a known infection or malignancy) in patients with advanced HIV disease. To evaluate the effect of thalidomide on HIV load in this patient population. Per 06/28/94 amendment, to evaluate the effectiveness of thalidomide in preventing recurrences in patients whose aphthae completely heal at the end of acute treatment. SECONDARY: To evaluate the effect of thalidomide on blood tumor necrosis factor (TNF) levels and to obtain pharmacokinetic data on the drug. Per 06/28/94 amendment, to evaluate the safety of thalidomide. GENERAL DESCRIPTION RATIONALE: Aphthous ulcers of the mouth or esophagus can interfere with eating, resulting in malnutrition and wasting. Thalidomide has been proposed as an effective therapy for severe forms of aphthous ulceration in AIDS patients. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive 4 weeks of either 200 mg thalidomide or placebo orally, administered once daily. Patients are followed weekly. Complete responders after 4 weeks of acute treatment enter a 24-week maintenance phase. A pharmacokinetic substudy will be included. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Aphthous ulcers of mouth or esophagus. DISEASES STATUS Patients have the following symptoms and conditions (Per amendment, patients initially enter an acute treatment phase; those who achieve complete response of aphthous healing enter a maintenance phase): ACUTE TREATMENT PHASE: 1. HIV infection documented by HIV antibody, HIV p24 antigen, or isolation of HIV in culture OR AIDS as defined by an AIDS-defining opportunistic infection confirmed by histology or culture. 2. Biopsy-confirmed aphthous ulceration of the mouth or esophagus lasting at least 2 weeks. Biopsy should be performed within 8 weeks prior to study entry and indicate no evidence of a recognizable viral or fungal infection. 3. Negative culture of ulcer for Herpes simplex within 8 weeks prior to study entry. 4. En face diameter of >= 5 mm for largest aphthous ulcer. MAINTENANCE PHASE: Complete response of oral and/or esophageal aphthae. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS IND 43,791 STUDY DESIGN Multicenter; Double-Blind; Randomized; Placebo-Controlled; 2-Arm; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 164 patients. (80 patients per treatment arm) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Minimum of 4 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 20/164 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 30 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection or AIDS. 2. Biopsy-confirmed aphthous ulceration of the mouth or esophagus lasting at least 2 weeks. 3. Negative culture of ulcer for Herpes simplex. 4. En face diameter of >= 5 mm for largest aphthous ulcer. 5. Life expectancy of at least 3 months. NOTE: This study is approved for prisoner participation. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 8 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 2.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase < 5 x ULN. Absolute neutrophils > 500 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 3 days prior to study entry. Abstinence or effective method of birth control / contraception during the study and for 30 days after. Breast-feeding. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Anti-HIV therapy provided therapy has remained constant in the 4 weeks prior to study entry. 2. Narcotic analgesia after the first week of treatment ONLY IF the patient is not experiencing somnolence. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of grade 2 or worse bilateral peripheral neuropathy. 2. Change in anti-HIV therapy within 4 weeks prior to study entry. 3. Prior enrollment in ACTG 251 or prior treatment of aphthous ulcers with thalidomide. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 3 days prior to study entry. No abstinence or no agreement to use effective method of birth control during study and for 30 days after. Not breast-feeding. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation to head and/or neck. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Systemic and/or oral topical corticosteroids within 2 weeks prior to study entry. 2. Other putative immunomodulators within 2 weeks prior to study entry. 3. Prior thalidomide for aphthous ulcers. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Acute therapy for opportunistic infection. 2. ddC. 3. Pentoxifylline. 4. Methotrexate, trimetrexate, alkylating agents. 5. Other putative immunomodulators. 6. CNS depressants and/or medications with sedative or hypnotic effect. 7. Systemic and/or oral topical corticosteroids. 8. Systemic chemotherapy for Kaposi's sarcoma or other malignancies. 9. Compounded antibacterial mouthwashes containing anti-infective agents (such as doxycycline, minocycline, tetracycline, or nystatin). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known allergy to thalidomide. 2. Grade 2 or worse bilateral peripheral neuropathy. EXCLUDED FOR MAINTENANCE PHASE: Toxicity other than somnolence in acute phase that required discontinuation of drug. SUBSTANCE IDENTIFICATION Drug 1 DRG-0184 Thalidomide MANUFACTURERS Drug 1: Andrulis Pharmaceuticals Corporation 11800 Baltimore Avenue Beltsville, MD 20705 Contact: Dr Peter Andrulis (301) 419-2400. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Acute treatment phase: 200 mg (or placebo) daily at bedtime for 4 weeks. Maintenance phase: 100 mg (or placebo) thrice weekly for 24 we SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: Acute treatment phase: 200 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg capsules OTHER TREATMENT INFO. TREATMENT DURATION: 4 weeks. OTHER TREATMENT INFO. END POINT: Acute phase: Resolution of aphthous ulcers, p24 antigen levels, toxicity, pharmacokinetic profile. Maintenance phase: Recurrence of aphthous ulcers. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Dose-limiting toxicity. 2. Pregnancy or unwillingness to practice contraception. 3. Patient noncompliance or desire to withdraw from study. OTHER TREATMENT INFO. MODIFICATION: For somnolence persisting at least 72 hours: Reduce daily dose by 50 percent. If somnolence persists for another 72 hours, then administer 50 percent dose every other day. If somnolence persists despite second dose reduction, then discontiue drug permanently. For grade 2 or worse peripheral neuropathy: Hold study drug until toxicity resolves to grade 1 or better. If toxicity resolves within 28 days, then resume drug at 50 percent of daily dose. If toxicity persists after 28 days of holding drug and ulcer has not completely healed, or if toxicity recurs on the reduced dose, then discontinue drug permanently. For other grade 3 toxicities: Hold study drug until toxicity resolves to grade 2 or better, then resume at full dose. If grade 3 toxicity recurs, hold study drug until toxicity resolves to grade 2 or better, then resume at 50 percent of daily dose. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Andrulis Pharmaceuticals Corporation. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Stomatitis, Aphthous/COMPLICATIONS/*DRUG THERAPY MESH HEADING Thalidomide/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE CAS REGISTRY NUMBER 50-35-1 (Thalidomide) LAST REVISION DATE 941207 ENTRY MONTH 9403 CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 940606 ACTU: 1201. CALIFORNIA Harbor General / REI Lab / UCLA 1124 West Carson Street Torrance, CA 90502 Contact: Sally Kruger (310) 222-3848 Contact: Rick Johnson OPEN 940308 ACTU: 0603. CALIFORNIA UCSF / AIDS Clinic Ambulatory Care Center 995 Potrero Avenue San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940308 ACTU: 0802. CALIFORNIA Kaiser Permanente Medical Group / Stanford University 2590 Geary Boulevard San Francisco, CA 94115 Contact: Gretchen Van Raalte (415) 202-3482 OPEN 941116 ACTU: 0502. COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 940308 ACTU: 6101. HAWAII Hawaii Aids Clinical Trails Unit Leahi Hospital / Young Bldg / 3675 Kilauea Avenue / 6th Flr Honolulu, HI 96816 Contact: Debra M Ogata Arakaki (808) 737-2751 OPEN 940902 ACTU: 5201. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 940303 ACTU: 2701. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940317 ACTU: 2702. ILLINOIS Illinois Masonic Med Ctr / Northwestern Univ Med Schl Passavant Pavilion Room 823 / 303 East Superior Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 941101 ACTU: 2707. ILLINOIS Louis A Weiss Memorial Hospital / Northwestern Univ Med Schl 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941205 ACTU: 2708. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940711 ACTU: 2601. MASSACHUSETTS Massachusetts General Hospital / Harvard 55 Fruit Street Gray 5 Boston, MA 02114 Contact: Ellen Godfrey (617) 726-5598 OPEN 941024 ACTU: 0101. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 941017 ACTU: 3201. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 940616 ACTU: 1802. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 940317 ACTU: 0401. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940308 ACTU: 1801. NEW YORK Mount Sinai School of Medicine / Pediatrics One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940308 ACTU: 4301. NEW YORK Montefiore Drug Treatment Center 418 Forchheimer-ID / 1300 Morris Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3639 Contact: (718) 920-5344 OPEN 940323 ACTU: 1905. NEW YORK North Central Bronx Hospital / Montefiore Family Health Cntr 418 Forchheimer-ID/1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940323 ACTU: 1906. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940323 ACTU: 1903. NEW YORK Albert Einstein College of Medicine 418 Forcheimer / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940323 ACTU: 1904. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940303 ACTU: 1901. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 940303 ACTU: 1902. NEW YORK Bronx Veterans Administration Medical Center 130 West Kingsbridge Road Bronx, NY 10468 Contact: Nancy Ostrow (718) 584-9000 X 667Contact: (718) 584-9000 X 667OPEN 940308 ACTU: 1804. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 941024 ACTU: 1103. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 940609 ACTU: 1102. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 940308 ACTU: 2501. OTHER University of Puerto Rico / Schl of Med / Inf Dis Sec / ACTU G P O Box 365067 San Juan, PR 00936-5067 Contact: Maritza Cruz-Ortiz (809) 767-9192 Contact: (809) 767-9193 OPEN 940504 ACTU: 5401. 24 UNIQUE IDENTIFIER NIH/00658 PROTOCOL ID NUMBERS NIAID ACTG 250 PROTOCOL TITLE A Phase I Study of Safety and Pharmacokinetics of Nevirapine in HIV-1 Infected Pregnant Women and Neonates Born to HIV-1 Infected Mothers. VERSION NUMBER & DATE 1 (940902) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child TRIAL CATEGORY Pregnancy TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Sullivan JL PROTOCOL CHAIRS CO-CHAIR Sperling R GENERAL DESCRIPTION PURPOSE: To determine the bioavailability, pharmacokinetics, and short-term safety and tolerance of nevirapine in HIV-1 infected pregnant women and their newborns when nevirapine is given to the mother during active labor, and when their neonates are dosed during the first week of life. To determine the short-term safety profile of mothers receiving zidovudine (AZT) who received nevirapine during active labor, and their neonates who received no dose, a single dose, or multiple doses of nevirapine and who are receiving AZT during the first 6 weeks of life. GENERAL DESCRIPTION RATIONALE: Treatment of HIV-1 infected pregnant women during active labor may result in therapeutic levels of nevirapine in the neonate at the time of exposure to HIV-1 during parturition, decreasing the neonate's risk of infection. GENERAL DESCRIPTION METHODOLOGY: Pregnant women in active labor receive single doses of oral nevirapine. The neonates of the first four mothers receive no drug, while the neonates of the second four-patient cohort receive a single dose of nevirapine. If neonatal antiviral levels of nevirapine are not sustained for 7 days after the single dose, a third cohort of pregnant women will receive a single dose of nevirapine and their neonates will receive multiple doses of nevirapine to maintain an antiviral effect for 7 days. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS MOTHERS have the following symptoms and conditions: 1. HIV infection by two ELISAs confirmed by an appropriate test (e.g., Western blot) or by a positive HIV culture (blood or CSF). Historical data may be used. 2. Estimated gestational age >= 34 weeks. 3. NO active opportunistic infection at study entry. NEONATES must meet the following criterion: Born to enrolled HIV-1 infected women who have received study drug. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND 42,003 STUDY DESIGN Drug Tolerance; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 36 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 6-8 weeks post-partum (mother); 6 mos. post-delivery (baby) PROTOCOL DETAILS ACTUAL ACCRUAL: 4/36 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 3 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: MOTHERS must have: 1. HIV infection. 2. Estimated gestational age >= 34 weeks. 3. No active opportunistic infection at study entry. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. SGPT(ALT): <= 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: < 1.5 mg/dl. PATIENT AGE AGE: 13 Years - 60 Years. PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Pregnant at term and either in or beginning active labor as defined by uterine contractions. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Phototherapy (neonates). OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. AZT (mothers and neonates). 2. Oral asthma inhalers (mothers). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. SEX: MALE PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Not pregnant at term and not in or beginning active labor. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Current use of illicit substances and/or active chronic alcohol use. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Prior nevirapine. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Any antiretroviral other than AZT. 2. Corticosteroids (other than oral asthma inhalers). 3. Anticoagulants. 4. Any clavulinic acid-containing formulation (e.g., Augmentin, Timentin). 5. Benzodiazepines other than study drug. 6. Phenobarbital. 7. Barbiturates. 8. Antacids. 9. Magnesium sulfate. PATIENT EXCLUSION CRIT. COMPLICATIONS: MOTHERS with the following symptoms or conditions are excluded: 1. Intrauterine growth retardation. 2. Fetal anomaly incompatible with life as determined by pre-entry ultrasound. 3. Participation during current pregnancy in any other therapeutic or vaccine perinatal trial. 4. Known hypersensitivity to any benzodiazepine. 5. Serious bacterial infection. PATIENT EXCLUSION CRIT. AVAILABILITY: No access to a participating site or unwilling to be followed at one participating site for the duration of the study. SUBSTANCE IDENTIFICATION Drug 1 DRG-0116 Nevirapine TRADE NAME OF SUBSTANCE Drug 1‰ BI-RG-587 MANUFACTURERS Drug 1: Boehringer Ingelheim Pharmaceuticals Incorporated 900 Ridgebury Road Ridgefield, CT 06877 Contact: Susannah Cort (203) 791-6063 Contact: Maureen Myers (203) 798-5583. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: MOTHERS: 100 mg as single dose (if tolerated, another group of patients will receive 200 mg as a single dose). NEONATES: 2 mg/kg (estimated dose to maintain a neonate blood lof >= 10 x IC50 (or 0.1 mcg/ml) over 7 days. If tolerated, additional patients will receive 4 mg/kg. Multiple doses, if utilized, will be determined using data from the single dose c SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg tablets and 10 mg/ml oral suspension OTHER TREATMENT INFO. END POINT: Drug-associated grade 3 or 4 toxicity; maintenance of antiviral drug levels for the first week of life. OTHER TREATMENT INFO. DISCONTINUE: MOTHERS discontinue treatment for the following reasons: 1. Pre-eclampsia or pregnancy-induced hypertension requiring intrapartum magnesium sulfate. 2. Severe maternal infection with sequelae of shock (e.g., acute respiratory disease, hypotension). 3. Uncontrolled hypertension. 4. Intrapartum complication requiring anticoagulation therapy. 5. Intrapartum seizures. 6. Condition whereby mother is unable to tolerate oral study drug. 7. Active opportunistic infection and/or serious bacterial infection. 8. Unacceptable toxicity. NEONATES discontinue treatment for the following reasons: 1. Severe congenital malformations or other conditions not compatible with life. 2. Severe anemia or hypovolemia requiring volume replacement and/or blood product therapy. 3. Severe hyperbilirubinemia necessitating transfusion or volume replacement. 4. Documented or suspected serious infectious, cardiac, respiratory, or metabolic illness, or other immediate life-threatening condition. 5. Unacceptable toxicity. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY/PREVENTION & CONTROL/TRANSMISSION MESH HEADING Human MESH HEADING Infant MESH HEADING Middle Age MESH HEADING Pregnancy MESH HEADING Pregnancy Complications, Infectious MESH HEADING Pyridines/*ADVERSE EFFECTS/PHARMACOKINETICS CAS REGISTRY NUMBER 129618-40-2 (BI-RG 587) LAST REVISION DATE 941207 ENTRY MONTH 9411 CALIFORNIA University of CA San Diego Medical Center / Pediatric 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 941103 ACTU: 4601. NEW YORK Mount Sinai School of Medicine / Pediatrics One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 941103 ACTU: 4301. OTHER San Juan City Hospital / Puerto Rico Medical Center Department of Pediatrics Third Floor Hematology Rio Piedras, PR 00927 Contact: Esther Rosa (809) 764-3083 Contact: (809) 274-0904 OPEN 941103 ACTU: 5031. 25 UNIQUE IDENTIFIER NIH/00677 PROTOCOL ID NUMBERS NIAID ACTG 245 PROTOCOL TITLE A Comparative Study of Combination Antiretroviral Therapy in Children and Adolescents with Advanced HIV Disease. VERSION NUMBER & DATE 2 (940719) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Burchett S PROTOCOL CHAIRS CO-CHAIR Luzuriaga K GENERAL DESCRIPTION PURPOSE: To compare the antiviral activity, safety, toxicity, and steady-state pharmacokinetics of zidovudine, didanosine, and nevirapine used in combination in patients with HIV infection. GENERAL DESCRIPTION RATIONALE: The duration of clinical benefit from zidovudine (AZT) may be limited because of development of viral resistance to the drug. Use of combination antiretroviral therapy potentially can reduce viral load and prevent emergence of multidrug resistance. GENERAL DESCRIPTION METHODOLOGY: In Stage 1 of the study, a minimum of 22 patients are randomized to each of three treatment arms: didanosine (ddI) plus AZT plus nevirapine (NVP); ddI plus AZT; and ddI plus NVP. After 12 weeks of treatment, the study proceeds to Stage 2 provided at least 40 percent of patients in Stage 1 showed a reduction of at least 40 percent from baseline ICD p24 antigen of >= 70 pg/ml AND fewer than two patients experienced grade 4 rash. Patients in Stage 1 continue treatment for an additional 36 weeks. In Stage 2, additional patients are randomized to each original treatment regimen until a maximum of 130 patients per arm have been entered. Stage 2 patients receive treatment for at least 48 weeks. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection as evidenced by positive viral culture, p24 antigen >= 30 pg/ml, proviral DNA on PCR, or two positive antibody tests determined by ELISA with one test confirmed by Western blot. 2. Disease progression defined by growth failure OR neurodevelopmental or neuropsychological regression OR two or more AIDS-defining opportunistic infections OR absolute CD4 cells <= 14 percent or a confirmed 50 percent reduction in CD4 cells from a previous value of >= 20 percent within 24 weeks prior to study entry. 3. At least 24 weeks prior cumulative nucleoside analog antiretroviral monotherapy or combination therapy. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND 42003 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Drug Combination; Drug Tolerance; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance, Combination drug therapy, Combination pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 390 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Until 48 weeks after enrollment of last patient. PROTOCOL DETAILS ACTUAL ACCRUAL: 73/390 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 44 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Progressive HIV disease. 2. At least 24 weeks prior cumulative nucleoside analog antiretroviral monotherapy or combination therapy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 7.0 g/dl. (EPO and transfusion allowed). PATIENT INCLUSION CRIT. PLATELET COUNT: > 25000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. (Patients relying on CD4 value as evidence of disease progression must have absolute CD4 cells <= 14 percent or a confirmed 50 percent reduction in CD4 cells from previous value of >= 20 percent within 24 w PATIENT INCLUSION CRIT. BILIRUBIN: < 3 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 15 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): < 15 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 35 ml/min. /1.73 m2. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 250 cells/mm3. Pancreatic amylase < 2 x ULN. PATIENT AGE AGE: 06 Months - 20 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Transfusion. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Erythropoetin. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of clinical pancreatitis. 2. History of grade 2 or worse peripheral neuropathy. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 05 Months. 21 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Acute treatment for a serious bacterial, viral, or opportunistic infection within 14 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded (unless exemption made by study chair): 1. Oral anticoagulants (warfarin, dicumarol). 2. Oral contraceptives. 3. Digitalis glycosides. 4. Phenytoin. 5. Theophylline. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active malignancy requiring chemotherapy. 2. Currently receiving therapy in an ACTG primary therapy or salvage protocol who have NOT met an endpoint on that study. 3. Known intolerance (other than hematologic) or toxicity to ddI, AZT, or NVP at the doses used in this study. SUBSTANCE IDENTIFICATION Drug 1 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0116 Nevirapine MANUFACTURERS Drug 1: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Colin McLaren (203) 284-6942. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 3: Boehringer Ingelheim Pharmaceutical Incorporated 900 Ridgebury Road Ridgefield, CT 06877 Contact: Dr Maureen Myers (203) 798-5583. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 100 mg/m2 (or placebo) BID for 48 weeks. Drug 2: 180 mg/m2 (or placebo) TID for 48 weeks. Drug 3: 120 mg/m2 (or placebo) BID for 48 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 200 mg/m2. Drug 2: 540 mg/m2. Drug 3: 240 mg/m2 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, pediatric powder for solution and 25 and 50 mg tablets. Drug 2: Oral, flavored syrup and 100 mg capsules. Drug 3: Oral, 10 mg/ml bottles and 50 and 100 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: Minimum of 12 weeks (Stage 1); Minimum of 48 weeks (Stage 2). OTHER TREATMENT INFO. END POINT: Primary: Virologic efficacy, safety, and pharmacokinetics / pharmacodynamics of combination therapy. Secondary: Clinical response to combination therapy. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Unacceptable toxicity. OTHER TREATMENT INFO. MODIFICATION: o For hemoglobin < 7.0 g/dl: hold AZT until toxicity resolves, then resume at 50 percent dose. o For neutrophils < 250 cells/mm3: hold AZT until toxicity resolves, then resume at 50 percent dose. If neutropenia persists for > 14 days or recurs within 30 days or > three times in 6 months, hold AZT and ddI until toxicity resolves, then resume both drugs at 50 percent dose. If neutropenia persists for 14 additional days, hold all study drugs until toxicity resolves, then restart all drugs at 50 percent dose. If neutropenia continues, discontinue study drugs permanently. o For grade 3 or 4 myositis or headache: hold AZT until toxicity resolves to grade 2 or better, then resume at 50 percent dose. If grade 3 or 4 myositis or headache persists for > 7 days or recurs within 30 days or > three times in 6 months, hold AZT and ddI until toxicity resolves to grade 2 or better, then resume both drugs at 50 percent dose. If toxicity persists for 7 additional days or recurs within 30 days, hold all study drugs until toxicity resolves, then resume all study drugs at 50 percent dose. If grade 3 or 4 toxicity still persists or recurs, discontinue all study drugs permanently. o For grade 3 or 4 nausea, vomiting, diarrhea, hyperamylasemia, or peripheral neuropathy: hold ddI until toxicity resolves to grade 2 or better, then resume at 50 percent dose. For persistent or recurrent toxicity, follow the same management pattern as for myositis. o For grade 3 or 4 thrombocytopenia or hyperbilirubinemia: hold NVP until toxicity resolves to grade 2 or better, then resume at 50 percent dose. If grade 3 or 4 toxicity persists for > 7 days or recurs within 30 days or > three times in 6 months, hold NVP and AZT until toxicity resolves to grade 2 or better, then resume both drugs at 50 percent dose. If toxicity persists or recurs, hold and then discontinue all study drugs. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Didanosine/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Pyridines/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE MESH HEADING Zidovudine/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE CAS REGISTRY NUMBER 129618-40-2 (BI-RG 587) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 941207 ENTRY MONTH 9410 ALABAMA University of Alabama at Birmingham School of Medicine 751 CHT / University Station Birmingham, AL 35294 Contact: Michael Cooney (205) 939-9552 Contact: beeper (205) 869-9524 OPEN 941011 ACTU: 5046. CALIFORNIA Los Angeles County USC Medical Center 1129 North State Street Los Angeles, CA 90033 Contact: Janice Ono (213) 226-3945 OPEN 941107 ACTU: 5048. CALIFORNIA University of CA San Diego Medical Center / Pediatric 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 941031 ACTU: 4601. CALIFORNIA UCSF / Moffitt Hospital 602 / Pediatrics 505 Parnassus / Box 0105 San Francisco, CA 94143-0105 Contact: Debbie Trevithick (415) 476-6480 OPEN 940921 ACTU: 4501. CALIFORNIA Children's Hospital Oakland 747 Fifty Second Street Oakland, CA 94609-1809 Contact: Jim Riddel (510) 428-3000 X 282Contact: (510) 539-6311 X PagOPEN 940919 ACTU: 4504. COLORADO University of Colorado Hlth Sciences Ctr / Peds Infect Dis 1056 East 19Th Avenue B055 Denver, CO 80218-1088 Contact: Carol Salbenblatt (303) 861-6751 OPEN 940919 ACTU: 7001. CONNECTICUT Univ of Connecticut Farmington / Univ of CT Health Center 263 Farmington Avenue Farmington, CT 06032 Contact: Lorraine Wells (203) 679-2320 OPEN 941014 ACTU: 7303. CONNECTICUT Yale University School of Medicine PO Box 3333 / 333 Cedar Street New Haven, CT 06510-8064 Contact: Unspecified (203) 737-4040 OPEN 940823 ACTU: 5038. DISTRICT OF COLUMBIA Children's National Medical Center / Special Immuno Svc Suite 2108 / 111 Michigan Avenue NW Washington, DC 20010-2970 Contact: Sandra Jones (202) 884-3682 OPEN 941107 ACTU: 7101. DISTRICT OF COLUMBIA Howard University Hospital 2041 Georgia Avenue NW Washington, DC 20060 Contact: Dr Helga Finke (202) 865-1248 OPEN 940919 ACTU: 5044. FLORIDA Northeast Florida AIDS Program / Div of Pediatric Inf Dis/Im 653-1 W 8th Street Jacksonville, FL 32209 Contact: Michelle Eagle (904) 549-3051 OPEN 941107 ACTU: 5051. FLORIDA Univ of Miami School of Medicine / Pediatric Imm Infect Dis 1800 NW Tenth Avenue Miami, FL 33136 Contact: Janet Gourley (305) 548-4446 OPEN 940923 ACTU: 4201. ILLINOIS University of Illinois at Chicago 840 S Wood Street Chicago, IL 60612 Contact: Patricia Naughton (312) 996-1778 OPEN 940919 ACTU: 5028. ILLINOIS Chicago Children's Memorial Hospital / Pediatric 2300 Childrens Plaza Box 20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 940829 ACTU: 4001. ILLINOIS Wyler Children's Hospital 5841 South Maryland Avenue Chicago, IL 60637-1470 Contact: Kim Stieglitz (312) 702-6176 OPEN 941005 ACTU: 4003. LOUISIANA Tulane University School of Medicine / Div of Ped Infect Dis 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 941005 ACTU: 7201. MASSACHUSETTS Baystate Medical Center / Department of Pediatrics 759 Chestnut Street / SHU-Main 3 Springfield, MA 01199 Contact: MaryPat Toye (413) 784-5399 OPEN 941005 ACTU: 7302. MASSACHUSETTS University of Massachusetts Medical School / Dept of Peds 55 Lake Avenue North Worcester, MA 01655-0001 Contact: Joanne Shepard (508) 856-1692 OPEN 940808 ACTU: 7301. MASSACHUSETTS Children's Hospital 300 Longwood Avenue / Carnegie 3 Boston, MA 02115 Contact: Robert Bishop (617) 735-8198 OPEN 940815 ACTU: 2901. MARYLAND University of Maryland School of Medicine / Pediatrics 120 Penn Street Baltimore, MD 21201 Contact: Sue Lovelace (410) 706-8220 OPEN 941103 ACTU: 3702. MARYLAND The Johns Hopkins University ( Pediatrics ) 600 North Wolfe Street Baltimore, MD 21287 Contact: Laura J Belcher (410) 955-9749 OPEN 941123 ACTU: 3701. MICHIGAN Children's Hospital of Michigan 3901 Beaubien Boulevard Detroit, MI 48201 Contact: Charnell Cromer (313) 745-5565 OPEN 940927 ACTU: 5041. NORTH CAROLINA Duke University Medical Center / Pediatrics Box 3499 Durham, NC 27710 Contact: John Swetnam (919) 684-6335 OPEN 941013 ACTU: 4701. NEW JERSEY Robert Wood Johnson University Hospital / UMDNJ One Robert Wood Johnson Place CN19 New Brunswick, NJ 08903-0019 Contact: Ida Kechula (908) 937-7894 OPEN 940921 ACTU: 5032. NEW YORK Beth Israel Medical Center / Pediatrics First Avenue at 16th Street Dazian Pavilion Tenth Floor New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 941007 ACTU: 4302. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue / Pediatric New York, NY 10016 Contact: Nagamah Deygoo (212) 263-6426 OPEN 940919 ACTU: 4401. NEW YORK Cornell Medical Center N-834 / Pediatric Infectious Disease 1300 York Avenue New York, NY 10021 Contact: Tony Hinds (212) 746-3326 OPEN 941207 ACTU: 5019. NEW YORK Mount Sinai School of Medicine / Pediatrics One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940909 ACTU: 4301. NEW YORK Incarnation Children's Ctr / c/o Columbia Presb Med Ctr 142 Audubon Avenue New York, NY 10032 Contact: Pam Clark (212) 928-2228 OPEN 941115 ACTU: 4103. NEW YORK The Columbia Presbyterian Medical Hosp (Pediatric) 622 West 168th St Room 1161 New York, NY 10032-3796 Contact: Kathy A Shea (212) 305-7222 OPEN 941115 ACTU: 4101. NEW YORK Harlem Hospital 506 Lenox Avenue New York, NY 10037 Contact: Rick Urbano (212) 939-4040 Contact: (212) 939-4045 OPEN 941014 ACTU: 5006. NEW YORK Bronx Lebanon Hospital Center / Department of Pediatrics 1650 Selwyn Avenue Room 2C Bronx, NY 10457 Contact: Patrice Edwards-Cihak (718) 960-1015 OPEN 940912 ACTU: 6901. NEW YORK King's County Hospital Center / SUNY HSCB 450 Clarkson Avenue Brooklyn, NY 11203 Contact: Helen Bergin (718) 245-3342 Contact: (718) 245-3341 Contact: (718) 245-4485 OPEN 941014 ACTU: 5035. NEW YORK SUNY at Brooklyn / Health Science Center / Pediatrics 450 Clarkson Avenue / Box 24 Brooklyn, NY 11203 Contact: Barbara Driscoll (718) 270-3081 OPEN 940830 ACTU: 5008. NEW YORK Children's Hospital at Albany Medical Center 22 New Scotland Avenue Albany, NY 12208 Contact: Mary Ellen Adams (518) 432-1501 OPEN 941114 ACTU: 5042. OHIO Children's Hospital 700 Children's Drive Columbus, OH 43205-2696 Contact: Jane Hunkler (614) 722-4460 Contact: (614) 722-6050 OPEN 941014 ACTU: 2302. OTHER Ramon Ruiz Arnau University Hospital Laurel Avenue Bayamon, PR 00619 Contact: Leticia Diaz (809) 798-2733 OPEN 941017 ACTU: 5033. OTHER San Juan City Hospital / Puerto Rico Medical Center Department of Pediatrics Third Floor Hematology Rio Piedras, PR 00927 Contact: Esther Rosa (809) 764-3083 Contact: (809) 274-0904 OPEN 940907 ACTU: 5031. OTHER University of Puerto Rico / University Pediatric Hospital 4th Floor South Wing Room 4B-45 / GPO Box 365067 San Juan, PR 00936-5067 Contact: Carmen Rivera (809) 759-9595 Contact: (809) 765-1979 X 724OPEN 940916 ACTU: 6601. PENNSYLVANIA Children's Hospital of Philadelphia 34th Street & Civic Center Blvd Philadelphia, PA 19104-4399 Contact: Dr Deborah Schaible (215) 590-2097 Contact: Hospital Information (215) 590-1000 OPEN 941116 ACTU: 6701. RHODE ISLAND Rhode Island Hospital / Brown University 593 Eddy Street Providence, RI 02903 Contact: Cathy Kneut (401) 467-9884 OPEN 941123 ACTU: 5047. SOUTH CAROLINA Medical University of South Carolina Clinical Science Building / 171 Ashley Avenue Charleston, SC 29425-3312 Contact: Genny Connelly (803) 792-2385 OPEN 940923 ACTU: 5037. 26 UNIQUE IDENTIFIER NIH/00675 PROTOCOL ID NUMBERS NIAID ACTG 244 PROTOCOL TITLE A Double-Blinded, Randomized Trial Comparing Zidovudine (AZT) Versus AZT Plus Didanosine (ddI) Versus AZT Plus ddI Plus Nevirapine in Asymptomatic Patients on AZT Monotherapy Who Develop a Mutation at Codon 215 of HIV Reverse Transcriptase in Serum/Plasma Viral RNA. VERSION NUMBER & DATE 2 (931217) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Merigan TC PROTOCOL CHAIRS CO-CHAIR Mayers DL GENERAL DESCRIPTION PURPOSE: To validate that the alteration of codon 215 of reverse transcriptase in plasma virus precedes the increase in viral burden as measured in the peripheral blood and the decline in CD4 count that have been observed in association with clinical failure on zidovudine (AZT). To determine whether alternative regimens of antiretroviral agents alter the course of viral burden as measured in the peripheral blood and CD4 changes in patients with HIV infection. To obtain further data on the safety and immunologic and virologic response to AZT/didanosine/nevirapine. GENERAL DESCRIPTION RATIONALE: Of the HIV-1 mutations reported to be associated with zidovudine resistance, the mutation at codon 215 of the reverse transcriptase gene is the most commonly occurring and has the greatest impact on susceptibility. When this mutation appears, a change in drugs may prevent further immunologic and virologic deterioration. GENERAL DESCRIPTION METHODOLOGY: Initially, all patients receive AZT alone. After detection of a 215 mutation in plasma RNA, patients are randomized to one of three treatment arms: AZT alone, AZT plus ddI, or AZT/ddI plus nevirapine. Patients are followed every 8 weeks and receive treatment for up to 4 years. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Asymptomatic HIV infection documented by ELISA. 2. CD4 count 300-600 cells/mm3. 3. No plasma/serum PCR for codon 215 mutation at screening. 4. AZT monotherapy (minimum 300 mg/day) for at least 1 month (uninterrupted) but no more than 2 years immediately prior to study entry. ELIGIBILITY ASYM. OTHER PROTOCOL NUMBERS IND 42,003 STUDY DESIGN Randomized; Placebo-Controlled; 3-Arm PROTOCOL DETAILS STUDY INTENT: Combination and single drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 300 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 4 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 139/300 (941207). PROTOCOL DETAILS STUDY DURATION: 4 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 47 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Asymptomatic HIV infection. 2. CD4 count 300-600 cells/mm3. 3. No plasma/serum PCR for codon 215 mutation at screeing. 4. Prior AZT monotherapy. NOTE: All Department of Defense-eligible patients must be at least 18 years of age. Enrollment of women is encouraged. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 10 g/dl. (men); >= 9.0 g/dl (women). No transfusion within the preceding two weeks. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 300 - 600 cells/mm3. ( 300 - 400 - 500 - 600 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 75 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. Total serum amylase <= 1.5 x ULN (if serum amylase > 1.5 x ULN, lipase <= 1.5 x ULN or pancreatic amylase may be used to qualify). Alkaline phosphatase <= 5 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Limited localized radiation therapy to the skin. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: AZT (minimum 300 mg/day) for at least 1 month (uninterrupted) but no more than 2 years immediately prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Chemoprophylaxis for Pneumocystis carinii pneumonia. 2. Antibiotics, antifungals, and antiviral medications, as clinically indicated. 3. Regularly prescribed medication such as antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, or any other medications deemed appropriate by the primary care provider. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of pancreatitis. 2. Chronic diarrhea for at least 4 of the 7 days immediately prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Illicit drug or alchohol abuse. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy other than limited localized therapy to skin. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior therapy with nucleoside or nonnucleoside antiretroviral agents other than AZT. 2. Blood transfusion within the preceding 2 weeks. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Systemic cytotoxic chemotherapy. 2. Biologic response modifiers (such as interferon, ampligen, or PEG-IL2). 3. Anti-HIV agents other than study drugs. 4. Other investigational agents. 5. Foscarnet unless clinically indicated for unresponsive herpes virus infection. 6. Chronic antacid or H-2 blocker use. 7. Rifampin or rifamycin class agents. 8. Antibiotics containing clavulanic acid. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Symptomatic grade 2 or worse peripheral neuropathy. 2. Unable to swallow capsules and tablets. 3. Other medical condition that contraindicates study participation. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 3 DRG-0116 Nevirapine MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle Park, NC 27709 Contact: Mary Maha Elkins (919) 248-3294. MANUFACTURERS Drug 2: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Colin McLaren (203) 284-6942. MANUFACTURERS Drug 3: Boehringer Ingelheim Pharmaceuticals Incorporated 900 Ridgebury Road Ridgefield, CT 06877 Contact: Susannah Cort (203) 791-6063 Contact: Maureen Myers (203) 798-5583. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg q 8 hr for up to 4 years. Drug 2: 200 mg (or placebo) q 12 hr for up to 4 years. Patientweighing <= 60 kg receive 125 mg (or placebo) q 12 hr. Drug 3: 200 g (or placebo) daily for the first 8 weeks, then 40(or placebo) daily for up to 4 years SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 600 mg. Drug 2: 400 mg. Drug 3: 200 mg for the first 8 weeks, then 400 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg capsules. Drug 2: Oral; 25, 50 and 100 mg tablets. Drug 3: Oral, 200 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: Up to 4 years. OTHER TREATMENT INFO. END POINT: Primary: Comparison of the slope of CD4 counts over time, before and after emergence of 215 mutation. Secondary: Change in proviral DNA in CD4 cells or in serum viral RNA of >= 1.0 log, change in p24 and beta-2 microglobulin, dose-limiting toxicity, correlation of baseline prognostic markers with development of 215 mutation, virologic and immunologic changes. ddI treatment is discontinued for the following reasons: 1. Development of an AIDS-defining condition. 2. Dose-limiting toxicity. 3. Decline in CD4 counts by more than 50 percent on two consecutive counts at least 72 hours apart. 4. Pregnancy. 5. Medical recommendation of the treating physician. 6. Discontinuation of study by sponsor, FDA, or pharmaceutical company, or desire of patient to withdraw. OTHER TREATMENT INFO. MODIFICATION: Dose is held or reduced for specific toxicities. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Burroughs Wellcome, Bristol-Myers Squibb Company. MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Didanosine/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Pyridines/*THERAPEUTIC USE MESH HEADING Zidovudine/*THERAPEUTIC USE CAS REGISTRY NUMBER 129618-40-2 (BI-RG 587) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 941207 ENTRY MONTH 9401 CALIFORNIA University of California at Los Angeles School of Medicine 60051 CHS / 10833 Le Conte Avenue Los Angeles, CA 90024-1793 Contact: Susan G McCarthy (310) 825-1301 OPEN 940210 ACTU: 0601. CALIFORNIA Harbor General / REI Lab / UCLA 1124 West Carson Street Torrance, CA 90502 Contact: Sally Kruger (310) 222-3848 Contact: Rick Johnson OPEN 940210 ACTU: 0603. CALIFORNIA AIDS Community Research Consortium 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harris (415) 364-5653 OPEN 940216 ACTU: 0505. CALIFORNIA Santa Clara Valley Med Ctr / ACRC 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harriss (415) 364-5653 OPEN 940311 ACTU: 0506. CALIFORNIA Kaiser Permanente Medical Group / Stanford University 2590 Geary Boulevard San Francisco, CA 94115 Contact: Gretchen Van Raalte (415) 202-3482 OPEN 940531 ACTU: 0502. CALIFORNIA Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Contact: Virginia Tallman (415) 723-2804 Contact: Dr Rami Ramachandran (415) 723-6231 OPEN 940114 ACTU: 0501. DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 940201 ACTU: 5701. HAWAII Hawaii Aids Clinical Trails Unit Leahi Hospital / Young Bldg / 3675 Kilauea Avenue / 6th Flr Honolulu, HI 96816 Contact: Debra M Ogata Arakaki (808) 737-2751 OPEN 941115 ACTU: 5201. IOWA University of Iowa / UH Nursing W321 GH Internal Medicine SW34-GH Iowa City, IA 52242 Contact: Julie Katseres (319) 353-8441 OPEN 940323 ACTU: 1504. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 941007 ACTU: 2601. MASSACHUSETTS Beth Israel Hospital 330 Brookline Avenue Boston, MA 02115 Contact: Sheila Hussey (617) 735-4103 OPEN 941207 ACTU: 0102. MARYLAND Walter Reed Army Medical Center 1600 East Gude Drive Room 222 Rockville, MD 20852 Contact: Lori Abrams (301) 217-9410 OPEN 940210 ACTU: 5502. MARYLAND Fitzsimmons Army Medical Center / Walter Reed Army Hospital 1600 East Gude Drive Room 222 Rockville, MD 20852 Contact: Lori Abrams (301) 217-9410 X 103OPEN 940923 ACTU: 5508. MARYLAND National Naval Medical Center 8901 Wisconsin Avenue Bethesda, MD 20899-5000 Contact: Unspecified (301) 295-5385 OPEN 940310. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 940425 ACTU: 0201. MARYLAND State of Maryland Div of Corrections c/o Johns Hopkins Hosp 1830 East Monument Street / Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 940425 ACTU: 0202. MINNESOTA St Paul-Ramsey Medical Center 640 Jackson Street St Paul, MN 55101 Contact: Ray Nelson (612) 221-1280 OPEN 940418 ACTU: 1503. MINNESOTA Hennepin County Med Clinic / Univ of Minnesota Hosp Clinic 420 Delaware Street SE / Room G255 Mayo Building Minneapolis, MN 55415 Contact: Renee St Jacques (612) 373-1810 OPEN 940406 ACTU: 1502. MINNESOTA University of Minnesota Hospital and Clinic PO Box 437 / UMHC / Harvard Street & East River Road Minneapolis, MN 55455 Contact: Nancy Reed (612) 625-1462 OPEN 940308 ACTU: 1501. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 941102 ACTU: 3201. NORTH CAROLINA Wake County Department of Health Hosp South Room 0207 Box 3284 Durham, NC 27710 Contact: Kelley Rayle (919) 250-1035 OPEN 941102 ACTU: 3206. NORTH CAROLINA Carolinas Medical Center / Department of Internal Medicine 1000 Blythe Blvd AHEC Room 507 Charlotte, NC 28203 Contact: Joan Connell (704) 355-5292 Contact: (704) 355-3165 OPEN 941123 ACTU: 3204. NEBRASKA University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-5130 Contact: Frances Tennant (402) 559-5750 OPEN 940323 ACTU: 1505. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 940317 ACTU: 0401. NEW YORK North Central Bronx Hospital / Montefiore Family Health Cntr 418 Forchheimer-ID/1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940531 ACTU: 1906. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940426 ACTU: 1901. NEW YORK Comprehensive Health Care Center 418 Forchheimer-ID / 1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940531 ACTU: 1908. NEW YORK Albert Einstein College of Medicine 418 Forcheimer / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940531 ACTU: 1904. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 940426 ACTU: 1902. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940531 ACTU: 1903. NEW YORK Montefiore Medical Center Adolescent AIDS Program 111 East 210th Street Bronx, NY 10467-2490 Contact: Dina Monte (718) 882-0023 OPEN 941116 ACTU: 5049. NEW YORK Adirondack Medical Center at Saranac Lake 47 New Scotland Avenue Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 940822 ACTU: 7403. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 940822 ACTU: 7401. NEW YORK Mid-Hudson Care Center / Albany Med College / Div Med Oncol 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 940822 ACTU: 7402. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 940308 ACTU: 1103. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 940124 ACTU: 1102. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 940201 ACTU: 1101. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 941006 ACTU: 2301. OHIO Medical College of Ohio / Department of Medicine 3000 Arlington Avenue Toledo, OH 43699 Contact: Lynn Lipton (419) 381-3729 Contact: (419) 381-4328 OPEN 940317 ACTU: 2502. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 940202 ACTU: 2501. OHIO Metrohealth Medical Center / Case Western Reserve Univ 2500 MetroHealth Drive Cleveland, OH 44109-1998 Contact: Nancy Frantz (216) 459-5136 OPEN 940511 ACTU: 2503. PENNSYLVANIA University of Pennsylvania / Div of Infectious Diseases 549 Johnson Pavillion / 6073 / 36th and Hamilton Walk Philadelphia, PA 19104-6073 Contact: Debora Dunbar (215) 349-8092 OPEN 940418 ACTU: 6201. PENNSYLVANIA Thomas Jefferson Unversity 1015 Chestnut Street Philadelphia, PA 19107 Contact: Lyle Jew (215) 955-7785 OPEN 940502 ACTU: 6202. 27 UNIQUE IDENTIFIER NIH/00581 PROTOCOL ID NUMBERS NIAID ACTG 243 PROTOCOL TITLE A Phase II Multicenter Study Comparing Antiretroviral Therapy Alone to Antiretroviral Therapy Plus Cytosine Arabinoside (Cytarabine; Ara-C) for the Treatment of Progressive Multifocal Leukoencephalopathy (PML) in Human Immunodeficiency Virus (HIV)-Infected Subjects. VERSION NUMBER & DATE 2 (940825) TRIAL CATEGORY Opportunistic Infections PROTOCOL CHAIRS CHAIR Hall C PROTOCOL CHAIRS CO-CHAIR Timpone J GENERAL DESCRIPTION PURPOSE: To compare the safety and efficacy of antiretroviral therapy (zidovudine plus either didanosine or dideoxycytidine) versus antiretroviral therapy plus intravenous cytarabine (Ara-C) versus antiretroviral therapy plus intrathecal Ara-C in the maintenance or improvement of neurological function over 6 months in HIV-infected individuals who have developed progressive multifocal leukoencephalopathy (PML). To compare the effect of these three treatment regimens on Karnofsky score and MRI studies. GENERAL DESCRIPTION RATIONALE: The effectiveness of Ara-C in the treatment of PML, caused by a human DNA papovavirus (designated JC virus) infection, has not been determined, although the most encouraging results have occurred with intrathecal administration of the drug. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive antiretroviral therapy alone (AZT plus ddI or ddC), antiretroviral therapy plus intravenous Ara-C, or antiretroviral therapy plus intrathecal Ara-C. All patients receive 24 weeks of antiretroviral therapy. Beginning at week 2, patients on the intravenous Ara-C arm receive daily infusions of Ara-C over 5 days, with cycles repeating every 21 days. Patients on the intrathecal Ara-C arm receive single administrations of Ara-C at weeks 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24. A brain biopsy confirmation or in situ hybridization will be required within 7 days after study entry. Patients are followed every 4 weeks. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Progressive multifocal leukoencephalopathy ( PML ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA confirmed by Western blot. 2. Clinical presentation and MRI compatible with PML within the past 2 months, confirmed by brain biopsy or in situ hybridization by 14 days after study entry. 3. No other current active opportunistic infections requiring systemic therapy. NOTE: Patients on stable maintenance or prophylaxis therapy for opportunistic infections for at least 2 weeks prior to study entry are permitted. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 44,084 STUDY DESIGN Randomized; Open Label; Multicenter; Drug Tolerance; Comparative administration route PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Combination drug therapy, Administration route comparison. PROTOCOL DETAILS PROJECTED ACCRUAL: 90 patients. (30 patients on each of three treatment arms) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Until last patient enrolled completes treatment. PROTOCOL DETAILS ACTUAL ACCRUAL: 16/90 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 12 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Confirmed PML. 3. No other current active opportunistic infections requiring systemic therapy. 4. Life expectancy of at least 3 months. NOTE: A durable power of attorney is recommended where severe neurologic or psychiatric impairment can be foreseen while the patient is on study. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 18 Years - 65 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Local radiation therapy for mucocutaneous Kaposi's sarcoma. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Local intralesional chemotherapy for mucocutaneous Kaposi's sarcoma. 2. Topical antifungals, clotrimazole, ketoconazole, fluconazole, and amphotericin B for treatment of mucosal and esophageal candidiasis. 3. Foscarnet for newly developed CMV infection, only after discussion with the protocol chair. 4. Prophylactic and maintenance therapy for other opportunistic infections, provided patients are considered clinically stable. 5. No more than 1000 mg/day acyclovir for herpes simplex. 6. Antibiotics for bacterial infections as clinically indicated. 7. Antipyretics, analgesics, and antiemetics. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of allergy or intolerance to G-CSF. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 66 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Any prior Ara-C. Excluded within 14 days prior to study: 1. Ganciclovir or foscarnet. 2. Interferon. 3. Antiretroviral medications other than AZT, ddI, or ddC. 4. Experimental medications for treatment of PML. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Ganciclovir. 2. Interferon. 3. Systemic chemotherapy other than Ara-C (unless specifically allowed). 4. Antiretroviral medications other than AZT, ddI, or ddC. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Current active cryptococcal meningitis, cytomegaloviral encephalitis, toxoplasmosis encephalitis, CNS lymphoma, or neurosyphilis. NOTE: Patients on maintenance therapy for cryptococcal meningitis or toxoplasmosis encephalitis that has been stable for 4 months are permitted. 2. Conditions that seriously increase risk of a surgical procedure (e.g., coagulopathy, severe thrombocytopenia). 3. Any other disease that would interfere with evaluation of the patient. 4. Other life-threatening complications likely to cause death in < 3 months. SUBSTANCE IDENTIFICATION Drug 1 DRG-0038 Cytarabine SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0015 Dideoxycytidine SUBSTANCE IDENTIFICATION Drug 4 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 5 DRG-0086 Granulocyte colony-stimulating factor TRADE NAME OF SUBSTANCE Drug 1‰ Cytosar-U TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir TRADE NAME OF SUBSTANCE Drug 3‰ Hivid TRADE NAME OF SUBSTANCE Drug 4‰ Videx TRADE NAME OF SUBSTANCE Drug 5‰ Neupogen MANUFACTURERS Drug 1: The Upjohn Company 301 Henrietta Street Kalamazoo, MI 49001 Contact: Dr Robert Earhart (616) 385-7677. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Kathryn Pattishall (919) 315-4440 Contact: Dr Andy Sopchak (919) 315-3891. MANUFACTURERS Drug 3: Hoffmann-La Roche Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Dr Miklos Salgo (201) 812-3587. MANUFACTURERS Drug 4: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Colin McLaren (203) 284-6942. MANUFACTURERS Drug 5: Amgen Inc 1840 DeHavilland Drive Thousand Oaks, CA 91320-1789 Contact: Susan Armstrong (805) 447-4175. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Intravenous: 4 mg/kg daily for 5 days, repeated every 2days for a total of eight cycles. Intrathecal: 50 mg through an Ommaya reservoir at weeks 2, 3, 46, 8, 10, 12, 16, 20, and 24. Drug 2: 300 mg TID for a total of 24 weeks. Drug 3: 0.75 mg TID for a total of 24 weeks. Drug 4: 125 mg (if <= 60 kg) or 200 mg (if > 60 kg) BID for a tof 24 weeks. Drug 5: 300 mcg daily until ANC reaches 2000 cells/mm3, then tito maintain the ANC in the 2000 to 10000 cells/mm3 range SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 2: 900 mg. Drug 3: 2.25 mg. Drug 4: 250 or 400 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV) or intrathecal, 100 mg vials. Drug 2: Oral, 100 mg capsules.. Drug 3: Oral, 0.375 and 0.75 mg tablets. Drug 4: Oral, 25, 50, and 100 mg tablets.. Drug 5: Subcutaneous, 300 mcg/ml vials OTHER TREATMENT INFO. TREATMENT DURATION: 24 weeks. OTHER TREATMENT INFO. END POINT: Primary: Death. Secondary: Change in neurologic function, change in Karnofsky performance score, development of drug-related toxicity. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Institution of prohibited medications. 3. Recurrent or severe persistent patient noncompliance. 4. Pregnancy. 5. Development of CNS disorders such as cryptococcal meningitis, toxoplasmic encephalitis, CNS lymphoma, and cytomegaloviral encephalitis, which could confound neurological assessment. 6. Diagnosis of PML not confirmed. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), The Upjohn Company, Bristol-Myers Squibb Company. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Cytarabine/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Didanosine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Granulocyte Colony-Stimulating Factor/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Infusions, Intravenous MESH HEADING Injections, Spinal MESH HEADING Leukoencephalopathy, Progressive Multifocal/ COMPLICATIONS/*DRUG THERAPY MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zalcitabine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Zidovudine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 147-94-4 (Cytarabine) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 62683-29-8 (Granulocyte Colony-Stimulating Factor) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) CAS REGISTRY NUMBER 7481-89-2 (Zalcitabine) LAST REVISION DATE 941207 ENTRY MONTH 9404 CALIFORNIA UCSF / AIDS Clinic Ambulatory Care Center 995 Potrero Avenue San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940421 ACTU: 0802. COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 940822 ACTU: 6101. CONNECTICUT Yale University School of Medicine / Sect of Infectious Dis 135 College Street New Haven, CT 06510-2483 Contact: Laurie Andrews (203) 737-4040 OPEN 940511 ACTU: 6401. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 940531 ACTU: 0901. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 940413 ACTU: 2701. MASSACHUSETTS Massachusetts General Hospital / Harvard 55 Fruit Street Gray 5 Boston, MA 02114 Contact: Ellen Godfrey (617) 726-5598 OPEN 940622 ACTU: 0101. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 940405 ACTU: 0201. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 940602 ACTU: 2101. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 940415 ACTU: 3201. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940414 ACTU: 1801. NEW YORK Columbia Presbyterian Medical Center 622 West 168 Street / Harkness Pavilion 5 Room 516 New York, NY 10032-3784 Contact: Mykyelle Wade (212) 305-8507 OPEN 940511 ACTU: 7501. 28 UNIQUE IDENTIFIER NIH/00582 PROTOCOL ID NUMBERS NIAID ACTG 242 PROTOCOL TITLE A Phase II/III Double-Blind Study of Amitriptyline and Mexiletine for Painful Neuropathy in HIV Infection. VERSION NUMBER & DATE 1 (931105) TRIAL CATEGORY Neurologic Manifestations PROTOCOL CHAIRS CHAIR Kieburtz K PROTOCOL CHAIRS CO-CHAIR Clifford D, Hall C, Max GENERAL DESCRIPTION PURPOSE: To assess the efficacy, safety, and tolerability of amitriptyline hydrochloride versus mexiletine hydrochloride in reducing pain intensity in patients with HIV-related painful peripheral neuropathy. GENERAL DESCRIPTION RATIONALE: No large-scale controlled clinical trials of symptomatic therapy for painful HIV-related neuropathy have been attempted. Both amitriptyline and mexiletine have been useful in the management of painful neuropathies; however, both are associated with certain toxicities. In this comparative study of amitriptyline and mexiletine, benztropine mesylate also will be included as an active placebo to mimic the side effects of the study drugs. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive amitriptyline, mexiletine, or benztropine mesylate as an active placebo to mimic the mild side effects associated with both amitriptyline and mexiletine. Doses are gradually increased over 4 weeks until a minimum effective dose or MTD is reached, then patients are treated for at least 4 additional weeks at the final dose before gradually tapering off. Neurologic exams are performed at screening and at the end of treatment. Intensity of pain is rated twice daily by the patient. Patients are followed at weeks 2, 4, and 8, and at 10 days after completely tapering off of drug. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Peripheral neuropathy. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by ELISA and confirmed by Western blot, positive viral culture, or detectable serum p24 antigen. 2. Painful peripheral neuropathy, indicated by - Primary symptoms of symmetrical pain, burning, or tingling discomfort in feet for at least 2 weeks, then rated as either mild all the time or moderate for at least 2 hours per day AND EITHER - Dimished or absent ankle reflexes OR - Distal diminution of vibration sensation in the legs or pain or temperature sensation. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS IND 44,014 STUDY DESIGN Randomized; Placebo-Controlled; Parallel-Group; 3-Arm; Drug Comparison; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Comparative drug therapy, Drug efficacy, Drug safety, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 240 patients. (80 patients per treatment arm) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Approximately 10 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 56/240 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 47 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. Painful peripheral neuropathy. NOTE: Patients in ACTG blinded studies of dideoxynucleosides such as ddI, ddC, and d4T are encouraged to enroll in this study. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. SGOT(AST): <= 5.0 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5.0 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. OTHER PATIENT INCL. CH. PRIOR TREATMENT: Allowed: Prior acupuncture. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Acupuncture. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: 1. Prior ddI, ddC, or d4T, if on a stable dose for at least 8 weeks prior to study entry. 2. Prior cimetidine if on a stable dose for at least 2 weeks prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Aspirin and acetaminophen. 2. Nonsteroidal anti-inflammatory agents. 3. Opiates. 4. Pyridoxine (only if accompanied by isoniazid). 5. ddI, ddC, and d4T if on a stable dose. 6. AZT. 7. Cimetidine if on a stable dose. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of cardiac disease. 3. History of allergy to, or intolerance of, tricyclic antidepressants, mexiletine, or benztropine. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active drug or alcohol abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior disopyramide. 2. Prior procainamide. 3. Prior quinidine. 4. Prior tocainide. 5. Prior flecainide acetate. 6. Prior encainide. 7. Prior lidocaine. 8. Cisplatin or vincristine within 8 weeks prior to study entry. 9. Chloramphenicol, disulfiram, ethionamide glutethimide, gold, hydralazine, iodoquinol, metronidazole, nitrofurantoin, or ribavirin within 8 weeks prior to study entry (only in patients in whom the onset or clear worsening of painful peripheral neuropathy was attributed to taking these drugs). 10. Heterocyclic or monoamine oxidase inhibitor antidepressants within 4 weeks prior to study entry. 11. More than 50 percent change in the weekly dosage of any pain control medications within 2 weeks prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Phenytoin or carbamazepine. 2. Capsaicin. 3. Heterocyclic or monoamine oxidase inhibitor antidepressants. 4. Disopyramide. 5. Procainamide. 6. Quinidine. 7. Tocainide. 8. Flecainide acetate. 9. Encainide. 10. Lidocaine. 11. Cisplatin. 12. Vincristine. 13. Chloramphenicol, disulfiram, ethionamide glutethimide, gold, hydralazine, iodoquinol, metronidazole, nitrofurantoin, or ribavirin (only in patients in whom the onset or clear worsening of painful peripheral neuropathy was attributed to previously taking these drugs). 14. Any investigational drugs other than d4T (except with permission of the protocol team). 15. Terfenadine (if concurrent with ketoconazole). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Diabetes mellitus. 2. Neurological disease of sufficient severity to confound the evaluation of peripheral neuropathy, such as myelopathy without neuropathy. (NOTE: Patients with both myelopathy AND painful peripheral neuropathy are eligible.) 3. Electrocardiogram (EKG) indicating malignant arrhythmia or cardiac conduction disturbances (such as second or third degree AV block, anterior hemi-block, or prolonged QT interval). 4. Suicidal thoughts of sufficient severity to require treatment with antidepressant medication. SUBSTANCE IDENTIFICATION Drug 1 DRG-0197 Mexiletine hydrochloride SUBSTANCE IDENTIFICATION Drug 2 DRG-0198 Benztropine mesylate SUBSTANCE IDENTIFICATION Drug 3 DRG-0169 Amitriptyline hydrochloride TRADE NAME OF SUBSTANCE Drug 1‰ Mexitil TRADE NAME OF SUBSTANCE Drug 2‰ Cogentin TRADE NAME OF SUBSTANCE Drug 3‰ Elavil MANUFACTURERS Drug 1: Boehringer Ingelheim Pharmaceuticals Inc 900 Ridgebury Road / PO Box 368 Ridgefield, CT 06877 Contact: Dr Pedro Urquilla (203) 791-6438. MANUFACTURERS Drug 2: Merck and Company Incorporated Professional Services West Point, PA 19486 Contact: Professional Information (215) 661-7300 Contact: Prof Info / Call Collect (215) 652-3298. MANUFACTURERS Drug 3: Stuart Pharmaceuticals Professional Services Wilmington, DE 19897 Contact: Professional Services (302) 886-2231. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 150 mg (or placebo) nightly as starting dose, with upwatitration over a period of 4 weeks to a maximum of 300 mg BID; followed by at least 4 additional weeks at the final dose and tgradual tapering off of drug. Drug 2: Minimum effective dose, MTD, or 0.5 mg nightly as activplacebo, taken on same schedule as mexiletine. Drug 3: 25 mg (or placebo) nightly as starting dose, with upwartitration over a period of 4 weeks to a maximum of 100 mg nightfollowed by at least 4 additional weeks at the final dose and tgradual tapering off of drug SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 150 mg - 600 mg. Drug 2: Up to 0.5 mg. Drug 3: 25 - 100 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 150 mg gelatin capsules. Drug 2: Oral, 0.125 mg gelatin capsules. Drug 3: Oral, 25 mg gelatin capsules OTHER TREATMENT INFO. TREATMENT DURATION: Approximately 10 weeks. OTHER TREATMENT INFO. END POINT: Primary: Decline in mean pain intensity score between baseline and week 8 of treatment, toxicity. Secondary: Global pain relief, mood, quality of life, requirement for additional analgesic agents, relation of drug level to pain intensity, patient compliance. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Grade 3 or 4 drug-related toxicity. 2. Seizure. 3. Cardiac conduction disturbance. 4. Malignant arrhythmia. 5. Pregnancy. OTHER TREATMENT INFO. MODIFICATION: For grade 3 and 4 drug-related toxicities: Hold study drug. If toxicity resolves to grade 2 or better within 21 days, then resume study drug at the next lower dose. If the reduced toxicity improves even further, then increase dose to the next higher level. If toxicity does not resolve to grade 2 or better after initially holding drug for 21 days, or if the reduced toxicity does not improve after 21 days at the next lower dose, then discontinue study drug permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Boehringer Ingelheim Pharmaceuticals Inc. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Amitriptyline/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Benztropine/ANALOGS & DERIVATIVES/ *ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/ THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Mexiletine/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Middle Age MESH HEADING Pain/*DRUG THERAPY MESH HEADING Parasympatholytics/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Peripheral Nervous System Diseases/ *COMPLICATIONS CAS REGISTRY NUMBER 0 (Parasympatholytics) CAS REGISTRY NUMBER 132-17-2 (benzatropine methanesulfonate) CAS REGISTRY NUMBER 31828-71-4 (Mexiletine) CAS REGISTRY NUMBER 50-48-6 (Amitriptyline) LAST REVISION DATE 941207 ENTRY MONTH 9403 ALABAMA University of Alabama at Birmingham 908 20th Street S / 1917 Research Clinic Room 135 Birmingham, AL 35294-2041 Contact: Susan Duncan (205) 934-3690 OPEN 940308 ACTU: 5801. CALIFORNIA University of California at Los Angeles School of Medicine 60051 CHS / 10833 Le Conte Avenue Los Angeles, CA 90024-1793 Contact: Susan G McCarthy (310) 825-1301 OPEN 940308 ACTU: 0601. CALIFORNIA Harbor General / REI Lab / UCLA 1124 West Carson Street Torrance, CA 90502 Contact: Sally Kruger (310) 222-3848 Contact: Rick Johnson OPEN 940216 ACTU: 0603. CALIFORNIA Veterans Admin Hospital at San Diego / UCSD Med Center 9500 Gilman Drive / # 0672 La Jolla, CA 92093 Contact: Candace McIvor (619) 534-7170 OPEN 941107 ACTU: 0702. CALIFORNIA University of California San Diego 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 940930 ACTU: 0701. CALIFORNIA San Francisco General Hospital / UCSF 995 Potrero Avenue / Building 80 Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940707 ACTU: 0801. CALIFORNIA UCSF / AIDS Clinic Ambulatory Care Center 995 Potrero Avenue San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940706 ACTU: 0802. CALIFORNIA Merrit-Peralta Medical Ctr/Adult Immunology Clinic U of CA 450 30th Street Oakland, CA 94609 Contact: Bruce Ross (510) 273-8200 Contact: David Greenberg OPEN 940707 ACTU: 0804. COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 940705 ACTU: 6101. COLORADO Rose Med Ctr / Univ of Colorado Hlth Sci Ctr / Colorado ACTU Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 941004 ACTU: 6104. CONNECTICUT Yale University School of Medicine / Sect of Infectious Dis 135 College Street New Haven, CT 06510-2483 Contact: Laurie Andrews (203) 737-4040 OPEN 941017 ACTU: 6401. DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 940906 ACTU: 5701. DISTRICT OF COLUMBIA Howard U Coll of Med / AIDS Minority Infrastructure Program 2112 Georgia Avenue NW Washington, DC 20059 Contact: Victoria Holly -Trimmer (202) 806-4700 Contact: (202) 806-4755 OPEN 940705 ACTU: 5301. IOWA University of Iowa / UH Nursing W321 GH Internal Medicine SW34-GH Iowa City, IA 52242 Contact: Julie Katseres (319) 353-8441 OPEN 940627 ACTU: 1504. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 940829 ACTU: 2701. ILLINOIS Louis A Weiss Memorial Hospital / Northwestern Univ Med Schl 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941017 ACTU: 2708. ILLINOIS Illinois Masonic Med Ctr / Northwestern Univ Med Schl Passavant Pavilion Room 823 / 303 East Superior Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 941006 ACTU: 2707. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940829 ACTU: 2702. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940701 ACTU: 2601. MASSACHUSETTS Massachusetts General Hospital / Harvard 55 Fruit Street Gray 5 Boston, MA 02114 Contact: Ellen Godfrey (617) 726-5598 OPEN 940713 ACTU: 0101. MASSACHUSETTS Boston City Hospital / AIDS Research Office 818 Harrison Avenue ACC 5th Floor Room 5D11 Boston, MA 02118 Contact: Beverly Byam (617) 534-5160 OPEN 940701 ACTU: 0104. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 940701 ACTU: 0201. MINNESOTA St Paul-Ramsey Medical Center 640 Jackson Street St Paul, MN 55101 Contact: Ray Nelson (612) 221-1280 OPEN 940701 ACTU: 1503. MINNESOTA Hennepin County Med Clinic / Univ of Minnesota Hosp Clinic 420 Delaware Street SE / Room G255 Mayo Building Minneapolis, MN 55415 Contact: Renee St Jacques (612) 373-1810 OPEN 940701 ACTU: 1502. MINNESOTA University of Minnesota Hospital and Clinic PO Box 437 / UMHC / Harvard Street & East River Road Minneapolis, MN 55455 Contact: Nancy Reed (612) 625-1462 OPEN 940308 ACTU: 1501. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 940809 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 940809 ACTU: 2102. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 941102 ACTU: 3201. NEBRASKA University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-5130 Contact: Frances Tennant (402) 559-5750 OPEN 940228 ACTU: 1505. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940701 ACTU: 1801. NEW YORK Columbia Presbyterian Medical Center 622 West 168 Street / Harkness Pavilion 5 Room 516 New York, NY 10032-3784 Contact: Mykyelle Wade (212) 305-8507 OPEN 941011 ACTU: 7501. NEW YORK Montefiore Drug Treatment Center 418 Forchheimer-ID / 1300 Morris Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3639 Contact: (718) 920-5344 OPEN 940804 ACTU: 1905. NEW YORK North Central Bronx Hospital / Montefiore Family Health Cntr 418 Forchheimer-ID/1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940803 ACTU: 1906. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940804 ACTU: 1903. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940301 ACTU: 1901. NEW YORK Comprehensive Health Care Center 418 Forchheimer-ID / 1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940808 ACTU: 1908. NEW YORK Albert Einstein College of Medicine 418 Forcheimer / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940804 ACTU: 1904. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 940228 ACTU: 1902. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 941102 ACTU: 1103. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 941205 ACTU: 1102. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 940701 ACTU: 1101. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 940706 ACTU: 2501. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 941207 ACTU: 2401. PENNSYLVANIA Thomas Jefferson Unversity 1015 Chestnut Street Philadelphia, PA 19107 Contact: Lyle Jew (215) 955-7785 OPEN 940701 ACTU: 6202. 29 UNIQUE IDENTIFIER NIH/00562 PROTOCOL ID NUMBERS NIAID ACTG 240 PROTOCOL TITLE A Randomized, Comparative Trial of Zidovudine (AZT) Versus 2',3'-Didehydro-3'-deoxythymidine (Stavudine; d4T) in Children With HIV Infection. VERSION NUMBER & DATE 2 (940110) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child PROTOCOL CHAIRS CHAIR Kline M PROTOCOL CHAIRS CO-CHAIR Van Dyke R GENERAL DESCRIPTION PURPOSE: PRIMARY: To compare the relative safety and tolerance of oral zidovudine (AZT) versus oral stavudine (d4T) in symptomatic HIV-infected children. SECONDARY: To compare the clinical, virologic, and immunologic responses between the two treatment groups, and to obtain pharmacokinetic data for both drugs. GENERAL DESCRIPTION RATIONALE: At present, AZT is considered the drug of choice for initial treatment of most children with HIV infection, although disease progression or drug intolerance is associated with its long-term use. In preliminary studies in children, d4T, another HIV inhibitor, has been well tolerated, although an optimum dose has not been determined. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either oral AZT or oral d4T. Treatment continues until the last patient enrolled has received 52 weeks of therapy, or until the study is terminated. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Evidence of HIV-1 infection as follows: o Children younger than 15 months must have one positive peripheral blood viral isolation, with a second blood specimen positive by qualitative culture, DNA-PCR, or neutralizable p24 antigen assay. NOTE: Cord blood is NOT acceptable. o Children older than 15 months must have either of the above criteria OR two positive tests for HIV antibody by ELISA, with one test confirmed by Western blot or immunofluorescence assay. 2. Immunologic evidence of HIV disease as follows: o Age < 12 months - < 1750 cells/mm3 o Ages 12-23 months - < 1000 cells/mm3 o Ages 2-6 - < 750 cells/mm3 AND/OR One or more of the following clinical symptoms: o AIDS by CDC criteria o Failure to thrive o Persistent or recurrent oral candidiasis o Thrombocytopenia o Two or more episodes of herpes simplex infection (other than herpes labialis) or one episode of herpes zoster o Persistent diarrhea o Lymphoid interstitial pneumonia and/or pulmonary lymphoid hyperplasia (LIP/PLH complex) o Cardiomyopathy o Nephropathy o Parotitis (chronic parotid enlargement for 8 weeks or longer after diagnosis of HIV o Splenomegaly o Two secondary bacterial or fungal infections such as septicemia, meningitis, or pneumonia. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS IND 43,550 STUDY DESIGN Randomized; Double-Blind; 2-Arm; Dose Comparison; Drug Comparison; Drug Tolerance; Multicenter; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Drug efficacy, Pharmacokinetics, Comparative toxicity, Comparative drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 230 patients. 06 PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Minimum of 52 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 172/230 (941207). PROTOCOL DETAILS STUDY DURATION: Until 52 weeks after last patient enrolled. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 63 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Symptomatic HIV infection. 2. No more than 6 weeks of prior antiretroviral or immunomodulator therapy (other than steroids and IVIG). 3. Consent of parent or guardian. NOTE: Coenrollment on another ACTG protocol not involving antiretroviral therapy is permitted. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 03 Months - 06 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: 1. Maternal immunomodulator or antiretroviral therapy (including during pregnancy). 2. Antiretroviral therapy prior to 2 months. 3. Up to 6 weeks of prior antiretroviral therapy or specific immunomodulator therapy (other than corticosteroids and IVIG). OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Recommended: PCP prophylaxis. Allowed: 1. Immunoglobulin. 2. Erythropoietin, G-CSF, and GM-CSF. 3. Corticosteroids. 4. Ethionamide or isoniazid for TB if no alternative is available. 5. Pyridoxine (up to 50 mg/day) as vitamin supplement. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of grade 3 or worse neuropathy / lower motor neuronopathy. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 02 Months. 07 Years - 99 Years. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Ongoing drug or alcohol abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. More than 6 weeks of prior antiretroviral or immunomodulator therapy. 2. Antiretroviral or immunomodulator therapy within 7 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Chemotherapy for active malignancy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Current grade 3 or worse neuropathy / lower motor neuronopathy. 2. Other grade 3 or worse clinical or laboratory toxicities. 3. Known intolerance to either AZT or d4T. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0043 Stavudine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir TRADE NAME OF SUBSTANCE Drug 2‰ d4T MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle Park, NC 27709 Contact: Mary Maha Elkins (919) 248-3294. MANUFACTURERS Drug 2: Bristol-Myers Squibb Company 5 Research Parkway Wallingford, CT 06492-7660 Contact: Dr Lisa Dunkle (203) 284-6903. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: BSA <= 1.11 m2: 180 mg/m2 (or placebo) q 6 hr for at least 52 weeks. BSA > 1.11: 200 mg (or placebo) q 6 hr for at least 52 weeks. Drug 2: Weight < 40 kg: 1 mg/kg (or placebo) q 12 hr for at leaweeks. Weight >= 40 kg: 40 mg (or placebo) q 12 hr for at least 52 we SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: Maximum 800 mg. Drug 2: Maximum 80 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg capsules and 10 mg/ml strawberry-flavored syrup. Drug 2: Oral, 5 and 10 mg capsules and 1 mg/ml powder for solu OTHER TREATMENT INFO. TREATMENT DURATION: Minimum of 52 weeks. OTHER TREATMENT INFO. END POINT: Drug-associated toxicity or intolerance. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Missed a total of 56 days of study drug. 2. Severe allergic reaction or life-threatening toxicity. 3. Development of aggressive Kaposi's sarcoma or other malignancies requiring chemotherapy or immunotherapy. 4. Patient noncompliance. 5. At the request of the FDA, pharmaceutical companies, IND sponsor, patient, parent or guardian, or investigator. OTHER TREATMENT INFO. MODIFICATION: For grade 3 toxicity: Hold study drug for up to 28 days; if toxicity has resolved to grade 1 or 2, then resume study drug at reduced dose. If toxicity remains at grade 1 or 2 after 28 days at reduced dose, then resume full dose. If grade 3 toxicity recurs at full dose, hold study drug for up to 28 days and then resume at permanent reduced dose. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Burroughs Wellcome, Bristol-Myers Squibb Company. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Child, Preschool MESH HEADING Female MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Stavudine/*ADVERSE EFFECTS MESH HEADING Zidovudine/*ADVERSE EFFECTS CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 3056-17-5 (Stavudine) LAST REVISION DATE 941207 ENTRY MONTH 9403 ALABAMA University of Alabama at Birmingham School of Medicine 751 CHT / University Station Birmingham, AL 35294 Contact: Michael Cooney (205) 939-9552 Contact: beeper (205) 869-9524 OPEN 940330 ACTU: 5046. CALIFORNIA Harbor General / UCLA Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 940513 ACTU: 3609. CALIFORNIA UCLA Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 940228 ACTU: 3601. CALIFORNIA Martin Luther King Jr / Drew Medical School / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 940502 ACTU: 3605. CALIFORNIA Long Beach Memorial Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 940602 ACTU: 3606. CALIFORNIA Los Angeles County USC Medical Center 1129 North State Street Los Angeles, CA 90033 Contact: Janice Ono (213) 226-3945 OPEN 940330 ACTU: 5048. CALIFORNIA University of CA San Diego Medical Center / Pediatric 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 940418 ACTU: 4601. CALIFORNIA UCSF / Moffitt Hospital 602 / Pediatrics 505 Parnassus / Box 0105 San Francisco, CA 94143-0105 Contact: Debbie Trevithick (415) 476-6480 OPEN 940311 ACTU: 4501. CALIFORNIA Children's Hospital Oakland 747 Fifty Second Street Oakland, CA 94609-1809 Contact: Jim Riddel (510) 428-3000 X 282Contact: (510) 539-6311 X PagOPEN 940218 ACTU: 4504. COLORADO University of Colorado Hlth Sciences Ctr / Peds Infect Dis 1056 East 19Th Avenue B055 Denver, CO 80218-1088 Contact: Carol Salbenblatt (303) 861-6751 OPEN 940624 ACTU: 7001. CONNECTICUT Univ of Connecticut Farmington / Univ of CT Health Center 263 Farmington Avenue Farmington, CT 06032 Contact: Lorraine Wells (203) 679-2320 OPEN 940721 ACTU: 7303. CONNECTICUT Yale University School of Medicine PO Box 3333 / 333 Cedar Street New Haven, CT 06510-8064 Contact: Unspecified (203) 737-4040 OPEN 940228 ACTU: 5038. DISTRICT OF COLUMBIA Children's National Medical Center / Special Immuno Svc Suite 2108 / 111 Michigan Avenue NW Washington, DC 20010-2970 Contact: Sandra Jones (202) 884-3682 OPEN 940325 ACTU: 7101. DISTRICT OF COLUMBIA Howard University Hospital 2041 Georgia Avenue NW Washington, DC 20060 Contact: Dr Helga Finke (202) 865-1248 OPEN 940323 ACTU: 5044. FLORIDA Northeast Florida AIDS Program / Div of Pediatric Inf Dis/Im 653-1 W 8th Street Jacksonville, FL 32209 Contact: Michelle Eagle (904) 549-3051 OPEN 940823 ACTU: 5051. FLORIDA Univ of Miami School of Medicine / Pediatric Imm Infect Dis 1800 NW Tenth Avenue Miami, FL 33136 Contact: Janet Gourley (305) 548-4446 OPEN 940608 ACTU: 4201. GEORGIA Emory University Hospital 69 Butler Street SE Atlanta, GA 30303 Contact: Judy Sarver (404) 616-6227 Contact: clinic (404) 616-4390 Contact: beeper (404) 899-5290 OPEN 940304 ACTU: 5030. ILLINOIS University of Illinois at Chicago 840 S Wood Street Chicago, IL 60612 Contact: Patricia Naughton (312) 996-1778 OPEN 940504 ACTU: 5028. ILLINOIS Chicago Children's Memorial Hospital / Pediatric 2300 Childrens Plaza Box 20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 940210 ACTU: 4001. ILLINOIS Cook County Hospital / Childrens Memorial 2300 Childrens Plaza Box #20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 940406 ACTU: 4002. ILLINOIS Wyler Children's Hospital 5841 South Maryland Avenue Chicago, IL 60637-1470 Contact: Kim Stieglitz (312) 702-6176 OPEN 940311 ACTU: 4003. LOUISIANA Tulane University School of Medicine / Div of Ped Infect Dis 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 940228 ACTU: 7201. MASSACHUSETTS Baystate Medical Center / Department of Pediatrics 759 Chestnut Street / SHU-Main 3 Springfield, MA 01199 Contact: MaryPat Toye (413) 784-5399 OPEN 940210 ACTU: 7302. MASSACHUSETTS University of Massachusetts Medical School / Dept of Peds 55 Lake Avenue North Worcester, MA 01655-0001 Contact: Joanne Shepard (508) 856-1692 OPEN 940516 ACTU: 7301. MASSACHUSETTS Children's Hospital 300 Longwood Avenue / Carnegie 3 Boston, MA 02115 Contact: Robert Bishop (617) 735-8198 OPEN 940210 ACTU: 2901. MASSACHUSETTS Boston City Hospital / Ped Infect Dis / Finland Lab 774 Albany Street / Finland Lab Room 301 Boston, MA 02118 Contact: Anne Marie Reagan (617) 534-5813 OPEN 940304 ACTU: 2903. MARYLAND University of Maryland School of Medicine / Pediatrics 120 Penn Street Baltimore, MD 21201 Contact: Sue Lovelace (410) 706-8220 OPEN 940303 ACTU: 3702. MICHIGAN Children's Hospital of Michigan 3901 Beaubien Boulevard Detroit, MI 48201 Contact: Charnell Cromer (313) 745-5565 OPEN 940128 ACTU: 5041. NORTH CAROLINA University of North Carolina at Chapel Hill / UNC CTU 516 Burnett Womack / CB# 7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-7883 OPEN 940323. NORTH CAROLINA Duke University Medical Center / Pediatrics Box 3499 Durham, NC 27710 Contact: John Swetnam (919) 684-6335 OPEN 940210 ACTU: 4701. NEW JERSEY Children's Hospital of New Jersey 15 South 9th Street / CHAP Program 5 East Newark, NJ 07107 Contact: George Donovan Mcsherry (201) 268-8273 OPEN 940307 ACTU: 2801. NEW JERSEY Children's Hospital of New Jersey 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan McSherry (201) 268-8273 OPEN 940307 ACTU: 2803. NEW JERSEY Robert Wood Johnson University Hospital / UMDNJ One Robert Wood Johnson Place CN19 New Brunswick, NJ 08903-0019 Contact: Ida Kechula (908) 937-7894 OPEN 940323 ACTU: 5032. NEW YORK Beth Israel Medical Center / Pediatrics First Avenue at 16th Street Dazian Pavilion Tenth Floor New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 940303 ACTU: 4302. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue / Pediatric New York, NY 10016 Contact: Nagamah Deygoo (212) 263-6426 OPEN 940308 ACTU: 4401. NEW YORK Mount Sinai School of Medicine / Pediatrics One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940228 ACTU: 4301. NEW YORK Metropolitan Hospital Center / Pediatrics Department 1901 First Avenue New York, NY 10029 Contact: Mavis Dummit (212) 230-7103 Contact: message machine (212) 230-6841 Contact: beeper (212) 537-1589 OPEN 940406 ACTU: 5003. NEW YORK Incarnation Children's Ctr / c/o Columbia Presb Med Ctr 142 Audubon Avenue New York, NY 10032 Contact: Pam Clark (212) 928-2228 OPEN 940228 ACTU: 4103. NEW YORK The Columbia Presbyterian Medical Hosp (Pediatric) 622 West 168th St Room 1161 New York, NY 10032-3796 Contact: Kathy A Shea (212) 305-7222 OPEN 940303 ACTU: 4101. NEW YORK Harlem Hospital 506 Lenox Avenue New York, NY 10037 Contact: Rick Urbano (212) 939-4040 Contact: (212) 939-4045 OPEN 940218 ACTU: 5006. NEW YORK Lincoln Hospital Center / Department of Pediatrics 234 East 149th Street Bronx, NY 10451 Contact: Annie Villareal (718) 579-5329 Contact: (718) 579-5000 OPEN 940509 ACTU: 5004. NEW YORK Bronx Lebanon Hospital Center / Department of Pediatrics 1650 Selwyn Avenue Room 2C Bronx, NY 10457 Contact: Patrice Edwards-Cihak (718) 960-1015 OPEN 940301 ACTU: 6901. NEW YORK Westchester Hospital / New York Medical College Munger Pavillion Room 134 Valhalla, NY 10595 Contact: Liz Ahern (914) 285-7898 Contact: (914) 993-4643 OPEN 940228 ACTU: 5005. NEW YORK North Shore University Hospital / Pediatric Immunology 350 Community Drive Manhasset, NY 11030 Contact: Cathy Macco (516) 773-7676 OPEN 940513 ACTU: 5010. NEW YORK King's County Hospital Center / SUNY HSCB 450 Clarkson Avenue Brooklyn, NY 11203 Contact: Helen Bergin (718) 245-3342 Contact: (718) 245-3341 Contact: (718) 245-4485 OPEN 940228 ACTU: 5035. NEW YORK SUNY at Brooklyn / Health Science Center / Pediatrics 450 Clarkson Avenue / Box 24 Brooklyn, NY 11203 Contact: Barbara Driscoll (718) 270-3081 OPEN 940210 ACTU: 5008. NEW YORK SUNY Health Science Center at Stony Brook HSC T 15 080 Stony Brook, NY 11794-8111 Contact: Peggy Melendez (516) 444-1313 Contact: (516) 444-7692 Contact: beeper (516) 282-8808 Contact: Jeannie Conner (516) 444-2724 OPEN 940323 ACTU: 5040. NEW YORK SUNY Health Science Center at Syracuse 750 East Adams Street Syracuse, NY 13210 Contact: Kathie Shea-Contello (315) 464-6331 OPEN 940504 ACTU: 5039. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 940311 ACTU: 1101. OHIO Children's Hospital 700 Children's Drive Columbus, OH 43205-2696 Contact: Jane Hunkler (614) 722-4460 Contact: (614) 722-6050 OPEN 940308 ACTU: 2302. OHIO Childrens Hospital of Cincinnati Eden and Bethesda Avenue Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 940504 ACTU: 2404. OTHER Ramon Ruiz Arnau University Hospital Laurel Avenue Bayamon, PR 00619 Contact: Leticia Diaz (809) 798-2733 OPEN 940317 ACTU: 5033. OTHER San Juan City Hospital / Puerto Rico Medical Center Department of Pediatrics Third Floor Hematology Rio Piedras, PR 00927 Contact: Esther Rosa (809) 764-3083 Contact: (809) 274-0904 OPEN 940311 ACTU: 5031. OTHER University of Puerto Rico / University Pediatric Hospital 4th Floor South Wing Room 4B-45 / GPO Box 365067 San Juan, PR 00936-5067 Contact: Carmen Rivera (809) 759-9595 Contact: (809) 765-1979 X 724OPEN 940308 ACTU: 6601. PENNSYLVANIA Children's Hospital of Philadelphia 34th Street & Civic Center Blvd Philadelphia, PA 19104-4399 Contact: Dr Deborah Schaible (215) 590-2097 Contact: Hospital Information (215) 590-1000 OPEN 940502 ACTU: 6701. PENNSYLVANIA Saint Christopher's Hospital for Children / Sect Imm & Rheum Erie Avenue at Front Street Philadelphia, PA 19134-1095 Contact: Carole Treston (215) 427-5284 Contact: FAX (215) 427-5555 OPEN 940301 ACTU: 6704. RHODE ISLAND Rhode Island Hospital / Brown University 593 Eddy Street Providence, RI 02903 Contact: Cathy Kneut (401) 467-9884 OPEN 940608 ACTU: 5047. SOUTH CAROLINA Medical University of South Carolina Clinical Science Building / 171 Ashley Avenue Charleston, SC 29425-3312 Contact: Genny Connelly (803) 792-2385 OPEN 940303 ACTU: 5037. 30 UNIQUE IDENTIFIER NIH/00589 PROTOCOL ID NUMBERS NIAID ACTG 239 PROTOCOL TITLE A Phase I/II Study to Evaluate the Safety, Toxicity, and Effect of Zidovudine Versus Combination Therapy With Zidovudine and Didanosine on CD4 Decline and Growth in Young Infants With HIV Infection. VERSION NUMBER & DATE 2 (940707) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Kovacs A PROTOCOL CHAIRS CO-CHAIR Husson R GENERAL DESCRIPTION PURPOSE: To determine the pharmacokinetics, safety, and efficacy of didanosine (ddI) alone or in combination with zidovudine (AZT) in HIV-infected infants. GENERAL DESCRIPTION RATIONALE: Early treatment of HIV-infected infants with antiretroviral agents may prevent the early and rapid decline of CD4 count and immunologic function. Combination therapy may be preferred over monotherapy, since resistance to a single agent can develop rapidly. Currently, there is little information on ddI monotherapy in young infants less than 90 days and no information on the use of combination therapy in this population. GENERAL DESCRIPTION METHODOLOGY: In Part A, a cohort of patients < 120 days of age receives open-label ddI monotherapy for 1 week before initiation of AZT/ddI combination therapy. After pharmacokinetic data is obtained, an additional cohort of patients receive ddI at a higher dose. An age-adjusted dose for ddI is determined for use in Part B. Part B patients (< 180 days of age) are randomized, on a double-blind basis, to receive AZT or AZT/ddI. All patients continue treatment until 12 months after the last patient on Part B is enrolled. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Documented HIV infection by positive culture or DNA-PCR (neutralizable p24 antigen also acceptable if age > 28 days), with confirmation by a second test. NOTE: Cord blood is not acceptable. 2. Asymptomatic infection with CD4 count <= 1750 cells/mm3 or < 30 percent OR symptomatic infection (diagnosis of AIDS permitted). ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND 35,208 STUDY DESIGN Randomized; Pharmacokinetic; Drug Tolerance; Drug Combination; Multicenter PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Combination and single drug therapy, Combination and single pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 164 - 184 patients. (14-34 patients in Part A; 150 patients total in Part B) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Until 12 months after last Part B patient is enrolled. PROTOCOL DETAILS ACTUAL ACCRUAL: 8/164 - 184 (941207). PROTOCOL DETAILS STUDY DURATION: 2.5 - 3 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 24 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. Asymptomatic disease with CD4 count >= 1750 cells/mm3 or < 30 percent OR symptomatic disease. NOTE: Per 07/07/94 amendment, patients in Part A are < 120 days of age and in Part B are < 180 days of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: > 24 percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: > 8 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 1750 cells/mm3. or < 30 percent (asymptomatic patients only). ( 0 - 100 - 200 - 300 - 400 - 500 - 600 - 700 - 800 - plus). PATIENT INCLUSION CRIT. BILIRUBIN: < 2.6 x ULN mg/dl. in the absence of other unexplained causes (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 10 x ULN. in the absence of other unexplained causes. PATIENT INCLUSION CRIT. CREATININE: < 1.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: WBC > 1500 cells/mm3. Neutrophils > 500 cells/mm3. Pancreatic amylase and lipase < 2 x ULN. PATIENT AGE AGE: 01 Days - 06 Months. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. PRIOR TREATMENT: Allowed: Recent transfusions. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior vaccine therapy. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Recommended: PCP prophylaxis. Allowed: Acetaminophen if not on a continual basis. NOTE: Drugs that are metabolized by hepatic glucuronidation or that are associated with occurrence of pancreatitis are allowed but should be used with caution. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: Pancreatitis at any time since birth. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded in Part B patients only: More than 90 days of prior antiretroviral or immunomodulator therapy, exclusive of therapy received in utero. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Vaccine therapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Pancreatitis. 2. Clinically unstable condition. 3. Current participation on a vaccine trial. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0016 Didanosine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir TRADE NAME OF SUBSTANCE Drug 2‰ Videx MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle Park, NC 27709 Contact: Mary Maha Elkins (919) 248-3294. MANUFACTURERS Drug 2: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Colin McLaren (203) 284-6942. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 3 or 180 mg/m2 q 6 hr, depending on age. Drug 2: 25, 50, or 90 mg/m2 q 12 hr, depending on age SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 12 or 720 mg/m2. Drug 2: 50, 100, or 180 mg/m2 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 10 mg/ml syrup. Drug 2: Oral, 10 or 20 mg/ml solution OTHER TREATMENT INFO. TREATMENT DURATION: Until 12 months after last patient is enrolled. OTHER TREATMENT INFO. END POINT: Part A: Safety, toxicity, and pharmacokinetic profile of ddI/AZT. Part B: Long-term toxicity of AZT and AZT/ddI, CD4 count and growth differences. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Missed a total of 56 days of study drug. 2. Severe allergic reaction or life-threatening toxicity. 3. Development of malignancies requiring chemotherapy or immunotherapy. 4. Patient noncompliance. 5. At request of FDA, pharmaceutical companies, IND sponsor, patient, parent, legal guardian, or investigator. OTHER TREATMENT INFO. MODIFICATION: Doses are reduced or discontinued for specific toxicities. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Didanosine/ADVERSE EFFECTS/*PHARMACOKINETICS/ THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Zidovudine/ADVERSE EFFECTS/*PHARMACOKINETICS/ THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 941207 ENTRY MONTH 9404 CALIFORNIA Long Beach Memorial Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 941024 ACTU: 3606. CALIFORNIA Los Angeles County USC Medical Center 1129 North State Street Los Angeles, CA 90033 Contact: Janice Ono (213) 226-3945 OPEN 940401 ACTU: 5048. COLORADO University of Colorado Hlth Sciences Ctr / Peds Infect Dis 1056 East 19Th Avenue B055 Denver, CO 80218-1088 Contact: Carol Salbenblatt (303) 861-6751 OPEN 940506 ACTU: 7001. DISTRICT OF COLUMBIA Howard University Hospital 2041 Georgia Avenue NW Washington, DC 20060 Contact: Dr Helga Finke (202) 865-1248 OPEN 940405 ACTU: 5044. FLORIDA Univ of Miami School of Medicine / Pediatric Imm Infect Dis 1800 NW Tenth Avenue Miami, FL 33136 Contact: Janet Gourley (305) 548-4446 OPEN 940504 ACTU: 4201. ILLINOIS Chicago Children's Memorial Hospital / Pediatric 2300 Childrens Plaza Box 20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 940426 ACTU: 4001. ILLINOIS Wyler Children's Hospital 5841 South Maryland Avenue Chicago, IL 60637-1470 Contact: Kim Stieglitz (312) 702-6176 OPEN 940919 ACTU: 4003. LOUISIANA Tulane University School of Medicine / Div of Ped Infect Dis 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 940927 ACTU: 7201. MASSACHUSETTS Baystate Medical Center / Department of Pediatrics 759 Chestnut Street / SHU-Main 3 Springfield, MA 01199 Contact: MaryPat Toye (413) 784-5399 OPEN 940406 ACTU: 7302. MASSACHUSETTS Children's Hospital 300 Longwood Avenue / Carnegie 3 Boston, MA 02115 Contact: Robert Bishop (617) 735-8198 OPEN 940401 ACTU: 2901. MICHIGAN Children's Hospital of Michigan 3901 Beaubien Boulevard Detroit, MI 48201 Contact: Charnell Cromer (313) 745-5565 OPEN 941024 ACTU: 5041. NORTH CAROLINA Duke University Medical Center / Pediatrics Box 3499 Durham, NC 27710 Contact: John Swetnam (919) 684-6335 OPEN 940401 ACTU: 4701. NEW JERSEY Children's Hospital of New Jersey 15 South 9th Street / CHAP Program 5 East Newark, NJ 07107 Contact: George Donovan Mcsherry (201) 268-8273 OPEN 940513 ACTU: 2801. NEW JERSEY Univ of Med & Dentistry of NJ / Univ Hospital 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan Mcsherry (201) 268-8273 OPEN 940406 ACTU: 2802. NEW YORK Dr Dorothy Friedberg 310 Lexington Avenue New York, NY 10016 Contact: Kathleen Farrell (212) 263-6485 Contact: Dr Dorothy Friedberg (212) 263-8473 OPEN 940624. NEW YORK Incarnation Children's Ctr / c/o Columbia Presb Med Ctr 142 Audubon Avenue New York, NY 10032 Contact: Pam Clark (212) 928-2228 OPEN 940502 ACTU: 4103. NEW YORK The Columbia Presbyterian Medical Hosp (Pediatric) 622 West 168th St Room 1161 New York, NY 10032-3796 Contact: Kathy A Shea (212) 305-7222 OPEN 940502 ACTU: 4101. NEW YORK Bronx Lebanon Hospital Center / Department of Pediatrics 1650 Selwyn Avenue Room 2C Bronx, NY 10457 Contact: Patrice Edwards-Cihak (718) 960-1015 OPEN 940906 ACTU: 6901. NEW YORK Children's Hospital at Albany Medical Center 22 New Scotland Avenue Albany, NY 12208 Contact: Mary Ellen Adams (518) 432-1501 OPEN 941005 ACTU: 5042. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 941130 ACTU: 1101. OTHER San Juan City Hospital / Puerto Rico Medical Center Department of Pediatrics Third Floor Hematology Rio Piedras, PR 00927 Contact: Esther Rosa (809) 764-3083 Contact: (809) 274-0904 OPEN 940610 ACTU: 5031. OTHER University of Puerto Rico / University Pediatric Hospital 4th Floor South Wing Room 4B-45 / GPO Box 365067 San Juan, PR 00936-5067 Contact: Carmen Rivera (809) 759-9595 Contact: (809) 765-1979 X 724OPEN 940706 ACTU: 6601. PENNSYLVANIA Children's Hospital of Philadelphia 34th Street & Civic Center Blvd Philadelphia, PA 19104-4399 Contact: Dr Deborah Schaible (215) 590-2097 Contact: Hospital Information (215) 590-1000 OPEN 940912 ACTU: 6701. SOUTH CAROLINA Medical University of South Carolina Clinical Science Building / 171 Ashley Avenue Charleston, SC 29425-3312 Contact: Genny Connelly (803) 792-2385 OPEN 940610 ACTU: 5037. 31 UNIQUE IDENTIFIER NIH/00530 PROTOCOL ID NUMBERS NIAID ACTG 238 PROTOCOL TITLE A Prospective Study of Multidrug Resistance and a Pilot Study of the Safety of and Clinical and Microbiologic Response to Levofloxacin in Combination With Other Antimycobacterial Drugs for Treatment of Multidrug-Resistant Pulmonary Tuberculosis (MDRTB) in HIV-Infected Patients. VERSION NUMBER & DATE 6 (940928) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Epidemiology GENERAL DESCRIPTION PURPOSE: To determine the demographic, behavioral, clinical, and geographic risk factors associated with the occurrence of multi-drug resistant pulmonary tuberculosis (MDRTB). To evaluate the clinical and microbiological responses and overall survival of MDRTB patients who are treated with levofloxacin-containing multiple-drug regimens chosen from a hierarchical list. Per 9/28/94 amendment, to assess whether persistent or recurrent positive sputum cultures of patients who show failure or relapse are due to the same strain or reinfection with a new strain. GENERAL DESCRIPTION RATIONALE: Among TB patients, there has been an increase in progressive disease due to the emergence of antimycobacterial drug-resistant strains of Mycobacterium tuberculosis. Failure to identify patients at high risk for MDRTB increases the hazard for both treatment failure and development of resistance to additional therapeutic agents. Efforts to improve survival in patients with MDRTB will depend on improved methods of assessing the risk of acquisition of MDRTB and identifying drug susceptibility patterns in a timely fashion. GENERAL DESCRIPTION METHODOLOGY: Patients are asked a series of questions to determine epidemiologic factors that may be predictive of MDRTB. Patients who are determined to be at low risk for MDRTB will be referred to another TB treatment protocol (ACTG 222), if appropriate. Patients suspected of having primary or acquired MDRTB or those with confirmed MDRTB will be offered a regimen of anti-TB therapy from a hierarchically ordered list of drugs, based on the patient's resistance status (suspect primary MDRTB, suspect acquired MDRTB, or confirmed MDRTB). The hierarchical list is as follows: isoniazid, rifampin, ethambutol, streptomycin, levofloxacin, ethionamide, cycloserine, capreomycin, aminosalicylic acid, and clofazimine. Treatment will be administered daily for at least 6 months, then on an intermittent schedule at the clinician's discretion. Patients with confirmed MDRTB (defined as known resistance to at least isoniazid and rifampin within 6 months prior to study entry) will receive a minimum of 18 months of treatment following sputum culture conversion. Follow-up is performed every 4 weeks for 8 weeks, and then every 8 weeks. PROTOCOL PHASE Epidemiology / Treatment Pilot OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Tuberculosis. DISEASES STATUS Patients have the following symptoms and conditions. EPIDEMIOLOGIC AND TREATMENT PILOT: 1. Working diagnosis of HIV infection based on medical history, behavioral history, clinical signs and symptoms, and laboratory tests. 2. Working diagnosis of pulmonary TB. Per 08/02/94 amendment, patients with confirmed MDRTB at baseline are not eligible for the epidemiologic study only. TREATMENT PILOT ONLY: 1. Positive sputum AFB smear (or a positive sputum culture for TB within 6 months prior to study entry). NOTE: Extrapulmonary TB is permitted. 2. Assessment of suspect primary, suspect acquired, AND/OR confirmed MDRTB. (Patients are NOT eligible if they are at low risk for MDRTB, i.e., have no risk factors for either primary or acquired MDRTB, or if they have confirmed pansusceptibility or monoresistance for the present episode to isoniazid or rifampin.) ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS CPCRA 026. IND 42,796 STUDY DESIGN Prospective; Multicenter; Drug Combination; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Epidemiology, Comparative drug therapy, Combination drug therapy, Drug efficacy, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 525 patients. (525 patients for epidemiologic portion; 30 patients with confirmed MDRTB for treatment pilot) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 3 - 4.5 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 50/525 (941207). PROTOCOL DETAILS STUDY DURATION: Until 3 years following enrollment of last patient. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 21 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Working diagnosis of HIV infection. 2. Working diagnosis of pulmonary TB. Per 08/02/94 amendment, patients with confirmed MDRTB at baseline are not eligible for the epidemiologic study only. FOR TREATMENT PILOT: 1. Positive sputum AFB smear (or a positive sputum culture for TB within 6 months prior to study entry). 2. Assessment of suspect primary, suspect acquired, AND/OR confirmed MDRTB. 3. Life expectancy of at least 2 weeks. 4. Age >= 18 years for suspect MDRTB. Age >= 13 years for confirmed MDRTB. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 5 x ULN mg/dl. (ULN = upper limit of normal). (Treatment pilot patients). PATIENT INCLUSION CRIT. CREATININE: <= 3 x ULN. (Treatment pilot patients). PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant (except patients with confirmed MDRTB). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant (except patients with confirmed MDRTB). PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: More than 6 weeks total therapy within 3 months prior to study entry using three or more drugs effective against the isolates. (Per 08/02/94 amendment, patients from protocol ACTG 222/CPCRA 019 who have MDRTB are eligible for rollover to this study regardless of treatment duration on ACTG 222/CPCRA 019). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known hypersensitivity or resistance to quinolones. 2. Other disorders or conditions for which the study drugs are contraindicated. SUBSTANCE IDENTIFICATION Drug 1 DRG-0112 Amikacin SUBSTANCE IDENTIFICATION Drug 2 DRG-0199 Capreomycin sulfate SUBSTANCE IDENTIFICATION Drug 3 DRG-0067 Clofazimine SUBSTANCE IDENTIFICATION Drug 4 DRG-0195 Cycloserine SUBSTANCE IDENTIFICATION Drug 5 DRG-0111 Ethambutol SUBSTANCE IDENTIFICATION Drug 6 DRG-0196 Ethionamide SUBSTANCE IDENTIFICATION Drug 7 DRG-0123 Isoniazid SUBSTANCE IDENTIFICATION Drug 8 DRG-0129 Levofloxacin SUBSTANCE IDENTIFICATION Drug 9 DRG-0200 Aminosalicylic acid SUBSTANCE IDENTIFICATION Drug 10: DRG-012 Pyrazinamide SUBSTANCE IDENTIFICATION Drug 11: DRG-012 Pyridoxine SUBSTANCE IDENTIFICATION Drug 12: DRG-010 Rifampin SUBSTANCE IDENTIFICATION Drug 13: DRG-020 Streptomycin sulfate MANUFACTURERS Drug 1: Bristol-Myers Squibb Company PO Box 4500 Princeton, NJ 08543-4500 Contact: Drug Information Department (800) 321-1335. MANUFACTURERS Drug 2: Eli Lilly and Company 307 East McCarty Street Indianapolis, IN 46285 Contact: Medical Department (800) 545-5979. MANUFACTURERS Drug 3: Ciba Pharmaceutical Company 556 Morris Avenue Summit, NJ 07901 Contact: Medical Services Department (908) 277-5000. MANUFACTURERS Drug 4: Eli Lilly and Company 307 East McCarty Street Indianapolis, IN 46285 Contact: Medical Department (800) 545-5979. MANUFACTURERS Drug 5: Lederle Laboratories Professional Services Department Pearl River, NY 10965 Contact: Professional Services (914) 735-2815. MANUFACTURERS Drug 6: Wyeth-Ayerst Laboratories PO Box 8299 Philadelphia, PA 19101 Contact: General Information (610) 688-4400. MANUFACTURERS Drug 7: Danbury Pharmacal 131 West Street Danbury, CT 06810 Contact: General Information (203) 744-7200. MANUFACTURERS Drug 8: Ortho Pharmaceutical Corporation Route 202 / PO Box 300 Raritan, NJ 08869-0602 Contact: Medical Inquiries (800) 682-6532. MANUFACTURERS Drug 9: Jacobus Pharmaceutical Company PO Box 5290 / 37 Cleveland Lane Princeton, NJ 08540 Contact: Professional Services (609) 921-7447. MANUFACTURERS Drug 10: Lederle Laboratories Professional Services Department Pearl River, NY 10965 Contact: Professional Services (914) 735-2815. MANUFACTURERS Drug 11: Tishcon Corporation 30 New York Avenue Westbury, NY 11590 Contact: Unspecified (516) 333-3050. MANUFACTURERS Drug 12: Marion Merrell Dow Medical Information / PO Box 9627 Kansas City, MO 64134-0627 Contact: Medical Information (800) 633-1610. MANUFACTURERS Drug 13: Pfizer Incorporated / Roerig Division 235 East 42nd Street New York, NY 10017-7851 Contact: Professional Information (212) 573-2187. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 15 mg/kg daily (only in patients whose isolates are resistant to streptomycin sulfate). Drug 2: 15 mg/kg daily. Drug 3: 100 - 200 mg daily. Drug 4: 0.5 - 1 g daily (given in doses of 250 mg BID or QID). Drug 5: 25 mg/kg daily or 25-30 mg/kg TIW (50 percent dose in patients with creatinine clearance < 50 ml/min; 25 percent dosethose with creatinine clearance < 10 ml/min). Drug 6: 0.5 - 1.0 g daily (given in doses of 250 mg BID or QID)Drug 7: 300 mg daily (600 mg daily at discretion of physician).Drug 8: 500 mg BID (50 percent dose in patients with creatinineclearance 20-50 ml/min). Drug 9: 4 g TID. Drug 10: 25 mg/kg daily or 50-70 mg/kg TIW, not to exceed 2.5 ggiven TIW. Drug 11: Administered with isoniazid. Drug 12: 600 mg daily. Drug 13: 15 mg/kg daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 15 mg/kg. Drug 2: 15 mg/kg. Drug 3: 100 - 200 mg. Drug 4: 0.5 - 1 g. Drug 5: 25 mg (if given daily). Drug 6: 0.5 - 1.0 g. Drug 7: 300 mg (600 mg at discretion of physician). Drug 8: 1000 mg (50 percent dose in patients with creatinine clearance 20-50 ml/min). Drug 9: 12 g. Drug 10: 25 mg/kg (if given daily). Drug 12: 600 mg. Drug 13: 15 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intramuscular (IM) or intravenous (IV), 500 mg vials. Drug 2: Intramuscular (IM) or intravenous (IV); 1 g vials. Drug 3: Oral, 100 mg capsules. Drug 4: Oral, 250 capsules. Drug 5: Oral, 400 mg tablets. Drug 6: Oral, 250 mg tablets. Drug 7: Oral, 300 mg tablets. Drug 8: Oral and intravenous; 125 and 500 mg tablets, 25 mg/ml Drug 9: Oral, 4 g packets. Drug 10: Oral, 500 mg tablets. Drug 11: Oral, 50 mg tablets. Drug 12: Oral, 150 and 300 mg tablets. Drug 13: Intramuscular (IM) or intravenous (IV); 1 g vials OTHER TREATMENT INFO. TREATMENT DURATION: At least 6 months. OTHER TREATMENT INFO. END POINT: Epidemiologic outcome measure: Drug susceptibility results of baseline sputum cultures. Treatment pilot: Survival, time to defervescence, weight change, time to sputum smear and culture conversion, treatment response, toxicity, and strain variation. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment permanently for the following reasons: 1. Found not to have MDRTB or HIV infection. 2. Not in the best interest of patient to continue. 3. Patient refusal to receive further therapy. 4. Termination of study. Patients discontinue treatment temporarily for the following reasons: 1. Unacceptable toxicity that resolves. 2. Development of acute opportunistic infection, acute bacterial infection, or malignancy. OTHER TREATMENT INFO. MODIFICATION: For grade 3 or 4 toxicity in the first 8-12 weeks of therapy: Hold drug or drugs most likely to be associated with the particular toxicity. For recurrent grade 3 or 4 toxicity, discontinue the drug permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), National Institute of Allergy & Infectious Diseases (CPCRA). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Amikacin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Aminosalicylic Acids/ADVERSE EFFECTS/ *THERAPEUTIC USE MESH HEADING Capreomycin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Clofazimine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Cycloserine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Resistance, Microbial MESH HEADING Drug Therapy, Combination MESH HEADING Ethambutol/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Ethionamide/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Isoniazid/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Ofloxacin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Opportunistic Infections/COMPLICATIONS/DRUG THERAPY/*EPIDEMIOLOGY MESH HEADING Pyrazinamide/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Pyridoxine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Rifampin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Streptomycin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Tuberculosis, Pulmonary/COMPLICATIONS/DRUG THERAPY/*EPIDEMIOLOGY MESH HEADING p-Aminosalicylic Acid/ADVERSE EFFECTS/ *THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Aminosalicylic Acids) CAS REGISTRY NUMBER 11003-38-6 (Capreomycin) CAS REGISTRY NUMBER 13292-46-1 (Rifampin) CAS REGISTRY NUMBER 2030-63-9 (Clofazimine) CAS REGISTRY NUMBER 37517-28-5 (Amikacin) CAS REGISTRY NUMBER 536-33-4 (Ethionamide) CAS REGISTRY NUMBER 54-85-3 (Isoniazid) CAS REGISTRY NUMBER 57-92-1 (Streptomycin) CAS REGISTRY NUMBER 65-23-6 (Pyridoxine) CAS REGISTRY NUMBER 65-49-6 (p-Aminosalicylic Acid) CAS REGISTRY NUMBER 68-41-7 (Cycloserine) CAS REGISTRY NUMBER 74-55-5 (Ethambutol) CAS REGISTRY NUMBER 82419-36-1 (Ofloxacin) CAS REGISTRY NUMBER 98-96-4 (Pyrazinamide) LAST REVISION DATE 941207 ENTRY MONTH 9403 ILLINOIS Cook County Hospital Passavant Pavilion / Room 823 / 303 East Superior Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940829 ACTU: 2705. MICHIGAN Henry Ford Hospital 2799 West Grand Boulevard Detroit, MI 48202 Contact: Diane Mastro-Polak (313) 876-7664 OPEN 940427. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 940210 ACTU: 1802. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 940317 ACTU: 0401. NEW YORK St Clare's Hospital and Health Center 415 West 51st Street New York, NY 10019 Contact: Phyllis Ristau (212) 459-8449 OPEN 940225 ACTU: 2204. NEW YORK Cornell University Medical Center 525 East 68th Street / Room 2434 New York, NY 10021 Contact: Brenda Greenhill (212) 746-4177 OPEN 940204 ACTU: 2201. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940627 ACTU: 1801. NEW YORK Columbia Presbyterian Medical Center 622 West 168 Street / Harkness Pavilion 5 Room 516 New York, NY 10032-3784 Contact: Mykyelle Wade (212) 305-8507 OPEN 940606 ACTU: 7501. NEW YORK Harlem AIDS Treatment Group Harlem Hospital / Women's Pavilion Room 126 New York, NY 10037 Contact: Joshua Standig (212) 939-2951 OPEN 940203. NEW YORK Bronx-Lebanon Hospital Center 1309 Fulton Avenue Bronx, NY 10456 Contact: Cathy Pollard (718) 293-2593 Contact: (718) 901-8916 OPEN 940204. NEW YORK Montefiore Drug Treatment Center 418 Forchheimer-ID / 1300 Morris Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3639 Contact: (718) 920-5344 OPEN 940228 ACTU: 1905. NEW YORK Comprehensive Health Care Center 418 Forchheimer-ID / 1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940228 ACTU: 1908. NEW YORK Albert Einstein College of Medicine 418 Forcheimer / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940228 ACTU: 1904. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940228 ACTU: 1903. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940204 ACTU: 1901. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 940204 ACTU: 1902. NEW YORK North Central Bronx Hospital / Montefiore Family Health Cntr 418 Forchheimer-ID/1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940228 ACTU: 1906. NEW YORK North Central Bronx Hospital / Samaritan Village Inc 418 Forchheimer ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940228 ACTU: 1907. NEW YORK SUNY Health Sciences Center at Brooklyn ACTU Box 77 / 450 Clarkson Avenue Brooklyn, NY 11203-2098 Contact: Donald Smith (718) 270-3372 Contact: (718) 270-3370 OPEN 940204 ACTU: 5901. NEW YORK Interfaith Medical Ctr / SUNY Brooklyn Health Sciences Ctr ACTU Box 77 / 450 Clarkson Avenue Brooklyn, NY 11203-2098 Contact: Donald Smith (718) 270-3372 Contact: (718) 270-3370 OPEN 940325 ACTU: 5902. NEW YORK Clinical Directors Network of Region II 5601 2nd Avenue #3 Brooklyn, NY 11220 Contact: Linda Podhurst (212) 255-3841 OPEN 940204. 32 UNIQUE IDENTIFIER NIH/00590 PROTOCOL ID NUMBERS NIAID ACTG 237 PROTOCOL TITLE Phase II Randomized Open-Label Trial of Atovaquone Plus Pyrimethamine and Atovaquone Plus Sulfadiazine for the Treatment of Acute Toxoplasmic Encephalitis. VERSION NUMBER & DATE 2 (940603) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the efficacy, safety, and tolerance of atovaquone with either pyrimethamine or sulfadiazine in AIDS patients with toxoplasmic encephalitis. GENERAL DESCRIPTION RATIONALE: AIDS patients with toxoplasmic encephalitis who receive the standard therapy combination of sulfadiazine and pyrimethamine experience a high frequency of severe toxicity. Atovaquone, an antibiotic that has demonstrated efficacy against toxoplasmosis in animal models and in preclinical testing has been well tolerated, is now available as a suspension, which is more readily absorbed than the tablet form of the drug. The efficacy and safety of atovaquone in combination with sulfadiazine or pyrimethamine will be studied. GENERAL DESCRIPTION METHODOLOGY: Seventy patients are randomized to receive atovaquone with either pyrimethamine or sulfadiazine for up to 48 weeks. Additionally, three cohorts of 10 patients each who have a history of treatment-limiting toxicity to pyrimethamine, sulfadiazine, or both drugs receive atovaquone plus the alternate drug or atovaquone plus clarithromycin. All patients receiving pyrimethamine also receive leucovorin protection. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Toxoplasmic encephalitis. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by ELISA (confirmed by Western blot), serum p24 antigen, or HIV culture OR prior diagnosis of AIDS by CDC definition (other than CD4 count < 200 cells/mm3). 2. Definitive, presumptive, or relapsed toxoplasmic encephalitis (progression of lesions or appearance of new lesions). ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS ANRS 039. IND 44,387 STUDY DESIGN Randomized; Open Label; 2-Arm; Noncomparative; Drug Tolerance; Drug Combination PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Combination drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 100 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 56 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 8/100 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 25 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection or diagnosis of AIDS (except for CD4 count < 200 cells/mm3). 2. Toxoplasmic encephalitis. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7 g/dl. (Transfusion permitted). PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 70 ml/min. (if creatinine value not available). PATIENT INCLUSION CRIT. KARNOFSKY: > 30. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Aerosolized pentamidine for PCP prophylaxis. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of treatment-limiting toxicity to atovaquone. 2. Receipt of > 72 hours of treatment prior to study entry for the current episode of toxoplasmic encephalitis. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Trimethoprim-sulfamethoxazole. 2. Primaquine. 3. Sulfonamides. 4. Antifolates. 5. Dapsone. 6. Clarithromycin (except for patients in the cohort to receive this drug). 7. Azithromycin. 8. Clindamycin. 9. Other macrolides. 10. Gamma interferon. 11. Metoclopramide. 12. G-CSF or GM-CSF. Excluded in patients receiving clarithromycin as study drug: Terfenadine, astemizole, or any other long-acting, non-sedating antihistamines. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Coma. 2. Opportunistic infection that requires either acute or maintenance treatment with disallowed medications. 3. Any infections or neoplasms of the central nervous system other than Toxoplasma, HIV encephalopathy, or syphilis. 4. Unable to take oral study drugs. 5. Malabsorption (i.e., three or more episodes of diarrhea per day that has caused >= 10 percent loss of body weight over the past 4 weeks). 6. Positive CSF for Cryptococcus antigen or culture. 7. Malignancy requiring use of cytotoxic chemotherapy. 8. Medical or social condition that would adversely affect study participation or compliance. SUBSTANCE IDENTIFICATION Drug 1 DRG-0084 Atovaquone SUBSTANCE IDENTIFICATION Drug 2 DRG-0027 Pyrimethamine SUBSTANCE IDENTIFICATION Drug 3 DRG-0002 Leucovorin calcium SUBSTANCE IDENTIFICATION Drug 4 DRG-0099 Clarithromycin SUBSTANCE IDENTIFICATION Drug 5 DRG-0214 Sulfadiazine TRADE NAME OF SUBSTANCE Drug 2‰ Daraprim TRADE NAME OF SUBSTANCE Drug 3‰ Wellcovorin TRADE NAME OF SUBSTANCE Drug 4‰ Biaxin MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 3: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 4: Abbott Laboratories One Abbott Park Road / Department 422 Abbott Park, IL 60064-3500 Contact: Medical Services (708) 938-0601. MANUFACTURERS Drug 5: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1500 mg BID for 6 weeks, with possible extension for anadditional 42 weeks. Drug 2: 200 mg on day 1, followed by 50 or 75 mg (depending on weight) daily for 6 weeks, with possible extension for an addit42 weeks. Drug 3: 10 mg daily administered with pyrimethamine. Drug 4: 500 mg BID for 6 weeks, with possible extension for an additional 42 weeks. Drug 5: 1000 or 1500 mg (depending on weight) QID for 6 weeks, possible extension for an additional 42 weeks at 1000 or 1500 mBID SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 3000 mg. Drug 2: 200 mg on day 1, then 50 or 75 mg. Drug 3: 10 mg. Drug 4: 1000 mg. Drug 5: 4000 or 6000 mg (for first 6 weeks), then 2000 or 3000 (for 42 weeks) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, micronized suspension (150 mg/ml) in 120 ml bottles. Drug 2: Oral, 25 mg scored tablets. Drug 3: Oral, 5 mg tablets. Drug 4: Oral, 500 mg tablets. Drug 5: Oral, 500 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: Up to 48 weeks. OTHER TREATMENT INFO. END POINT: Clinical response (quantifiable neurologic exam); radiologic response (CT or MRI). OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Negative Toxoplasma serology. 2. Brain biopsy or aspirate positive for an etiology other than toxoplasmosis. 3. Therapeutic failure on clinical or radiographic evaluation. 4. Unacceptable toxicity. 5. Requirement for therapy with a prohibited drug. 6. Pregnancy. 7. Development of malabsorption syndrome. 8. Currently receiving a rifamycin and has documented low plasma levels of atovaquone defined as <= 7 mcg/ml. 9. Considered in best interest of patient to withdraw from study or desire of patient to withdraw. OTHER TREATMENT INFO. MODIFICATION: Dose is held for specific toxicities. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Clarithromycin/ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Encephalitis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Human MESH HEADING Leucovorin/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Middle Age MESH HEADING Naphthoquinones/ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Pyrimethamine/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Sulfadiazine/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Toxoplasmosis, Cerebral/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 58-05-9 (Leucovorin) CAS REGISTRY NUMBER 58-14-0 (Pyrimethamine) CAS REGISTRY NUMBER 68-35-9 (Sulfadiazine) CAS REGISTRY NUMBER 81103-11-9 (Clarithromycin) CAS REGISTRY NUMBER 94015-53-9 (atovaquone) LAST REVISION DATE 941207 ENTRY MONTH 9408 FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 940720 ACTU: 0901. HAWAII Hawaii Aids Clinical Trails Unit Leahi Hospital / Young Bldg / 3675 Kilauea Avenue / 6th Flr Honolulu, HI 96816 Contact: Debra M Ogata Arakaki (808) 737-2751 OPEN 940922 ACTU: 5201. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 940907 ACTU: 2701. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940718 ACTU: 2601. INDIANA Methodist Hospital Of Indiana 550 North University Boulevard Room 5550 Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 941114 ACTU: 2602. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 940902 ACTU: 0201. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 940822 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 940822 ACTU: 2102. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 940817 ACTU: 1802. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 940822 ACTU: 0401. NEW YORK Harlem Hospital Center 506 Lenox Avenue / Room 3101A New York, NY 10037 Contact: Robin Flam (212) 939-3948 OPEN 941013 ACTU: 7502. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 940718 ACTU: 1902. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940718 ACTU: 1901. NEW YORK Bronx Veterans Administration Medical Center 130 West Kingsbridge Road Bronx, NY 10468 Contact: Nancy Ostrow (718) 584-9000 X 667Contact: (718) 584-9000 X 667OPEN 941014 ACTU: 1804. NEW YORK SUNY Health Sciences Center at Brooklyn ACTU Box 77 / 450 Clarkson Avenue Brooklyn, NY 11203-2098 Contact: Donald Smith (718) 270-3372 Contact: (718) 270-3370 OPEN 940728 ACTU: 5901. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 940822 ACTU: 1103. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 941006 ACTU: 1102. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 940824 ACTU: 2301. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 941101 ACTU: 2401. OTHER Hopital Cochin 46 Rue Henri Huchard Paris, FR Contact: Sophie Puget (331)402-5889 0 OPEN 940916 ACTU: 8703. OTHER Hopital Bichat-Claude Bernard 46 rue Henri Huchard Paris cedex 8, FR Contact: Sophie Puget (331)402-5889 0 OPEN 940916 ACTU: 8713. OTHER Hopital Hotel-Dieu 46 Rue Henri Huchard Paris Cedex 8, FR BP 1005 Contact: Sophie Puget (331)402-5889 0 OPEN 940916 ACTU: 8714. OTHER Hopital Jean Verdier 46 Rue Henri Huchard Paris Cedex 8, FR Contact: Sophie Puget (331)402-5889 0 OPEN 940920 ACTU: 8712. OTHER Hopital Pateur / Infectious Diseases Unit 46 Rue Henri Huchard Paris Cedex 8, FR Contact: Sophie Puget (331)402-5889 0 OPEN 940916 ACTU: 8716. OTHER Hopital Saint-Andre 46 Rue Henri Huchard Paris Cedex 8, FR Contact: Sophie Puget (331)402-5889 0 OPEN 940916 ACTU: 8715. 33 UNIQUE IDENTIFIER NIH/00487 PROTOCOL ID NUMBERS NIAID ACTG 236 PROTOCOL TITLE Safety and Efficacy of Polyethylene Glycolated IL-2 (PEG IL-2) Plus Zidovudine and Thymosin alpha 1 in HIV-Positive, Asymptomatic and Symptomatic Individuals. VERSION NUMBER & DATE (921201) TRIAL CATEGORY HIV Infection PROTOCOL CHAIRS CHAIR Merigan TC GENERAL DESCRIPTION PURPOSE: To determine the safety of thymosin alpha 1 given twice weekly in a regimen of daily oral zidovudine (AZT) and biweekly polyethylene glycolated interleukin-2 (PEG IL-2). To determine the effect of thymosin alpha 1 and PEG IL-2 in combination with AZT on immunologic and pharmacokinetic markers. GENERAL DESCRIPTION RATIONALE: AIDS is characterized by diminished T helper cell number and function. Thymosin alpha 1 appears to both increase IL-2 receptors on lymphocytes in vitro and enhance lymphocyte maturation in vivo; thus, the drug may further enhance the CD4 T cell levels in patients receiving AZT and PEG IL-2. GENERAL DESCRIPTION METHODOLOGY: Patients are stabilized on oral AZT (500 mg) daily for 8 weeks and then begin receiving bolus infusions of PEG IL-2 (1 million IU/m2) every other week for at least four doses. Thymosin alpha 1 is then added to this regimen at a dose of 0.4 mg SC twice weekly for 4 weeks. If no significant toxicity occurs, thymosin alpha 1 is increased to 1.6 mg and administered along with scheduled doses of PEG IL-2 for an additional 8 weeks. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive confirmed by Western blot (or immunofluorescence) at Stanford Hospital. 2. CD4 lymphocyte count > 50 and < 200 cells/mm3 within 2 weeks of study entry. 3. No active opportunistic infections. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Drug Combination; Drug Tolerance; Pharmacokinetic; Dose Escalating PROTOCOL DETAILS STUDY INTENT: Drug safety, Pharmacokinetics, Immunology, Combination drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 12 patients. PROTOCOL DETAILS ACTUAL ACCRUAL: 13/12 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. CD4 count > 50 and < 200 cells/mm3. 3. No active opportunistic infections. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: >= 30 percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 10 g/dl. (No transfusion in previous month). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: > 50 < 200 cells/mm3. ( 100 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 1.5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 1.5 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: >= 90. PATIENT INCLUSION CRIT. OTHER: Neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Prophylactic pentamidine for Pneumocystis carinii. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: 1. Transfusion within 4 weeks prior to study entry. 2. Radiation within 30 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Known anti-HIV medication (other than AZT) or known immunomodulators (e.g., systemic steroids, interferons, interleukins) or other chemotherapy within 30 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antihypertensive medication other than diuretics. 2. Chemotherapy, hormonal therapy, or other immunotherapy. 3. Other investigational drugs, agents, or devices. 4. Beta-blockers. 5. Non-topical steroids. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Concurrent neoplasms other than basal cell carcinoma of the skin, in situ carcinoma of the cervix, or Kaposi's sarcoma. 2. Significant cardiac disease or CNS lesions or other neurologic abnormalities. 3. Score of > 0.5 on ACTG AIDS Dementia Complex staging. 4. Major organ allograft. 5. Intolerance to AZT at 500 mg/day. SUBSTANCE IDENTIFICATION Drug 1 DRG-0165 Thymosin alpha 1 SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0093 Polyethylene Glycolated IL-2 TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir MANUFACTURERS Drug 1: Alpha I Biomedicals / Viral Technologies Inc 6903 Rockledge Drive / Suite 1200 Bethesda, MD 20817 Contact: Dr Vincent Simmon (301) 564-4400. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 3: Cetus Corporation 1400 Fifty-Third Street Emeryville, CA 94608 Contact: Dr Gwen Fyfe (510) 601-3169. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 0.4 mg/m2 twice weekly for 4 weeks, then 1.6 mg/m2 twicweekly for 8 weeks. Drug 2: 100 mg 5 times daily. Drug 3: 1 million IU/m2 over 30 min q other week for 20 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 2: 500 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Subcutaneous. Drug 2: Oral. Drug 3: Intravenous OTHER TREATMENT INFO. TREATMENT DURATION: Minimum of 20 weeks. OTHER TREATMENT INFO. END POINT: Toxicity, clinical improvement, enhanced immune response. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Grade 4 toxicity of any type. 2. Significant adverse effects or major organ toxicities associated with PEG IL-2. 3. Two consecutive occurrences of previously undetectable viral growth after the first dose of PEG IL-2. 4. Intolerance to 500 mg AZT daily. 5. Disease progression or a new occurrence or recurrence of an AIDS-defining illness. 6. Need for treatment with another drug that would potentiate the toxicity of the study drugs or would have an antiretroviral effect. OTHER TREATMENT INFO. MODIFICATION: For grade 3 toxicity (other than anemia): Hold thymosin alpha 1 until toxicity resolves, then resume at 50 percent dose at the investigator's discretion. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY/IMMUNOLOGY MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Interleukin-2/*ADVERSE EFFECTS/IMMUNOLOGY/ THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Polyethylene Glycols MESH HEADING T-Lymphocytes/IMMUNOLOGY MESH HEADING Thymosin/ANALOGS & DERIVATIVES/*ADVERSE EFFECTS/IMMUNOLOGY/THERAPEUTIC USE MESH HEADING Zidovudine/*ADVERSE EFFECTS/THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Interleukin-2) CAS REGISTRY NUMBER 0 (Polyethylene Glycols) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69521-94-4 (thymosin alpha(1)) LAST REVISION DATE 941207 ENTRY MONTH 9303 CALIFORNIA Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Contact: Virginia Tallman (415) 723-2804 Contact: Dr Rami Ramachandran (415) 723-6231 OPEN 930303 ACTU: 0501. 34 UNIQUE IDENTIFIER NIH/00505 PROTOCOL ID NUMBERS NIAID ACTG 235 PROTOCOL TITLE Active Immunization of HIV-1 Infected, Pregnant Women With CD4 Lymphocyte Counts >= 400/mm3: A Phase I Study of Safety and Immunogenicity of MN rgp120/HIV-1 Vaccine (NOTE: Some Patients Receive Placebo). VERSION NUMBER & DATE (940601) TRIAL CATEGORY Vaccines TRIAL CATEGORY Pregnancy TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Wara DW PROTOCOL CHAIRS CO-CHAIR Lambert JS, Wright PF GENERAL DESCRIPTION PURPOSE: To evaluate the safety of rgp120/HIV-1MN vaccine in HIV-1 infected pregnant women with CD4 counts >= 400 cells/mm3. To evaluate the immunogenicity of this vaccine in pregnant women and the passive acquisition of vaccine-specific antibody in their infants. To evaluate the induction or augmentation by rgp120/HIV-1MN vaccine of mucosal immune response in the gastrointestinal and reproductive tracts during pregnancy. To isolate and genetically characterize the HIV-1 present in cervicovaginal fluid specimens of pregnant women and compare it to that present in their peripheral blood mononuclear cells and to that of their infected infants. GENERAL DESCRIPTION RATIONALE: Evidence suggests that an advanced stage of disease with high plasma viremia is associated with increased transmission of HIV-1 to the fetus. Slowing the progression of disease, reducing the titer of virus in plasma, and increasing the titer of epitope-specific antibody are potentially attainable goals through active immunization of the mother during pregnancy. GENERAL DESCRIPTION METHODOLOGY: Pregnant women are randomized to receive an initial injection of MN rgp120 vaccine or alum placebo between week 16 and week 24 of gestation, followed by monthly booster injections concluding at the end of pregnancy, for a total of five injections. Patients may have optional booster immunizations (vaccine or placebo) at 3, 6, 9, and 12 months after delivery. Mothers and infants are followed through 18 months after delivery. Per 06/94 addendum, patients will be contacted once or twice per year for at least 5 years to check on health status of patient and child. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV-1 infection documented by ELISA and another confirmatory test such as Western blot or culture. 2. CD4 count >= 400 cells/mm3. 3. No AIDS-defining illness or other systemic manifestations related to HIV (other than generalized lymphadenopathy). 4. HIV p24 < 30 pg/ml. 5. Proven pregnancy in the 16th to 24th week of gestation at study entry, with no special obstetrical risks. 6. Concurrent AZT therapy is permitted. ELIGIBILITY ASYM. PGL. OTHER PROTOCOL NUMBERS VEU 104. IND BB4705 STUDY DESIGN Double-Blind; Randomized; Placebo-Controlled; 2-Arm PROTOCOL DETAILS STUDY INTENT: Vaccine prophylaxis, Immunology. PROTOCOL DETAILS PROJECTED ACCRUAL: 24 patients. (16 patients receive vaccine, 8 patients receive placebo) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 24 months, with follow-up once or twice yearly for at least 5 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 34/24 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 10 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV-1 infection. 2. CD4 count >= 400 cells/mm3. 3. No AIDS-defining illness or other systemic manifestations related to HIV (other than generalized lymphadenopathy). 4. HIV p24 < 30 pg/ml. 5. Proven pregnancy in the 16th to 24th week of gestation at study entry, with no special obstetrical risks. 6. Concurrent AZT therapy is permitted. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: > 28 percent. PATIENT INCLUSION CRIT. PLATELET COUNT: > 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 400 cells/mm3. ( 400 - 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: < 1.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: Total white blood count >= 3000 cells/mm3. PATIENT AGE AGE: 16 Years - 40 Years. PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Pregnant. Not breast-feeding. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. AZT. 2. Acyclovir. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 15 Years. 41 Years - 99 Years. PATIENT EXCLUSION CRIT. SEX: MALE PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Not pregnant. Breast-feeding. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Current use of illicit drugs or known chronic alcohol use. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Antiretroviral or immunomodulating agent other than AZT within 90 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Antiretroviral or immunomodulating agent other than AZT during the pregnancy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Known hypersensitivity to a component of the vaccine. 2. Evidence of fetal abnormality on ultrasound. 3. Evidence of maternal risk factors including insulin-dependent diabetes, moderate to severe hypertension, repeated fetal wastage (> 3), Rh-sensitization or other blood group alloimmunization, severe renal disease, previous infants with malformations or other factors that obstetrically are judged to constitute a special risk of spontaneous abortion or premature birth. 4. Active syphilis. 5. Hepatitis B surface antigen positive. SUBSTANCE IDENTIFICATION Drug 1 DRG-0153 rgp120/HIV-1MN MANUFACTURERS Drug 1: Genentech Incorporated 460 Point San Bruno Boulevard South San Francisco, CA 94080 Contact: Professional Services (800) 821-8590. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 300 mcg (or placebo) administered between week 16 and week 24 of gestation, followed by monthly booster injections concluding at end of pregnancy for a total of 5 injections, witoptional booster immunizations at 3, 6, 9, and 12 months after delivery SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intramuscular injection, 300 mcg vials OTHER TREATMENT INFO. END POINT: Outcome of pregnancy, clinical and virological course of maternal HIV disease, maternal immune responses, and incidence of definitive HIV infection in the infants. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Progression of HIV disease, defined by occurrence of an AIDS-defining illness, increase in p24 to over 80 pg/ml, or decrease in CD4 count to < 200 cells/mm3 or <= 50 percent of baseline on two consecutive determinations. 2. Intolerance to the vaccine. 3. Evidence of fetal abnormality. 4. Pregnancy complications necessitating or resulting in preterm delivery. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), National Institute of Allergy & Infectious Diseases (VEU). MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Female MESH HEADING HIV Envelope Protein gp120/*ADVERSE EFFECTS/ IMMUNOLOGY MESH HEADING HIV Infections/IMMUNOLOGY/*THERAPY MESH HEADING Human MESH HEADING Pregnancy MESH HEADING Pregnancy Complications, Infectious MESH HEADING Vaccines, Synthetic CAS REGISTRY NUMBER 0 (HIV Envelope Protein gp120) CAS REGISTRY NUMBER 0 (Vaccines, Synthetic) LAST REVISION DATE 941207 ENTRY MONTH 9304 CALIFORNIA San Francisco General Hospital / UCSF 995 Potrero Avenue / Building 80 Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840ACTU: 0801. MARYLAND Johns Hopkins University / Center for Immunization Research Hampton House Rm 125 / 624 North Broadway Baltimore, MD 21205 Contact: Karen Charron (410) 955-7283 OPEN 930910 ACTU: 6002. MARYLAND The Johns Hopkins University ( Pediatrics ) 600 North Wolfe Street Baltimore, MD 21287 Contact: Laura J Belcher (410) 955-9749 OPEN 940228 ACTU: 3701. MISSOURI St Louis University School of Medicine / Sec Inf Dis 1402 South Grand Boulevard St Louis, MO 63104 Contact: Dr Robert B Belshe (314) 577-8648 Contact: Heidi Israel (314) 577-8649 OPEN 930409 ACTU: 6007. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 940422 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 940422 ACTU: 2102. NEW YORK University of Rochester Medical Center Box 689 / Room 36209 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Dr Michael Keefer (716) 275-0810 OPEN 930430 ACTU: 6005. 35 UNIQUE IDENTIFIER NIH/00518 PROTOCOL ID NUMBERS NIAID ACTG 232 PROTOCOL TITLE A Phase I Clinical Trial to Study the Toxicity, Pharmacokinetics, and Efficacy of a Human Monoclonal Antibody, F105, for Treating Human Immunodeficiency Virus Infection. VERSION NUMBER & DATE 2 (940930) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Samore MH GENERAL DESCRIPTION PURPOSE: To determine the safety and pharmacokinetics of F105 human monoclonal antibody both following a single dose and during intermittent administration in HIV-infected patients. To determine specific dose concentrations sufficient to achieve efficacy and avoid toxicity. To determine the effect of F105 on virologic and serologic parameters. GENERAL DESCRIPTION RATIONALE: Early in the course of HIV infection, the primary humoral immune response appears to be highly strain specific and to be directed at a hypervariable portion of the viral gp120. The F105 human monoclonal antibody reacts with the CD4 binding region of gp120 and has been shown to neutralize the IIIB, SF2, and MN strains of HIV at concentrations readily achievable in humans. GENERAL DESCRIPTION METHODOLOGY: In Part A, cohorts of four patients each receive a single intravenous (IV) injection of F105 human monoclonal antibody at 100, 500, or 1000 mg/m2. The IV catheter will remain in the patient's arm for 12 hours after injection for subsequent drawing of blood samples. The third group (1000 mg/m2) will be studied only after the first two groups are analyzed for pharmacokinetics. No more than two patients are enrolled per week. Patients on Part A undergo follow-up three to four times within the first week after injection and weekly thereafter for 7 weeks. Pharmacokinetic and toxicity data generated from Part A will be used to select two dose levels for intermittent administration in Part B. In this part, cohorts of four to six patients receive one of two doses of F105 for 8-12 weeks. Per 9/30/94 amendment, eight patients receive one dose of F105 (500 mg/m2) every 21 days for four doses (dose determined from analysis of Part A data). PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV-1 infection as documented by ELISA confirmed by Western blot. 2. CD4 count (within 15-90 days prior to study entry) of 200 - 500 cells/mm3 for Part A or 100 - 400 cells/mm3 for Part B (per 9/30/94 amendment). 3. No diagnosis of AIDS (Part A only, per 9/30/94 amendment). Part B patients only (per 9/30/94 amendment): 1. Primary (viral) isolates sensitive to F105 antibody using the yield reduction assay currently under development by ACTG, determined within 15-90 days prior to study entry. 2. Plasma viremia by qualitative plasma culture. 3. NO active opportunistic infection within 6 weeks prior to drawing of first isolate. 4. NO AIDS-related malignancy other than minimal Kaposi's sarcoma. ELIGIBILITY ASYM. ARC. OTHER PROTOCOL NUMBERS IND BB5090 STUDY DESIGN Open Label; Dose Escalating; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Drug efficacy, Pharmacokinetics, Immunotherapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 20 patients. (12 patients in Part A; 8 patients in Part B) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Part A: At least 8 weeks. Part B: At least 8-12 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 8/20 (941012). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV-1 infection. 2. CD4 count 200 - 500 cells/mm3 (Part A) or 100 - 400 cells/mm3 (Part B, per amendment). 3. No diagnosis of AIDS (Part A only, per amendment). 4. Life expectancy of at least 6 months. Part B patients only (per amendment): Primary (viral) isolates sensitive to F105 antibody using the yield reduction assay currently under development by ACTG, determined within 15-90 days prior to study entry. 2. Plasma viremia by qualitative plasma culture. 3. NO active opportunistic infection within 6 weeks prior to drawing of first isolate. 4. NO AIDS-related malignancy other than minimal Kaposi's sarcoma. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.5 g/dl. (Must not be transfusion dependent). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 500 cells/mm3. (Part A only). ( 200 - 300 - 400 - 500 ). 100 - 400 cells/mm3 (Part B only, per amendment). ( 100 - 200 - 300 - 400 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.8 mg/dl. (Part A only). PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 70 ml/min. (If creatinine value unavailable). PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. Prothrombin <= 1.5 x ULN (Part A only). Alkaline phosphatase <= 5 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior AZT or other nucleoside antiviral agents. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: PART B ONLY. Allowed: Concomitant AZT or other antiretroviral drugs if patient is on a stable dose of such therapy within 3 months prior to study entry. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active alcohol or drug abuse that may compromise ability to comply with study requirements. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Red cell transfusions administered to maintain hemoglobin at acceptable level or alleviate symptoms of anemia. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 6 weeks prior to study entry: 1. Intravenous gamma globulin. 2. Chemotherapy. 3. Corticosteroids. 4. Other experimental therapy. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: EXCLUDED IN ALL PATIENTS: 1. Immunosuppressive treatments, cytokine therapy, or biologic response modifiers not included in this study, including interferons or adjuvant treatment for chronic and severe fungal infections such as cryptococcal meningitis. 2. Intravenous gamma globulin. 3. Chemotherapy. 4. Corticosteroids. 5. Other experimental therapy. 6. G-CSF, GM-CSF, or erythropoietin. EXCLUDED IN PART A ONLY: Drugs known to enhance or block metabolism of other drugs. EXCLUDED IN PART B ONLY: AZT or other antiretroviral drugs IF INITIATED during or within 1 month after completion of study. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Evidence of active renal disease as manifested by sediment containing red or white cell casts. SUBSTANCE IDENTIFICATION Drug 1 DRG-0192 F105 human monoclonal antibody MANUFACTURERS Drug 1: Centocor Incorporated 200 Great Valley Parkway Malvern, PA 19355-1307 Contact: Dr Richard McCloskey (610) 889-4793 Contact: pager (215) 452-8233. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Part A: 100, 500, or 1000 mg/m2 in a single dose over 6min, via infusion pump. Part B: Doses to be determined following analysis of pharmacokidata in Part A, administered for 8-12 weeks. Per 9/30/94 amendm500 mg/m2 q 21 days for four doses SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous, 5.0 mg/ml vials OTHER TREATMENT INFO. END POINT: Part A: Safety and pharmacokinetic parameters. Part B: Safety, virologic parameters to assess preliminary efficacy, pharmacokinetics, changes in CD4 counts. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: PART A: Grade 3 or worse cytopenia. PART B: 1. Dose-limiting toxicity. 2. Condition has deteriorated and requires new antiretroviral therapy. 3. New medical illness intervenes. 4. An event occurs that would seriously limit patient compliance or preclude continuation on study. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Antibodies, Monoclonal/*ADVERSE EFFECTS/ IMMUNOLOGY MESH HEADING Female MESH HEADING HIV Infections/*THERAPY MESH HEADING Human MESH HEADING Immunization, Passive MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antibodies, Monoclonal) LAST REVISION DATE 941207 ENTRY MONTH 9401 MASSACHUSETTS New England Deaconess Hospital 185 Pilgrim Road Boston, MA 02215 Contact: Helen Fitch (617) 735-0785 OPEN 941207 ACTU: 0103. 36 UNIQUE IDENTIFIER NIH/00509 PROTOCOL ID NUMBERS NIAID ACTG 230 PROTOCOL TITLE A Phase I Study to Evaluate the Safety and Immunogenicity of Recombinant HIV-1 Envelope Antigen in Children Born to HIV-Infected Mothers. VERSION NUMBER & DATE 3 (940719) TRIAL CATEGORY HIV Infection TRIAL CATEGORY HIV Negative TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic TRIAL CATEGORY Vaccines PROTOCOL CHAIRS CHAIR Borkowsky W PROTOCOL CHAIRS CO-CHAIR Wara D GENERAL DESCRIPTION PURPOSE: PRIMARY: To determine the safety of envelope recombinant proteins rgp120/HIV-1MN and rgp120/HIV-1SF2 in infants who are of indeterminate HIV status born to HIV-infected women. To evaluate changes in viral load in infants proven to be infected and absolute CD4 counts in all immunized infants. SECONDARY: To evaluate the immunogenicity of these envelope recombinant proteins in infants of indeterminate HIV status born to HIV-infected women. GENERAL DESCRIPTION RATIONALE: Only 30-50 percent of HIV-infected infants have detectable virus at birth. Successful early sensitization to HIV envelope epitopes may help prevent infection or, alternatively, may enhance HIV-specific immune function to alter HIV replication and disease progression. GENERAL DESCRIPTION METHODOLOGY: Newborns are randomized to one of three different doses of either rgp120/HIV-1MN or rgp120/HIV-1SF2 or their matching placebos. At each dose level, 12 patients receive vaccine and three patients receive placebo. Immunizations are performed at 0, 4, 12, and 20 weeks, and patients are followed until 2 years of age. Three of four patients treated at a given dose level must have received two immunizations without evidence of grade 3 or 4 clinical or laboratory toxicity before dose escalation occurs. Twelve additional patients are treated with the optimal dose of each vaccine at weeks 0, 4, 8, and 20, accompanied by three additional placebo patients per vaccine. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940928) DISEASE STUDIED Primary HIV infection, Healthy. DISEASES STATUS Patients have the following symptoms and conditions: 1. > 37 weeks gestation and < 72 hours of age born to HIV-infected women. 2. NOT born to women who received either passive or active immunotherapy during pregnancy. 3. NOT breast-fed. 4. NOT born to women who are hepatitis B surface antigen positive. 5. Receiving AZT at study entry (except infants enrolled in ACTG 076). ELIGIBILITY ASYM. HIV Seronegative. OTHER PROTOCOL NUMBERS IND BB 4714 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Dose Comparison; Drug Comparison PROTOCOL DETAILS STUDY INTENT: Immunology, Drug safety, Vaccine prophylaxis. PROTOCOL DETAILS PROJECTED ACCRUAL: 120 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 104 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 106/120 (940928). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 37 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must be: 1. > 37 weeks gestation and < 72 hours of age born to HIV-infected women. 2. NOT born to women who received either passive or active immunotherapy during pregnancy. 3. NOT breast-fed. 4. NOT born to women who are hepatitis B surface antigen positive. 5. Receiving AZT at study entry (except infants enrolled in ACTG 076). NOTE: Parent or guardian must provide informed consent and be willing to comply with study requirements. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 12.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. SGPT(ALT): <= 3 x ULN. (ULN = upper limit of normal for age). PATIENT INCLUSION CRIT. CREATININE: < 1.3 mg/dl. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 1500 cells/mm3. PATIENT AGE AGE: 01 Days - 03 Days. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antiretroviral therapy. 2. Coenrollment in a therapeutic protocol if begun at least 30 days following the week 20 immunization. 3. Routine immunizations if given more than 1 week before or after study vaccine. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Passive or active HIV-specific immunotherapy other than the study candidate vaccines. 2. Investigational medications. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Documented or suspected serious bacterial infection, metabolic illness, or other immediate life-threatening conditions. SUBSTANCE IDENTIFICATION Drug 1 DRG-0153 rgp120/HIV-1MN SUBSTANCE IDENTIFICATION Drug 2 DRG-0103 rgp120/HIV-1SF2 MANUFACTURERS Drug 1: Genentech Incorporated 460 Point San Bruno Blvd South San Francisco, CA 94080 Contact: Dr Don Francis (415) 255-5806. MANUFACTURERS Drug 2: The BIOCINE Company 4560 Horton Street Emeryville, CA 94608-2916 Contact: Dr Anne-Marie Duliege (510) 601-2715. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 30, 100, or 300 mcg (or placebo) at weeks 0, 4, 12, and20. Drug 2: 5, 15, or 50 mcg (or placebo) at weeks 0, 4, 12 and 20 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intramuscular. Drug 2: Intramuscular, 300 mcg vials OTHER TREATMENT INFO. END POINT: Vaccine safety, effects on viral load and absolute CD4 counts, immunogenicity. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable (grade 4 or recurrent grade 3) toxicity. 2. Disease progression to P-2 status specifically for the following: - AIDS-defining opportunistic infection. - Wasting disease or failure to thrive. - HIV-associated progressive encephalopathy. - HIV-associated malignancy. - Two or more episodes of bacterial septicemia and/or meningitis. - Hypogammaglobulinemia (IgG) < 250 mg/dl. 3. Immunological decline defined as <= 20 percent CD4, regardless of HIV infection status. 4. Noncompliance. 5. At the request of the patient, parent or guardian, investigator, FDA, IND sponsor, or pharmaceutical companies. OTHER TREATMENT INFO. MODIFICATION: For grade 3 toxicity: If toxicity resolves to grade 2 or better prior to the next scheduled immunization, administer vaccine at 50 percent dose; if toxicity has not resolved or if it recurs, discontinue immunizations permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), The BIOCINE Company, Genentech Incorporated. MESH HEADING Female MESH HEADING HIV/*IMMUNOLOGY MESH HEADING HIV Envelope Protein gp120/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS/IMMUNOLOGY MESH HEADING HIV Infections/*PREVENTION & CONTROL/THERAPY MESH HEADING Human MESH HEADING Infant, Newborn MESH HEADING Male MESH HEADING Vaccines, Synthetic MESH HEADING Virus Replication/DRUG EFFECTS CAS REGISTRY NUMBER 0 (HIV Envelope Protein gp120) CAS REGISTRY NUMBER 0 (Vaccines, Synthetic) LAST REVISION DATE 940928 ENTRY MONTH 9308 CALIFORNIA Harbor General / UCLA Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 940701 ACTU: 3609. CALIFORNIA UCLA Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 940706 ACTU: 3601. CALIFORNIA Long Beach Memorial Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 940706 ACTU: 3606. CALIFORNIA University of CA San Diego Medical Center / Pediatric 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 940706 ACTU: 4601. CALIFORNIA UCSF / Moffitt Hospital 602 / Pediatrics 505 Parnassus / Box 0105 San Francisco, CA 94143-0105 Contact: Debbie Trevithick (415) 476-6480 OPEN 940706 ACTU: 4501. CALIFORNIA San Francisco General Hospital (Pediatric) Box 0105 Moffitt Hospital 602 / 505 Parnassus San Francisco, CA 94143-0105 Contact: Debbie Trevithick (415) 476-6480 OPEN 940706 ACTU: 4502. COLORADO University of Colorado Hlth Sciences Ctr / Peds Infect Dis 1056 East 19Th Avenue B055 Denver, CO 80218-1088 Contact: Carol Salbenblatt (303) 861-6751 OPEN 940706 ACTU: 7001. CONNECTICUT Yale University School of Medicine PO Box 3333 / 333 Cedar Street New Haven, CT 06510-8064 Contact: Unspecified (203) 737-4040 OPEN 941005 ACTU: 5038. ILLINOIS Chicago Children's Memorial Hospital / Pediatric 2300 Childrens Plaza Box 20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 940706 ACTU: 4001. ILLINOIS Cook County Hospital / Childrens Memorial 2300 Childrens Plaza Box #20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 940706 ACTU: 4002. ILLINOIS Wyler Children's Hospital 5841 South Maryland Avenue Chicago, IL 60637-1470 Contact: Kim Stieglitz (312) 702-6176 OPEN 940706 ACTU: 4003. LOUISIANA Tulane University School of Medicine / Div of Ped Infect Dis 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 940706 ACTU: 7201. LOUISIANA Univ Hospital / Tulane Univ Med Schl / Tulane - LSU Ped ACTU 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 941003 ACTU: 7204. MASSACHUSETTS Baystate Medical Center / Department of Pediatrics 759 Chestnut Street / SHU-Main 3 Springfield, MA 01199 Contact: MaryPat Toye (413) 784-5399 OPEN 940706 ACTU: 7302. MASSACHUSETTS University of Massachusetts Medical School / Dept of Peds 55 Lake Avenue North Worcester, MA 01655-0001 Contact: Joanne Shepard (508) 856-1692 OPEN 940706 ACTU: 7301. MASSACHUSETTS Children's Hospital 300 Longwood Avenue / Carnegie 3 Boston, MA 02115 Contact: Robert Bishop (617) 735-8198 OPEN 940706 ACTU: 2901. MASSACHUSETTS Boston City Hospital / Ped Infect Dis / Finland Lab 774 Albany Street / Finland Lab Room 301 Boston, MA 02118 Contact: Anne Marie Reagan (617) 534-5813 OPEN 940706 ACTU: 2903. MARYLAND The Johns Hopkins University ( Pediatrics ) 600 North Wolfe Street Baltimore, MD 21287 Contact: Laura J Belcher (410) 955-9749 OPEN 940706 ACTU: 3701. NORTH CAROLINA Duke University Medical Center / Pediatrics Box 3499 Durham, NC 27710 Contact: John Swetnam (919) 684-6335 OPEN 940706 ACTU: 4701. NEW JERSEY Children's Hospital of New Jersey 15 South 9th Street / CHAP Program 5 East Newark, NJ 07107 Contact: George Donovan Mcsherry (201) 268-8273 OPEN 940706 ACTU: 2801. NEW JERSEY Univ of Med & Dentistry of NJ / Univ Hospital 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan Mcsherry (201) 268-8273 OPEN 940706 ACTU: 2802. NEW JERSEY Children's Hospital of New Jersey 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan McSherry (201) 268-8273 OPEN 940706 ACTU: 2803. NEW YORK Beth Israel Medical Center / Pediatrics First Avenue at 16th Street Dazian Pavilion Tenth Floor New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 940706 ACTU: 4302. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue / Pediatric New York, NY 10016 Contact: Nagamah Deygoo (212) 263-6426 OPEN 940706 ACTU: 4401. NEW YORK Mount Sinai School of Medicine / Pediatrics One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940706 ACTU: 4301. NEW YORK Incarnation Children's Ctr / c/o Columbia Presb Med Ctr 142 Audubon Avenue New York, NY 10032 Contact: Pam Clark (212) 928-2228 OPEN 940706 ACTU: 4103. NEW YORK The Columbia Presbyterian Medical Hosp (Pediatric) 622 West 168th St Room 1161 New York, NY 10032-3796 Contact: Kathy A Shea (212) 305-7222 OPEN 940706 ACTU: 4101. NEW YORK Bronx Lebanon Hospital Center / Department of Pediatrics 1650 Selwyn Avenue Room 2C Bronx, NY 10457 Contact: Patrice Edwards-Cihak (718) 960-1015 OPEN 940706 ACTU: 6901. NEW YORK SUNY Health Science Center at Stony Brook HSC T 15 080 Stony Brook, NY 11794-8111 Contact: Peggy Melendez (516) 444-1313 Contact: (516) 444-7692 Contact: beeper (516) 282-8808 Contact: Jeannie Conner (516) 444-2724 OPEN 940706 ACTU: 5040. NEW YORK SUNY Health Science Center at Syracuse 750 East Adams Street Syracuse, NY 13210 Contact: Kathie Shea-Contello (315) 464-6331 OPEN 940706 ACTU: 5039. NEW YORK Children's Hospital 219 Bryant Street Buffalo, NY 14222 Contact: Cynthia Kelly (716) 878-7908 OPEN 940706 ACTU: 1104. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 940706 ACTU: 1101. OTHER San Juan City Hospital / Puerto Rico Medical Center Department of Pediatrics Third Floor Hematology Rio Piedras, PR 00927 Contact: Esther Rosa (809) 764-3083 Contact: (809) 274-0904 OPEN 940706 ACTU: 5031. PENNSYLVANIA Hospital of the Univ of PA / Children's Hosp of Philadelphia 3400 Spruce Street Maloney Building 2Nd Floor Philadelphia, PA 19104 Contact: Kathy Mooney (215) 662-3225 OPEN 940706 ACTU: 6702. PENNSYLVANIA Children's Hospital of Philadelphia 34th Street & Civic Center Blvd Philadelphia, PA 19104-4399 Contact: Dr Deborah Schaible (215) 590-2097 Contact: Hospital Information (215) 590-1000 OPEN 940706 ACTU: 6701. 37 UNIQUE IDENTIFIER NIH/00488 PROTOCOL ID NUMBERS NIAID ACTG 228 PROTOCOL TITLE CMV Retinitis Retreatment Trial. VERSION NUMBER & DATE 3 (921201) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To assess the safety and efficacy of three therapeutic regimens (foscarnet, ganciclovir, or the combination) for recurrent or persistent AIDS-related cytomegalovirus (CMV) retinitis. GENERAL DESCRIPTION RATIONALE: Although therapy with foscarnet or ganciclovir halts retinitis progression in 90 percent of patients treated, relapses are common and may accelerate due to development of drug resistance, deteriorating immune function, or other factors. Treatment strategies currently being investigated include switching patients from one drug to the other or combining the two drugs. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive foscarnet, ganciclovir, or a combination of the two drugs (administered sequentially). Initially, patients undergo single or multiple cycles of induction therapy for 14 days followed by maintenance therapy. Patients in whom the retinitis continues to progress or who are intolerant of the initial treatment switch to the alternative drug for further cycles of induction and maintenance. Patients on the combination arm in whom retinitis continues to progress are given further cycles of the combination at an increased dose, or, if one drug is causing toxicity, are given further cycles with the alternative drug. Patients are followed monthly for 6 months and then every 3 months thereafter. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Cytomegalovirus retinitis ( CMV retinitis ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Documented HIV infection or AIDS by CDC criteria. 2. Active CMV retinitis after 28 or more days of either foscarnet or ganciclovir therapy. 3. At least one lesion with one-quarter disk area or more that can be photographed. 4. Visual acuity of 3 or more letters on ETDRS (Early Treatment Diabetic Retinopathy Study) chart at 1 meter (5/200 Snellen) in an affected eye. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Multicenter; Randomized; 3-Arm; Comparative PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Comparative drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 300 patients. (100 per treatment arm) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Until death or study termination. PROTOCOL DETAILS ACTUAL ACCRUAL: 184/300 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 5 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection or AIDS. 2. Active CMV retinitis after 28 or more days of either foscarnet or ganciclovir therapy. 3. At least one lesion with one-quarter disk area or more that can be photographed. 4. Visual acuity of 3 or more letters on ETDRS chart (5/200 Snellen) in an affected eye. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: >= 20000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CREATININE: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 500 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: At least 28 days of prior foscarnet or ganciclovir. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: G-CSF. Recommended: Antiretroviral therapy. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of intolerance to ganciclovir or foscarnet sufficient to contraindicate use. 2. History of combination foscarnet/ganciclovir therapy. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active drug or alcohol abuse sufficient to prevent compliance. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Media opacity severe enough to preclude visualization of both fundi. 2. Retinal detachment not scheduled for surgical repair. SUBSTANCE IDENTIFICATION Drug 1 DRG-0017 Foscarnet sodium SUBSTANCE IDENTIFICATION Drug 2 DRG-0018 Ganciclovir TRADE NAME OF SUBSTANCE Drug 1‰ Foscavir TRADE NAME OF SUBSTANCE Drug 2‰ Cytovene MANUFACTURERS Drug 1: Johns Hopkins University / SOCA 615 North Wolfe Street Room 5010 Baltimore, MD 21205 Contact: Janet Holbrook (410) 955-8175 Contact: (410) 955-0930. MANUFACTURERS Drug 2: Syntex Laboratories Incorporated 3401 Hillview Avenue / PO Box 10850 Palo Alto, CA 94303 Contact: Unspecified (800) 444-4200. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Arms 1 and 2: 90 mg/kg/12 hr for 14 days as induction, followed by 120 mg/kg/day as maintenance. Foscarnet is given asfirst drug in Arm 1 and as the second drug (after progression) Arm 2. Arm 3: 90 mg/kg/day for 14 days OR 90 mg/kg/12 hr for 14 days ainduction, followed by 90 mg/kg/day as maintenance for the inittreatment or 120 mg/kg/day as maintenance for the post-progresstreatment. Drug 2: Arms 1 and 2: 5 mg/kg/12 hr for 14 days as induction, followed by 10 mg/kg/day as maintenance. Ganciclovir is given asecond drug (after progression) in Arm 1 and as the first drug Arm 2. In Arm 2, patients requiring additional induction receivincreased dose of 7.5 mg/kg/day. Arm 3: 5 mg/kg/12 hr for 14 days OR 5 mg/kg/day for 14 days as induction, followed by 5 mg/kg/day as maintenance for both the initial treatment and the post-progression treatment SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: Induction: 90 - 180 mg/kg. Maintenance: 90 - 120 mg/kg.Drug 2: Induction: 5 - 10 mg/kg. Maintenance: 5 - 10 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous. Drug 2: Intravenous OTHER TREATMENT INFO. TREATMENT DURATION: Until patient death or study termination. OTHER TREATMENT INFO. END POINT: Mortality, CMV retinitis progression, loss of visual function, toxicity, retinal detachment, morbidity, quality of life. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Unacceptable toxicity. OTHER TREATMENT INFO. MODIFICATION: For serum creatinine >= 3.0 mg/dl: hold foscarnet therapy, then restart if toxicity resolves to <= 2.0 mg/dl. For ANC < 500 cells/mm3 and platelets < 10000 cells/mm3: hold ganciclovir until ANC >= 750 cells/mm3 and platelets >= 20000 cells/mm3. For other drug-related grade 4 toxicity: discontinue treatment. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Cytomegalovirus Infections/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Female MESH HEADING Foscarnet/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Ganciclovir/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Retinitis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 4428-95-9 (Foscarnet) CAS REGISTRY NUMBER 82410-32-0 (Ganciclovir) LAST REVISION DATE 941207 ENTRY MONTH 9301 CALIFORNIA University of California San Diego 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 930113 ACTU: 0701. CALIFORNIA General Hospital / AIDS Clinical Trials Unit 995 Potrero Avenue / Bldg 80 / Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 846OPEN 930113 ACTU: 0808. LOUISIANA Tulane University / Charity Hospital 1430 Tulane Avenue New Orleans, LA 70112-2699 Contact: Russell Strada (504) 584-1692 Contact: (504) 584-3605 OPEN 930413 ACTU: 1702. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 930113 ACTU: 0401. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 930427 ACTU: 1801. 38 UNIQUE IDENTIFIER NIH/00504 PROTOCOL ID NUMBERS NIAID ACTG 227 PROTOCOL TITLE Phase I Safety and Pharmacokinetics Study of Microparticulate Atovaquone (m-Atovaquone; 566C80) in HIV-Infected Infants and Children. VERSION NUMBER & DATE 2 (940930) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Hughes W PROTOCOL CHAIRS CO-CHAIR Dorenbaum A GENERAL DESCRIPTION PURPOSE: To determine the safety, tolerance, and pharmacokinetics of a new improved microparticulate suspension formulation of atovaquone administered at one of two dose levels (per 09/30/94 amendment, a third dose level was added) daily for 12 days in HIV-infected infants and children who are at risk of developing Pneumocystis carinii pneumonia (PCP). GENERAL DESCRIPTION RATIONALE: Atovaquone has shown prophylactic potential in adults in the treatment of PCP but is poorly absorbed in tablet form. To improve the bioavailability of atovaquone, a new formulation has been prepared as a microparticulate suspension. Since studies in adults have demonstrated substantial safety of this drug, evaluation in children is being pursued. GENERAL DESCRIPTION METHODOLOGY: Three cohorts of four patients each (ages 2-12 years, 3 months to < 2 years, and 1 month to < 3 months) receive 10 mg/kg atovaquone daily for 12 days. The oldest age group is treated first. In the absence of unacceptable toxicity, the dose of atovaquone is escalated to 30 mg/kg daily in subsequent 4-patient cohorts representing each of the age stratifications and (per 9/30/94 amendment) to 45 mg/kg in a separate 4-patient cohort aged 3 months to < 2 years. If two of four patients in a given cohort experience unacceptable toxicity at the initial dose, two additional patients in the same age range are entered. Blood samples are drawn for pharmacokinetic evaluation. Patients are followed to day 24. Per 9/30/94 amendment, patients aged 3 months to < 2 years of age who received 10 or 30 mg/kg may re-enroll in the 45 mg/kg cohort after a 1-month washout. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Pneumocystis carinii pneumonia ( PCP ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Symptoms of AIDS by CDC definition OR documented HIV infection as follows: o Infants < 15 months of age - Positive viral culture of PBMC AND either a second separate confirmatory test (positive viral culture, p24 antigen, or PCR) or evidence of Class P-2 (Subclass A, C, or F) symptomatic HIV infection. o Children >= 15 months of age - Criteria as listed for infants < 15 months OR two or more positive tests for HIV antibody by ELISA, with at least one test confirmed by Western blot or IFA. NOTE: Umbilical cord blood is not acceptable for confirmatory tests. 2. At risk of developing PCP and requiring prophylaxis according to MMWR guidelines. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND 41,828 STUDY DESIGN Dose Escalating; Open Label; Pharmacokinetic; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Pharmacokinetics, Bioavailability, Drug prophylaxis, Drug toxicity. PROTOCOL DETAILS PROJECTED ACCRUAL: 24 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 24 days. PROTOCOL DETAILS ACTUAL ACCRUAL: 18/24 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 4 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS or documented HIV infection. 2. Risk of developing PCP. 3. Normal EKG and chest radiograph. 4. No blood or protein on urinalysis. 5. Consent of parent or guardian. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. (< two years of age); >= 10.0 g/dl (>= two years of age). PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 1.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. OTHER: Neutrophils >= 1200 cells/mm3. BUN < 35 mg/dl. Uric acid <= 10 mg/dl. Amylase/lipase < 1.5 x ULN. PT <= 20 seconds. PTT <= 35 seconds (except in patients with hereditary clotting factor deficiencies). PATIENT AGE AGE: 01 Months - 12 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. OTHER PATIENT INCL. CH. WEIGHT: >= 4 kg. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: 1. Prophylactic TMP/SMX if given no less than 3 days prior to study entry. 2. Prophylactic aerosolized pentamidine (or a single intravenous dose of 4.0 mg/kg pentamidine) if given no less than 7 days prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Zidovudine (AZT). 2. Dideoxycytidine (zalcitabine; ddC). 3. Didanosine (ddI). 4. Nonaminoglycoside, nonmacrolide, and nonsulfonamide antibiotics. 7. Factor VIII. 8. IVIG. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of G6PD deficiency. 2. Prior enrollment on this study. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 29 Days. 13 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. PATIENT EXCLUSION CRIT. WEIGHT: < 4 kg. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Trimethoprim/sulfamethoxazole. 2. Sulfadoxine and pyrimethamine (Fansidar). 3. Primaquine. 4. Aspirin. 5. Amphotericin B. 6. Aminoglycoside antibiotics. 7. Sulfonamides. 8. Dapsone. 9. Benzodiazepines. 10. Rifampin. 11. Erythromycin, clarithromycin, and azithromycin. 12. Digitalis. 13. Para-aminosalicylic acid (PAS). 14. Isoniazid. 15. Anticoagulants. 16. Any other investigational therapies. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Anticipated organ system or laboratory abnormalities (other than immune system abnormalities) from the primary disease and its treatment during the study. 2. Acute or chronic infections requiring treatment during the study. NOTE: Thrush and herpes labialis are allowed if these conditions do not require treatment. 3. Diarrhea or vomiting. SUBSTANCE IDENTIFICATION Drug 1 DRG-0084 Atovaquone TRADE NAME OF SUBSTANCE Drug 1‰ 566C80 MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 10, 30, or 45 mg/kg daily for 12 days SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 10, 30, or 45 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, syrup OTHER TREATMENT INFO. TREATMENT DURATION: 12 days. OTHER TREATMENT INFO. END POINT: Toxicity, pharmacokinetics. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. More than three doses of drug missed. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Antifungal Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Biological Availability MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Naphthoquinones/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Pneumonia, Pneumocystis carinii/COMPLICATIONS/ *PREVENTION & CONTROL CAS REGISTRY NUMBER 0 (Antifungal Agents) CAS REGISTRY NUMBER 94015-53-9 (atovaquone) LAST REVISION DATE 941207 ENTRY MONTH 9306 CALIFORNIA UCSF / Moffitt Hospital 602 / Pediatrics 505 Parnassus / Box 0105 San Francisco, CA 94143-0105 Contact: Debbie Trevithick (415) 476-6480 OPEN 930630 ACTU: 4501. ILLINOIS Chicago Children's Memorial Hospital / Pediatric 2300 Childrens Plaza Box 20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 930615 ACTU: 4001. OTHER University of Puerto Rico / University Pediatric Hospital 4th Floor South Wing Room 4B-45 / GPO Box 365067 San Juan, PR 00936-5067 Contact: Carmen Rivera (809) 759-9595 Contact: (809) 765-1979 X 724OPEN 940506 ACTU: 6601. 39 UNIQUE IDENTIFIER NIH/00648 PROTOCOL ID NUMBERS NIAID ACTG 226 PROTOCOL TITLE A Pharmacokinetic and Tolerance Study of Oral Ganciclovir in HIV-Infected Children With Asymptomatic Cytomegalovirus Infection and Low CD4 Cell Counts or Quiescent Cytomegalovirus Disease. VERSION NUMBER & DATE 1 (940726) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Child PROTOCOL CHAIRS CHAIR Frenkel L PROTOCOL CHAIRS CO-CHAIR Dankner W GENERAL DESCRIPTION PURPOSE: PRIMARY: To determine the pharmacokinetics, MTD, and long-term safety and tolerance of oral ganciclovir in HIV-infected infants, children, and adolescents. SECONDARY: To evaluate the effect of oral ganciclovir on the virologic parameters of CMV. GENERAL DESCRIPTION RATIONALE: Maintenance treatment with intravenous (IV) ganciclovir for cytomegalovirus retinitis in AIDS patients is now standard therapy, but daily IV therapy can be complicated by catheter infections and thrombosis. An oral regimen of ganciclovir has been administered safely in adult AID patients and may be of significant benefit to children as well. GENERAL DESCRIPTION METHODOLOGY: Patients are assigned to one of four oral (syrup or capsules) dose levels following a single intravenous dose of ganciclovir. Treatment continues for 24 weeks total. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Pending first patient enrolled (941207) DISEASE STUDIED Cytomegalovirus infection ( CMV infection ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection as evidenced by positive viral culture, with a second confirmatory test of positive viral culture, p24 antigen, or PCR. If >= 18 months of age, HIV infection may also be demonstrated by ELISA confirmed by Western blot or IFA (provided both tests are obtained after 18 months of age). NOTE: Cord blood is not acceptable for diagnosis. 2. CMV infection documented by body fluid or tissue culture. (If >= 12 months of age, CMV infection may be documented by serology). 3. CD4 count < 150 cells/mm3 or < 15 percent AND/OR quiescent CMV disease. Quiescent CMV disease is defined as non-sight-threatening CMV retinitis that is clinically stable for at least 4 weeks, CMV gastrointestinal disease that is clinically stable for at least 2 weeks, congenital CMV infection with hepatitis and/or thrombocytopenia, or other CMV quiescent disease that has been discussed with the protocol chair. 4. NO loss of sight from CMV retinitis. 5. NO acute opportunistic infection. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 41,649 STUDY DESIGN Open Label; Dose Escalating PROTOCOL DETAILS STUDY INTENT: Maximum tolerated dose (MTD), Pharmacokinetics, Drug safety, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 32 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 24 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 6 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CMV infection. 3. CD4 count < 150 cells/mm3 or < 15 percent AND/OR quiescent CMV disease. 4. NO loss of sight from CMV retinitis. 5. NO acute opportunistic infection. 6. Life expectancy at least to study completion. 7. Consent of parent or guardian. NOTE: Infants < 6 months of age at enrollment must have been >= 36 weeks gestational age at birth. NOTE: Patients may co-enroll in other ACTG protocols that do not involve the administration of disallowed medications. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: < 150 cells/mm3. Or < 15 percent (required only if patients do not have quiescent CMV disease). ( 0 - 100 ). PATIENT AGE AGE: 14 Days - 20 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 13 Days. 21 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 30 days prior to study entry: G-CSF or GM-CSF. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Foscarnet. 2. Acyclovir. 3. Interferon. 4. Myelotoxic agents for malignancy or other condition. 5. Other agents with anti-CMV activity. (NOTE: Enrollment of patients on IVIG must be discussed with protocol chair). 6. Imipenem/cilastatin sodium. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Loss of sight in one eye for any reason, with evidence of CMV retinitis in the other eye. 2. Acute or chronic diarrhea that would affect absorption. 3. Clinical or laboratory toxicities of grade 3 or worse. SUBSTANCE IDENTIFICATION Drug 1 DRG-0018 Ganciclovir MANUFACTURERS Drug 1: Syntex Research 3401 Hillview Avenue/PO Box 10850 Palo Alto, CA 94303 Contact: Drug Information (800) 444-4200. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Intravenous: 5 mg/kg over 1 hr on day 1. Oral suspension: 10, 20, 30, or 40 mg in a single assigned doseday 3, followed by the same dose q 8 hr beginning on day 4 and continuing for a total of 24 weeks. Optional oral capsules (offered if 6 patients taking oral suspedose have AUC >= 4.3 mcg/ml/hr): given as a single dose on day a dose equal to the suspension dose given on day 3), followed bsame dose q 8 hr beginning on day 6 and continuing for a total weeks SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous and oral; 10 ml vials, oral suspension, capsules OTHER TREATMENT INFO. TREATMENT DURATION: 24 weeks. OTHER TREATMENT INFO. END POINT: Short-term and long-term toxicity, CMV retinitis and end organ disease. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Unacceptable toxicity. OTHER TREATMENT INFO. MODIFICATION: For grade 3 or 4 neutropenia or thrombocytopenia: Hold study drug. If toxicity resolves to grade 2 within 14 days, resume at original dose. If grade 3 or 4 neutropenia or thrombocytopenia recurs, discontinue study drug permanently. (Recurrence of neutropenia will not require permanent discontinuation if ANC <= grade 2 toxicity can be maintained by G-CSF.) For grade 3 or 4 nausea, vomiting, or diarrhea: Hold study drug. If toxicity resolves to grade 2 within 28 days, resume study drug at original dose. For recurrent grade 3 or 4 nausea/vomiting/diarrhea, discontinue study drug permanently. For other grade 3 or 4 toxicities: Discuss with protocol chair. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Cytomegalovirus Infections/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Female MESH HEADING Ganciclovir/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Human MESH HEADING Infant MESH HEADING Male CAS REGISTRY NUMBER 82410-32-0 (Ganciclovir) LAST REVISION DATE 941207 ENTRY MONTH 9411 CALIFORNIA Los Angeles County USC Medical Center 1129 North State Street Los Angeles, CA 90033 Contact: Janice Ono (213) 226-3945 OPEN 941123 ACTU: 5048. CALIFORNIA University of CA San Diego Medical Center / Pediatric 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 941102 ACTU: 4601. COLORADO University of Colorado Hlth Sciences Ctr / Peds Infect Dis 1056 East 19Th Avenue B055 Denver, CO 80218-1088 Contact: Carol Salbenblatt (303) 861-6751 OPEN 941123 ACTU: 7001. FLORIDA Univ of Miami School of Medicine / Pediatric Imm Infect Dis 1800 NW Tenth Avenue Miami, FL 33136 Contact: Janet Gourley (305) 548-4446 OPEN 941103 ACTU: 4201. MASSACHUSETTS Children's Hosp of Boston / c/o Children's Hosp AIDS Program 300 Longwood Avenue / Carnegie Bldg / Third Floor Boston, MA 02115 Contact: Robert Bishop (617) 735-8198 OPEN 941130 ACTU: 2901. PENNSYLVANIA Saint Christopher's Hospital for Children / Sect Imm & Rheum Erie Avenue at Front Street Philadelphia, PA 19134-1095 Contact: Carole Treston (215) 427-5284 Contact: FAX (215) 427-5555 OPEN 941115 ACTU: 6704. 40 UNIQUE IDENTIFIER NIH/00495 PROTOCOL ID NUMBERS NIAID ACTG 224 PROTOCOL TITLE A Phase I/II Study of Recombinant Interleukin-4 in AIDS and Kaposi's Sarcoma. VERSION NUMBER & DATE 3 (940506) TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Miles S PROTOCOL CHAIRS CO-CHAIR Scadden D GENERAL DESCRIPTION PURPOSE: To determine the safety and tolerance of interleukin-4 (IL-4) in patients with AIDS-related Kaposi's sarcoma. To determine the effects of IL-4 on tumor growth in patients with AIDS-related Kaposi's sarcoma. GENERAL DESCRIPTION RATIONALE: IL-4 exhibits a variety of beneficial effects on the immune system and is a potent inhibitor of Kaposi's sarcoma cells in vitro. GENERAL DESCRIPTION METHODOLOGY: Patients are stratified according to CD4 count and are enrolled in cohorts of six patients at each of four dose levels of IL-4 per strata. If patients at a given dose level have received at least 2 weeks of study therapy and no more than two patients experienced grade 3 or 4 drug-related toxicity, dose escalation in subsequent patients may begin. The MTD is defined as the dose at which 50 percent of patients develop grade 3 or worse toxicity. Patients must be on antiretroviral therapy during study treatment PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. Biopsy-proven AIDS-related Kaposi's sarcoma (NOTE: Patients with systemic pulmonary Kaposi's sarcoma or documented Kaposi's sarcoma of the gastrointestinal tract are not eligible). 2. Serum HIV antibody positive, documented by ELISA. 3. CD4 count <= 500 cells/mm3. 4. Must be receiving some form of antiretroviral therapy for at least 21 days prior to study entry. 5. No active AIDS-related opportunistic infections that require induction therapy, such as Pneumocystis carinii pneumonia (PCP), toxoplasma brain abscess, cytomegalovirus retinitis or colitis, cryptococcal meningitis, and symptomatic Mycobacterium avium-intracellulare (MAI). NOTE: Patients with CD4 count >= 100 cells/mm3 may not have any history of opportunistic infection. Patients with CD4 count < 100 cells/mm3 and stable opportunistic infections requiring maintenance therapy are eligible at the discretion of the investigator. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND BB4950 STUDY DESIGN Open Label; Dose Escalating PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 64 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 52 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 15/64 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS-related Kaposi's sarcoma. 2. HIV infection. 3. Current antiretroviral therapy. 4. No active opportunistic infections requiring induction therapy. 5. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1000 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 500 cells/mm3. ( 0 - 100 - 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 70. PATIENT INCLUSION CRIT. OTHER: BUN <= 40 mg/dl. Lactate dehydrogenase (LDH) or LDH1-2 isoenzymes within normal limits. Creatine phosphokinase (CPK) or CPK2(MB) isoenzymes within normal limits. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control /contraception during the study and for 60 days after. OTHER PATIENT INCL. CH. PRIOR TREATMENT: Allowed: Radiation therapy for Kaposi's sarcoma, to lesions other than marker lesions. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Antiretroviral therapy (AZT, ddI and/or ddC, d4T) for at least 21 days prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: Antiretroviral therapy during study treatment. Allowed: 1. Nonsteroidal anti-inflammatory agents including acetaminophen for drug-related fevers. 2. Systemic steroids for no more than 1 week in any 30-day period. 3. PCP prophylaxis with TMP/SMX, dapsone, or inhaled pentamidine, if patient has a history of PCP or a CD4 count < 250 cells/mm3. Allowed only in patients with CD4 count < 100 cells/mm3: 1. Maintenance doses of ganciclovir, pyrimethamine/sulfa and TMP/SMX for stable, well-controlled opportunistic infections. 2. Non-myelosuppressive treatment IND medications. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of myocardial infarction or significant arrhythmias. 2. History of symptomatic hypoglycemia. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 60 days after. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Systemic therapy (including chemotherapy, interferons, and immune modulators) for Kaposi's sarcoma within 4 weeks prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Chemotherapy, interferons, or immune modulators for Kaposi's sarcoma. 2. Myelosuppressive agents such as induction doses of ganciclovir, Fansidar (pyrimethamine/sulfadoxine), or any other investigational drugs (with the exception of non-myelosuppressive treatment IND medications in specific patients). 3. GM-CSF or erythropoietin (except for a second grade 3/4 neutropenia or anemia). 4. G-CSF. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Other active malignancies (except basal cell carcinoma of the skin and in situ cervical cancer). 2. Alteration in mental status that may prevent compliance. 3. Cardiac functional capacity of Class II or worse OR regional wall abnormalities or abnormal ejection fraction on two-dimensional echocardiogram, if performed. SUBSTANCE IDENTIFICATION Drug 1 DRG-0168 Interleukin-4 MANUFACTURERS Drug 1: Schering-Plough Corporation 2000 Galloping Hill Road Kenilworth, NJ 07033 Contact: Dr Nicholas Pelliccione (908) 298-5680. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 0.5 - 4.0 mcg/kg/day for 52 weeks, preferably early in the day and at the same time q day SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 0.5 - 4.0 mcg/kg/day SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Subcutaneous OTHER TREATMENT INFO. TREATMENT DURATION: 52 weeks. OTHER TREATMENT INFO. END POINT: Dose-limiting toxicity, progressive Kaposi's sarcoma, development of an AIDS-defining opportunistic infection, death. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Interruption of study drugs for > 14 days. 3. Disease progression. 4. Development of a new AIDS-defining opportunistic infection. 5. Pregnancy. 6. Patient noncompliance or desire to withdraw from study. 7. Termination of study. OTHER TREATMENT INFO. MODIFICATION: For grade 3 noncardiac or nonhematologic toxicity or grade 4 hematologic toxicity or fever attributable to the study drug: Hold study drug until toxicity resolves to baseline. If toxicity resolves within 14 days, resume drug at 50 percent dose. If the same toxicity recurs, discontinue study drug permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Human MESH HEADING Interleukin-4/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*ETIOLOGY/ THERAPY CAS REGISTRY NUMBER 0 (Interleukin-4) LAST REVISION DATE 941207 ENTRY MONTH 9304 CALIFORNIA University of California at Los Angeles School of Medicine 60051 CHS / 10833 Le Conte Avenue Los Angeles, CA 90024-1793 Contact: Susan G McCarthy (310) 825-1301 OPEN 930602 ACTU: 0601. MASSACHUSETTS New England Deaconess Hospital 185 Pilgrim Road Boston, MA 02215 Contact: Helen Fitch (617) 735-0785 OPEN 930326 ACTU: 0103. 41 UNIQUE IDENTIFIER NIH/00573 PROTOCOL ID NUMBERS NIAID ACTG 223 PROTOCOL TITLE A Phase II/III Prospective, Multicenter, Randomized, Controlled Trial Comparing the Safety and Efficacy of Three Clarithromycin-Containing Combination Drug Regimens for the Treatment of Disseminated Mycobacterium avium Complex ( MAC ) Disease in Persons With AIDS. VERSION NUMBER & DATE 2 (940801) TRIAL CATEGORY Opportunistic Infections PROTOCOL CHAIRS CHAIR Benson CA PROTOCOL CHAIRS CO-CHAIR Chaisson RE, Currier JS GENERAL DESCRIPTION PURPOSE: To compare the efficacy and safety of clarithromycin combined with rifabutin, ethambutol, or both in the treatment of disseminated Mycobacterium avium Complex (MAC) disease in persons with AIDS, including individuals who have or have not received prior MAC prophylaxis. GENERAL DESCRIPTION RATIONALE: It is believed that effective theapy for MAC disease in patients with AIDS requires combinations of two or more antimycobacterial agents in order to overcome drug resistance and the unfavorable influence of the profound immunosuppression associated with AIDS. Data suggest that clarithromycin may have substantial activity in two- or three-drug combination regimens with clofazimine, rifamycin derivatives, ethambutol, or the 4-quinolones. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to one of three treatment arms containing clarithromycin in combination with ethambutol, rifabutin, or both. Clarithromycin alone is taken on days 1 through 3 to determine tolerance; the other agents are added on day 4. Treatment continues daily for 48 weeks. Patients with complete or partial response at week 12 continue on their originally assigned regimen for duration of therapy or until relapse. Patients with treatment failure or relapse at any time are rolled over to three-drug salvage therapy with clarithromycin plus two new drugs not previously received in their original regimen, as follows: rifabutin/clofazimine, ethambutol/clofazimine, or clofazimine/ciprofloxacin. Patients are followed twice in the first week, then every 2 weeks for the first 2 months, then monthly for the next 4 months, and then every 2 months thereafter until the end of 12 months. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Pending first patient enrolled (941207) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection. 2. Symptomatic MAC disease with one blood culture positive for MAC or AFB obtained within the past 90 days, or asymptomatic MAC disease defined by two blood cultures positive for MAC or AFB obtained at least 24 hours apart within the past 90 days. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 43,856 STUDY DESIGN Prospective; Multicenter; Randomized; Controlled; Drug Combination; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Combination drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 246 patients. (82 patients in each of three study arms) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 48 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 18 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Disseminated MAC disease. 3. Life expectancy of at least 8 weeks. NOTE: This protocol is approved for prisoner participation. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. SGOT(AST): <= 10 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 2.5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 30 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 50. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 500 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antiretroviral therapy. 2. Maintenance or prophylactic therapy for other opportunistic infections (with the exception of specifically excluded drugs). 3. Carbamazepine or theophylline. 4. Isoniazid for TB prophylaxis. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of severe hypersensitivity to erythromycin, clarithromycin, azithromycin, ethambutol, rifampin, or rifabutin (including Type 1 hypersensitivity reaction, Stevens-Johnson syndrome, hepatitis, optic neuritis, or exfoliative dermatitis). [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 1 week prior to study entry: All antimycobacterial drugs (other than isoniazid for TB prophylaxis). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other antimycobacterial drugs (with the exception of isoniazid for TB prophylaxis). 2. Therapy for any acute infectious process other than MAC. 3. Terfenadine or astemizole. 4. Active treatment with fluconazole for more than 21 days (patients who are receiving fluconazole for maintenance suppression of cryptococcal meningitis and who have been on a stable dose for 4 weeks or longer are permitted with approval of the protocol chair). 5. Other investigational drugs unless approved by protocol chair. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Active mycobacterial infection other than MAC that requires treatment, with the exception of isoniazid used solely for TB prophylaxis. SUBSTANCE IDENTIFICATION Drug 1 DRG-0099 Clarithromycin SUBSTANCE IDENTIFICATION Drug 2 DRG-0111 Ethambutol SUBSTANCE IDENTIFICATION Drug 3 DRG-0085 Rifabutin SUBSTANCE IDENTIFICATION Drug 4 DRG-0067 Clofazimine SUBSTANCE IDENTIFICATION Drug 5 DRG-0110 Ciprofloxacin TRADE NAME OF SUBSTANCE Drug 1‰ Biaxin MANUFACTURERS Drug 1: Abbott Laboratories One Abbott Park Road Abbott Park, IL 60064 Contact: Dr J Carl Craft (708) 937-8147. MANUFACTURERS Drug 2: Lederle Laboratories North Middletown Road Pearl River, NY 10965 Contact: Dr Amy Baim (914) 732-2147 Contact: Dr John Riefler (914) 732-2035. MANUFACTURERS Drug 3: Adria Laboratories Incorporated PO Box 16529 Columbus, OH 43216-6529 Contact: Beverly Wynne (614) 764-8307. MANUFACTURERS Drug 4: Ciba Pharmaceutical Company 556 Morris Avenue Summit, NJ 07901 Contact: Medical Services Department (908) 277-5000. MANUFACTURERS Drug 5: Miles Incorporated Pharmaceutical Division 400 Morgan Lane West Haven, CT 06516-4175 Contact: Professional Services (800) 468-0894. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 500 mg BID for 48 weeks. Drug 2: 15 mg/kg daily for 48 weeks. Drug 3: 450 mg daily for 48 weeks. Drug 4: 100 mg daily for 48 weeks. Drug 5: 750 mg BID for 48 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 1000 mg. Drug 2: 15 mg/kg. Drug 3: 450 mg. Drug 4: 100 mg. Drug 5: 1500 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 500 mg tablets. Drug 2: Oral, 400 mg tablets. Drug 3: Oral, 150 mg capsules. Drug 4: Oral, 100 mg capsules. Drug 5: Oral, 500 and 750 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 48 weeks. OTHER TREATMENT INFO. END POINT: Response to treatment, time to response, association of drug plasma concentrations to changes in quantitative MAC blood colony counts. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Requirement for treatment with prohibited medications. 3. Relapse following rollover to salvage regimen. OTHER TREATMENT INFO. MODIFICATION: Doses are reduced or discontinued for specific toxicities. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Ciprofloxacin/*THERAPEUTIC USE MESH HEADING Clarithromycin/*THERAPEUTIC USE MESH HEADING Clofazimine/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Ethambutol/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*DRUG THERAPY MESH HEADING Rifabutin/*THERAPEUTIC USE CAS REGISTRY NUMBER 2030-63-9 (Clofazimine) CAS REGISTRY NUMBER 72559-06-9 (Rifabutin) CAS REGISTRY NUMBER 74-55-5 (Ethambutol) CAS REGISTRY NUMBER 81103-11-9 (Clarithromycin) CAS REGISTRY NUMBER 85721-33-1 (Ciprofloxacin) LAST REVISION DATE 941207 ENTRY MONTH 9412 ALABAMA University of Alabama at Birmingham 908 20th Street S / 1917 Research Clinic Room 135 Birmingham, AL 35294-2041 Contact: Susan Duncan (205) 934-3690 OPEN 941123 ACTU: 5801. COLORADO Rose Med Ctr / Univ of Colorado Hlth Sci Ctr / Colorado ACTU Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 941123 ACTU: 6104. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941123 ACTU: 2701. ILLINOIS Louis A Weiss Memorial Hospital / Northwestern Univ Med Schl 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941123 ACTU: 2708. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 941123 ACTU: 2702. MASSACHUSETTS Beth Israel Hospital 330 Brookline Avenue Boston, MA 02115 Contact: Sheila Hussey (617) 735-4103 OPEN 941123 ACTU: 0102. MINNESOTA St Paul-Ramsey Medical Center 640 Jackson Street St Paul, MN 55101 Contact: Ray Nelson (612) 221-1280 OPEN 941205 ACTU: 1503. MINNESOTA University of Minnesota Hospital and Clinic PO Box 437 / UMHC / Harvard Street & East River Road Minneapolis, MN 55455 Contact: Nancy Reed (612) 625-1462 OPEN 941205 ACTU: 1501. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 941123 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 941123 ACTU: 2102. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 941128 ACTU: 3201. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 941123 ACTU: 0401. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 941123 ACTU: 1902. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 941123 ACTU: 1901. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 941123 ACTU: 1102. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 941123 ACTU: 2301. PENNSYLVANIA University of Pennsylvania / Div of Infectious Diseases 549 Johnson Pavillion / 6073 / 36th and Hamilton Walk Philadelphia, PA 19104-6073 Contact: Debora Dunbar (215) 349-8092 OPEN 941123 ACTU: 6201. 42 UNIQUE IDENTIFIER NIH/00469 PROTOCOL ID NUMBERS NIAID ACTG 222 PROTOCOL TITLE The Treatment of Pulmonary Mycobacterium Tuberculosis in HIV Infection. VERSION NUMBER & DATE 3 (940927) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To compare the efficacy and safety of induction and continuation therapies for the treatment of pulmonary tuberculosis (TB) in HIV-infected patients who are either from areas with known high rates of resistance to one or more anti-TB drugs or from areas where TB is expected to be susceptible to commonly used anti-TB drugs. GENERAL DESCRIPTION RATIONALE: In some areas of the country, resistance to one or more of the drugs commonly used to treat TB has emerged. Thus, the need to test regimens containing a new drug exists. Furthermore, the optimal duration of anti-TB therapy for HIV-infected patients with TB needs to be determined. GENERAL DESCRIPTION METHODOLOGY: In the induction phase, patients enrolled in drug-susceptible areas (defined as metropolitan areas with a resistance rate for isoniazid therapy of less than 10 percent) receive four drugs: isoniazid (plus pyridoxine), rifampin, pyrazinamide, and ethambutol. Patients enrolled in drug-resistant areas (resistance rate for isoniazid of 10 percent or higher) receive the four-drug regimen with or without a fifth drug, levofloxacin. After 8 weeks of induction, patients with multi-drug resistance are removed from study regimens; all other patients enter a continuation phase. Pansusceptible patients (showing susceptibility to all first-line anti-TB drugs) receive two study drugs for an additional 18 or 31 weeks; patients with isoniazid-resistant (or intolerant) TB receive two or three study drugs for an additional 44 weeks, while those with rifampin-resistant TB receive two or three study drugs for an additional 70 weeks. Patients are evaluated every 2 weeks in the induction phase and every 12 weeks in the continuation phase. Minimum follow-up is 2 years. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Tuberculosis. DISEASES STATUS Patients have the following symptoms and conditions: INDUCTION PHASE. 1. Working diagnosis of HIV infection by medical and behavioral histories, clinical signs and symptoms, and laboratory tests. 2. Working diagnosis of TB. CONTINUATION PHASE. 1. Successful completion of induction phase and confirmation of TB by culture and susceptibility results. 2. Susceptible to and tolerant of study drugs in the appropriate continuation regimen. NOTE: Per 09/27/94 amendment, alternate entry criteria for the continuation phase have been established as a secondary recourse. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS CPCRA 019. IND 41,372 STUDY DESIGN Multicenter; Randomized; Open Label; Comparative; Prospective PROTOCOL DETAILS STUDY INTENT: Combination drug therapy, Drug efficacy, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 650 patients. (450 patients in drug-resistant areas; 200 patients in drug-susceptible areas) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 2-4 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 106/650 (941207). PROTOCOL DETAILS STUDY DURATION: Approximately 4 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 43 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: INDUCTION PHASE. 1. HIV infection. 2. Diagnosis of pulmonary TB. NOTE: Patients from susceptible areas may be 13 years of age or older. Patients from resistant areas must be 18 years of age or older. CONTINUATION PHASE. 1. Successful completion of induction phase and confirmation of TB by culture and susceptibility results. 2. Susceptibility to and tolerance of study drugs in the appropriate continuation regimen. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 3 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. (if creatinine value not available). PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: More than 3 weeks of continuous anti-TB therapy immediately prior to study entry, or more than 12 weeks total of anti-TB therapy within the past 2 years. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Other medications with anti-TB activity. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Multi-drug resistance to at least isoniazid and rifampin or known to have had close contact with a person with known multi-drug resistant TB. 2. Known treatment-limiting reaction to any of the study drugs. 3. Other disorders or conditions for which the study drugs are contraindicated. SUBSTANCE IDENTIFICATION Drug 1 DRG-0123 Isoniazid SUBSTANCE IDENTIFICATION Drug 2 DRG-0109 Rifampin SUBSTANCE IDENTIFICATION Drug 3 DRG-0124 Pyrazinamide SUBSTANCE IDENTIFICATION Drug 4 DRG-0111 Ethambutol SUBSTANCE IDENTIFICATION Drug 5 DRG-0129 Levofloxacin SUBSTANCE IDENTIFICATION Drug 6 DRG-0125 Pyridoxine MANUFACTURERS Drug 1: Schein Pharmaceuticals Incorporated / Regulatory Affairs Mount Ebo Corporate Park / Route 22 Brewster, NY 10509 Contact: Dr William McIntyre (914) 278-3742. MANUFACTURERS Drug 2: Marion Merrell Dow Medical Information / PO Box 9627 Kansas City, MO 64134-0627 Contact: Medical Information (800) 633-1610. MANUFACTURERS Drug 3: Lederle Laboratories North Middletown Road Pearl River, NY 10965 Contact: Dr Amy Baim (914) 732-2147 Contact: Dr John Riefler (914) 732-2035. MANUFACTURERS Drug 4: Lederle Laboratories North Middletown Road Pearl River, NY 10965 Contact: Dr Amy Baim (914) 732-2147 Contact: Dr John Riefler (914) 732-2035. MANUFACTURERS Drug 5: Ortho Pharmaceutical Corporation Route 202 / PO Box 300 Raritan, NJ 08869-0602 Contact: Dr Vincent Ahonkha (908) 704-4991. MANUFACTURERS Drug 6: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: INDUCTION PHASE: Resistant and susceptible areas - 300 mg daily for 2 weeks, followed by 600 or 900 mg thrice weekfor 6 weeks. CONTINUATION PHASE: 600 or 900 mg administered twice weekly for31 weeks in pansusceptible patients and for 70 weeks in rifampin-resistant/intolerant patients (not administered in patwho are isoniazid-resistant/intolerant). Drug 2: INDUCTION PHASE: Resistant and susceptible areas - 600 mg daily for 2 weeks, followed by 600 mg thrice weekly for weeks. CONTINUATION PHASE: 600 mg twice weekly for 44 weeks in patientare pansusceptible or isoniazid-resistant/intolerant (not administered in those who are rifampin-resistant/intolerant). Drug 3: INDUCTION PHASE: Resistant and susceptible areas - 2.0 g daily for 2 weeks, followed by 2.0 or 2.5 g thrice weekly6 weeks. CONTINUATION PHASE: 3.0 or 3.5 g twice weekly for 70 weeks in rifampin-resistant/intolerant patients who received a four-druginduction regimen (not administered in those who are pansusceptisoniazid-resistant/intolerant, or rifampin-resistant/intoleranthe five-drug induction regimen). Drug 4: INDUCTION PHASE: Resistant and susceptible areas - mg/kg (maximum 2.4 g) daily for 2 weeks, followed by 30 mg/kg (maximum 2.4 g) thrice weekly for 6 weeks. CONTINUATION PHASE: 50 mg/kg (maximum 2.4 g) for 44 weeks in isoniazid-resistant/intolerant patients and 70 weeks in in rifampin-resistant/intolerant patients (not administered in patwith pansusceptibility). Drug 5: INDUCTION PHASE: Resistant areas only - 500 mg daily weeks, followed by 750 mg thrice weekly for 6 weeks. CONTINUATION PHASE: 750 mg twice weekly for 44 weeks in isoniazid-resistant/intolerant patients who received the five-dinduction regimen and for 70 weeks in rifampin-resistant/intolepatients who received the five-drug regimen (not administered ipatients who received the four-drug induction regimen). Drug 6: INDUCTION PHASE: Resistant and susceptible areas - daily for 2 weeks, followed by 50 mg thrice weekly for 6 weeks (administered with isoniazid). CONTINUATION PHASE: 50 mg twice weekly in pansusceptible and rifampin-resistant/intolerant patients (no SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 300 mg (first 2 weeks of induction). Drug 2: 450 or 600 mg (first 2 weeks of induction). Drug 3: 1.5 or 2.0 g (first 2 weeks of induction). Drug 4: 20 mg/kg (first 2 weeks of induction). Drug 5: 500 mg (first 2 weeks of induction phase). Drug 6: 50 mg (first 2 weeks of induction phase) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 300 mg tablets. Drug 2: Oral, 150 and 300 mg capsules. Drug 3: Oral, 500 mg tablets. Drug 4: Oral, 400 mg tablets. Drug 5: Oral, 125 and 500 mg tablets. Drug 6: Oral, 50 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 26-78 weeks. OTHER TREATMENT INFO. END POINT: Induction phase: Culture conversion at 8 weeks. Continuation phase: Failure while on therapy and relapse after completion of therapy. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Development of multi-drug resistance in induction phase. 2. Failure to complete induction therapy within 10 weeks. 3. Unacceptable toxicity. 4. Not in the patient's best interest to continue. OTHER TREATMENT INFO. MODIFICATION: For grade 3 toxicity: Hold causative study drug, then restart at the discretion of the primary physician. For recurrent grade 3 or any grade 4 toxicity: Hold study drugs temporarily; discontinue permanently at the discretion of the primary physician. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), National Institute of Allergy & Infectious Diseases (CPCRA). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Ethambutol/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Isoniazid/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Ofloxacin/ANALOGS & DERIVATIVES/ ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/ *THERAPEUTIC USE MESH HEADING Opportunistic Infections/COMPLICATIONS/DRUG THERAPY MESH HEADING Pyrazinamide/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Pyridoxine/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Rifampin/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Tuberculosis, Pulmonary/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 13292-46-1 (Rifampin) CAS REGISTRY NUMBER 54-85-3 (Isoniazid) CAS REGISTRY NUMBER 65-23-6 (Pyridoxine) CAS REGISTRY NUMBER 74-55-5 (Ethambutol) CAS REGISTRY NUMBER 82419-36-1 (Ofloxacin) CAS REGISTRY NUMBER 98-96-4 (Pyrazinamide) LAST REVISION DATE 941207 ENTRY MONTH 9304 CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 940311 ACTU: 1201. COLORADO Denver / CPCRA 605 Bannock Street Denver, CO 80204-4507 Contact: Jack Rouff (303) 436-7184 Contact: (303) 436-7224 OPEN 930609. CONNECTICUT Yale University School of Medicine / Sect of Infectious Dis 135 College Street New Haven, CT 06510-2483 Contact: Laurie Andrews (203) 737-4040 OPEN 930715 ACTU: 6401. DISTRICT OF COLUMBIA Howard U Coll of Med / AIDS Minority Infrastructure Program 2112 Georgia Avenue NW Washington, DC 20059 Contact: Victoria Holly -Trimmer (202) 806-4700 Contact: (202) 806-4755 OPEN 931130 ACTU: 5301. DISTRICT OF COLUMBIA Washington Regional AIDS Program 50 Irving St N W / Room ID-151B Washington, DC 20422 Contact: John Scott (202) 745-8695 OPEN 930405. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 930607 ACTU: 0901. HAWAII Hawaii Aids Clinical Trails Unit Leahi Hospital / Young Bldg / 3675 Kilauea Avenue / 6th Flr Honolulu, HI 96816 Contact: Debra M Ogata Arakaki (808) 737-2751 OPEN 930610 ACTU: 5201. ILLINOIS Cook County Hospital Passavant Pavilion / Room 823 / 303 East Superior Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 930716 ACTU: 2705. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 940513 ACTU: 0201. MARYLAND State of Maryland Div of Corrections c/o Johns Hopkins Hosp 1830 East Monument Street / Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 940513 ACTU: 0202. MICHIGAN Comprehensive AIDS Alliance of Detroit 4160 John R / Harper Hospital Prof Bldg / Suite 202 Detroit, MI 48201 Contact: Constance Rowley (313) 993-0934 OPEN 940216. MICHIGAN Henry Ford Hospital 2799 West Grand Boulevard Detroit, MI 48202 Contact: Diane Mastro-Polak (313) 876-7664 OPEN 930618. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 930405 ACTU: 1802. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 930412 ACTU: 0401. NEW YORK St Clare's Hospital and Health Center 415 West 51st Street New York, NY 10019 Contact: Phyllis Ristau (212) 459-8449 OPEN 940427 ACTU: 2204. NEW YORK Cornell University Medical Center 525 East 68th Street / Room 2434 New York, NY 10021 Contact: Brenda Greenhill (212) 746-4177 OPEN 930721 ACTU: 2201. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 930412 ACTU: 1801. NEW YORK Columbia Presbyterian Medical Center 622 West 168 Street / Harkness Pavilion 5 Room 516 New York, NY 10032-3784 Contact: Mykyelle Wade (212) 305-8507 OPEN 931207 ACTU: 7501. NEW YORK Harlem AIDS Treatment Group Harlem Hospital / Women's Pavilion Room 126 New York, NY 10037 Contact: Joshua Standig (212) 939-2951 OPEN 930405. NEW YORK Bronx-Lebanon Hospital Center 1309 Fulton Avenue Bronx, NY 10456 Contact: Cathy Pollard (718) 293-2593 Contact: (718) 901-8916 OPEN 930405. NEW YORK Montefiore Drug Treatment Center 418 Forchheimer-ID / 1300 Morris Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3639 Contact: (718) 920-5344 OPEN 930405 ACTU: 1905. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 930405 ACTU: 1902. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 930405 ACTU: 1903. NEW YORK Comprehensive Health Care Center 418 Forchheimer-ID / 1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 930405 ACTU: 1908. NEW YORK Albert Einstein College of Medicine 418 Forcheimer / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 930405 ACTU: 1904. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 930405 ACTU: 1901. NEW YORK North Central Bronx Hospital / Montefiore Family Health Cntr 418 Forchheimer-ID/1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 930405 ACTU: 1906. NEW YORK North Central Bronx Hospital / Samaritan Village Inc 418 Forchheimer ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 930405 ACTU: 1907. NEW YORK Montefiore Medical Center / Adolescent AIDS Program 111 East 210th Street / NW674 Bronx, NY 10467 Contact: Dina Monte (718) 882-0023 OPEN 930405 ACTU: 4903. NEW YORK Bronx Veterans Administration Medical Center 130 West Kingsbridge Road Bronx, NY 10468 Contact: Nancy Ostrow (718) 584-9000 X 667Contact: (718) 584-9000 X 667OPEN 930519 ACTU: 1804. NEW YORK Addiction Research And Treatment Corporation 22 Chapel Street Brooklyn, NY 11201 Contact: Dr Robert Sawyer (718) 260-2917 OPEN 930707. NEW YORK SUNY Health Sciences Center at Brooklyn ACTU Box 77 / 450 Clarkson Avenue Brooklyn, NY 11203-2098 Contact: Donald Smith (718) 270-3372 Contact: (718) 270-3370 OPEN 930405 ACTU: 5901. NEW YORK Clinical Directors Network of Region II 5601 2nd Avenue #3 Brooklyn, NY 11220 Contact: Linda Podhurst (212) 255-3841 OPEN 930405. NEW YORK City Hospital at Elmhurst / Mt Sinai 79-01 Broadway Room D1-29 Elmhurst, NY 11373 Contact: Dinah Reitman (718) 334-3963 OPEN 940706 ACTU: 1803. NEW YORK Adirondack Medical Center at Saranac Lake 47 New Scotland Avenue Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930722 ACTU: 7403. NEW YORK Mid-Hudson Care Center / Albany Med College / Div Med Oncol 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930722 ACTU: 7402. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930722 ACTU: 7401. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 930602 ACTU: 1102. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 931001 ACTU: 2401. PENNSYLVANIA University of Pennsylvania / Div of Infectious Diseases 549 Johnson Pavillion / 6073 / 36th and Hamilton Walk Philadelphia, PA 19104-6073 Contact: Debora Dunbar (215) 349-8092 OPEN 940720 ACTU: 6201. 43 UNIQUE IDENTIFIER NIH/00533 PROTOCOL ID NUMBERS NIAID ACTG 221 PROTOCOL TITLE A Phase I/II Study of Delayed-Type Hypersensitivity (DTH) Reactions to Intradermal HIV Envelope Antigen. VERSION NUMBER & DATE 4 (941027) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Katzenstein D GENERAL DESCRIPTION PURPOSE: To determine the frequency of delayed-type hypersensitivity (DTH) reactions in HIV-positive patients to two doses of two envelope glycoprotein antigens prepared differently. To determine whether patients who have previously demonstrated a DTH response to intradermal MGStage HIV-1 gp160 IIIB baculovirus (MicroGeneSys) have a reproducible response to a repeat injection of gp160 and whether there is cross-reactivity to intradermal HIV-1 rgp160 IIIB vero cell expressed (Immuno-AG). GENERAL DESCRIPTION RATIONALE: Previous studies in individuals immunized with gp160 suggest that a skin test response in immunized patients can be used as a surrogate marker for new proliferative and cytotoxic responses induced by vaccination. GENERAL DESCRIPTION METHODOLOGY: Patients are stratified into three groups. Fifteen patients who are not on antiretroviral therapy and received prior MicroGeneSys gp160 antigen in ACTG 137 (stratum 1) will receive intradermal injections of Immuno-AG gp160 IIIB in one arm, followed 1 week later by intradermal injections of MicroGeneSys gp160 IIIB antigen in the opposite arm. Twenty patients who are not on antiretroviral therapy and not previously immunized with gp160 (stratum 2), as well as 20 other patients who are currently on antiretroviral therapy with zidovudine, didanosine, dideoxycytidine, or stavudine and not previously immunized with gp160 (stratum 3), will receive intradermal injections of Immuno-AG gp160 IIIB in one arm simultaneously with MicroGeneSys gp160 IIIB in the opposite arm. All patients return 48 hours after each injection session for skin test reading. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA and Western blot, culture, PCR, or p24 antigen. 2. CD4 count >= 400 cells/mm3 within 90 days prior to study entry. 3. NO current active opportunistic infection or neoplasm (other than cutaneous Kaposi's sarcoma that is stable with < 10 lesions). ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS IND BB5177 STUDY DESIGN Blinded; Comparative PROTOCOL DETAILS STUDY INTENT: Immunology, Adverse effects. PROTOCOL DETAILS PROJECTED ACCRUAL: 55 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 1-2 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 37/55 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 4 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. CD4 count >= 400 cells/mm3. 3. NO current active opportunistic infection or neoplasm (other than stable cutaneous Kaposi's sarcoma). [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 400 cells/mm3. ( 400 - 500 - 600 - 700 - 800 - plus ). PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 30 days prior to study entry: 1. Any antiretroviral drugs (other than AZT, ddI, ddC, or d4T for patients in stratum 3). 2. Systemic corticosteroids, topical corticosteroids on the arms, or other systemic immunosuppressant agents or antineoplastic agents. Excluded within 72 hours prior to intradermal injections: Antihistamine or anti-inflammatory medications. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antihistamine or anti-inflammatory medications for the 48-hour period between injection and skin test reading. 2. Topical steroids. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Known hypersensitivity to insect proteins. SUBSTANCE IDENTIFICATION Drug 1 DRG-0041 gp160 Vaccine (MicroGeneSys) SUBSTANCE IDENTIFICATION Drug 2 DRG-0162 gp160 Vaccine (Immuno-AG) MANUFACTURERS Drug 1: MicroGeneSys Incorporated 1000 Research Parkway Meridan, CT 06450-7159 Contact: Frank Volvovitz (203) 686-0800. MANUFACTURERS Drug 2: Immuno-US Incorporated / Media Information Office c/o Cooney/Waters Group / 99 Park Avenue / Suite 25 New York, NY 10016 Contact: Sherri Michelstein (212) 557-7111. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1 and 10 mcg in one arm (administered 1 week prior to MicroGeneSys gp160 antigen OR simultaneously with MicroGeneSys antigen). Drug 2: 1 and 10 mcg in one arm (administered sequentially one after Immuno-AG gp160 antigen OR simultaneously with Immuno-AG antigen) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intradermal injection. Drug 2: Intradermal injection OTHER TREATMENT INFO. END POINT: DTH reaction 48 hours after injections. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Gene Products, env/ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/*IMMUNOLOGY MESH HEADING HIV Antigens/*IMMUNOLOGY MESH HEADING HIV Infections/*THERAPY MESH HEADING HIV-1/*IMMUNOLOGY MESH HEADING Human MESH HEADING Hypersensitivity, Delayed MESH HEADING Injections, Intradermal MESH HEADING Male MESH HEADING Middle Age MESH HEADING Protein Precursors/ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/*IMMUNOLOGY MESH HEADING Vaccines, Synthetic CAS REGISTRY NUMBER 0 (HIV Antigens) CAS REGISTRY NUMBER 0 (HIV envelope protein gp160) CAS REGISTRY NUMBER 0 (Vaccines, Synthetic) LAST REVISION DATE 941207 ENTRY MONTH 9405 CALIFORNIA AIDS Community Research Consortium 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harris (415) 364-5653 OPEN 940824 ACTU: 0505. CALIFORNIA Santa Clara Valley Med Ctr / ACRC 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harriss (415) 364-5653 OPEN 941019 ACTU: 0506. CALIFORNIA Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Contact: Virginia Tallman (415) 723-2804 Contact: Dr Rami Ramachandran (415) 723-6231 OPEN 940824 ACTU: 0501. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 940824 ACTU: 0401. 44 UNIQUE IDENTIFIER NIH/00527 PROTOCOL ID NUMBERS NIAID ACTG 220 PROTOCOL TITLE A Pre-Enrollment Protocol for HIV-Infected Adolescents. VERSION NUMBER & DATE 1 (930519) TRIAL CATEGORY Epidemiology TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR D'Angelo LJ PROTOCOL CHAIRS CO-CHAIR Futterman D, Abdalian S GENERAL DESCRIPTION PURPOSE: PRIMARY: To identify, characterize, and co-enroll HIV-infected adolescents into existing and future ACTG (or other NIH-sponsored) HIV treatment protocols through the systematic and recurrent assessment of eligibility. To assess the ability of adolescents enrolled in ACTG 220 to adhere to ACTG (or other NIH-sponsored) HIV treatment protocols; and to define factors that influence the adolescent's ability to enter or adhere to study protocols. SECONDARY: To describe the nature, stage, and progression of HIV infection in adolescents. GENERAL DESCRIPTION RATIONALE: Little is known about HIV-infected adolescents as a group and, as a result, small numbers of them are currently enrolled in ACTG drug studies. Creative approaches are needed to encourage enrollment of HIV-infected adolescents whose socio-demographic profile has made access to NIH-sponsored research unlikely. GENERAL DESCRIPTION METHODOLOGY: At entry and at every subsequent visit, participants are systematically evaluated for eligibility and willingness to enter ACTG (or other NIH-sponsored) HIV treatment protocols from a menu developed and updated by the Pediatric Adolescent Working Group of the ACTG. A survey of participant attitudes, behaviors, and beliefs is administered and updated semiannually. Participants attend clinic visits every 3 months and are followed for a minimum of 6 months, until the end of the study. They receive periodic physical exams, STD and gynecologic or genitourinary evaluations, HIV symptom assessment and related diagnoses, TB evaluation, and laboratory tests (hematology and immunology). PROTOCOL PHASE Epidemiology OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Participants meet the following criteria: Laboratory evidence of HIV infection (positive HIV antibody test with standard confirmatory tests). ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Prospective PROTOCOL DETAILS STUDY INTENT: Epidemiology. PROTOCOL DETAILS PROJECTED ACCRUAL: 250 patients. 0 PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Minimum of 6 months. PROTOCOL DETAILS ACTUAL ACCRUAL: 161/250 (941207). PROTOCOL DETAILS STUDY DURATION: 4 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 46 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Participants must meet the following criteria: 1. HIV infection. 2. NOT currently enrolled in an ACTG treatment protocol. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: Non-applicable percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: Non-applicable g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: Non-applicable cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: Non-applicable platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CD4/CD8 RATION: Non-applicable. PATIENT INCLUSION CRIT. BILIRUBIN: Non-applicable mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): Non-applicable. PATIENT INCLUSION CRIT. SGPT(ALT): Non-applicable. PATIENT INCLUSION CRIT. CREATININE: Non-applicable. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: Non-applicable ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: Non-applicable. PATIENT AGE AGE: 13 Years - 20 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. 21 Years - 99 Years. PATIENT EXCLUSION CRIT. COMPLICATIONS: Participants with the following condition are excluded: No legal provision for consent to participate in clinical research can be determined. PATIENT EXCLUSION CRIT. AVAILABILITY: No access to or ability to be followed at a participating ACTG site. OTHER TREATMENT INFO. END POINT: Co-enrollment of patient in ACTG (or other NIH-sponsored) HIV treatment protocol(s); demonstration of patient adherence with the requirements of ACTG 220; identification of factors that interfere with patient adherence to study protocol(s). SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*EPIDEMIOLOGY/ETIOLOGY MESH HEADING Acquired Immunodeficiency Syndrome/ *EPIDEMIOLOGY/ETIOLOGY MESH HEADING Adolescence MESH HEADING Adolescent Behavior MESH HEADING Female MESH HEADING HIV Infections/*EPIDEMIOLOGY/ETIOLOGY MESH HEADING Human MESH HEADING Male LAST REVISION DATE 941207 ENTRY MONTH 9311 ALABAMA University of Alabama at Birmingham School of Medicine 751 CHT / University Station Birmingham, AL 35294 Contact: Michael Cooney (205) 939-9552 Contact: beeper (205) 869-9524 OPEN 930831 ACTU: 5046. CALIFORNIA UCLA Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 931118 ACTU: 3601. CALIFORNIA Children's Hospital of Los Angeles 10833 Le Conte Avenue Los Angeles, CA 90024-1757 Contact: Leslie Spring (310) 206-6369 OPEN 940427 ACTU: 3602. CALIFORNIA Children's Hospital of Los Angeles / Children's AIDS Center 4650 Sunset Blvd / Mail Stop #54 Los Angeles, CA 90027 Contact: Antonieta Sosa (213) 669-2180 OPEN 940606 ACTU: 9916. CALIFORNIA Los Angeles County USC Medical Center 1129 North State Street Los Angeles, CA 90033 Contact: Janice Ono (213) 226-3945 OPEN 940413 ACTU: 5048. CALIFORNIA UCSF / Moffitt Hospital 602 / Pediatrics 505 Parnassus / Box 0105 San Francisco, CA 94143-0105 Contact: Debbie Trevithick (415) 476-6480 OPEN 930930 ACTU: 4501. CALIFORNIA Children's Hospital Oakland 747 Fifty Second Street Oakland, CA 94609-1809 Contact: Jim Riddel (510) 428-3000 X 282Contact: (510) 539-6311 X PagOPEN 930729 ACTU: 4504. COLORADO University of Colorado Hlth Sciences Ctr / Peds Infect Dis 1056 East 19Th Avenue B055 Denver, CO 80218-1088 Contact: Carol Salbenblatt (303) 861-6751 OPEN 931004 ACTU: 7001. DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 931014 ACTU: 5701. DISTRICT OF COLUMBIA Children's National Medical Center / Special Immuno Svc Suite 2108 / 111 Michigan Avenue NW Washington, DC 20010-2970 Contact: Sandra Jones (202) 884-3682 OPEN 930726 ACTU: 7101. FLORIDA Univ of Miami School of Medicine / Pediatric Imm Infect Dis 1800 NW Tenth Avenue Miami, FL 33136 Contact: Janet Gourley (305) 548-4446 OPEN 940824 ACTU: 4201. GEORGIA Emory University Hospital 69 Butler Street SE Atlanta, GA 30303 Contact: Judy Sarver (404) 616-6227 Contact: clinic (404) 616-4390 Contact: beeper (404) 899-5290 OPEN 931020 ACTU: 5030. ILLINOIS Chicago Children's Memorial Hospital / Pediatric 2300 Childrens Plaza Box 20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 940405 ACTU: 4001. ILLINOIS Wyler Children's Hospital 5841 South Maryland Avenue Chicago, IL 60637-1470 Contact: Kim Stieglitz (312) 702-6176 OPEN 931109 ACTU: 4003. LOUISIANA Tulane University School of Medicine / Div of Ped Infect Dis 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 930729 ACTU: 7201. MASSACHUSETTS Children's Hosp of Boston / c/o Children's Hosp AIDS Program 300 Longwood Avenue / Carnegie Bldg / Third Floor Boston, MA 02115 Contact: Robert Bishop (617) 735-8198 OPEN 931208 ACTU: 2901. MASSACHUSETTS Boston City Hospital / Ped Infect Dis / Finland Lab 774 Albany Street / Finland Lab Room 301 Boston, MA 02118 Contact: Anne Marie Reagan (617) 534-5813 OPEN 940304 ACTU: 2903. NORTH CAROLINA Duke University Medical Center / Pediatrics Box 3499 Durham, NC 27710 Contact: John Swetnam (919) 684-6335 OPEN 930708 ACTU: 4701. NEBRASKA University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-5130 Contact: Frances Tennant (402) 559-5750 OPEN 940919 ACTU: 1505. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue / Pediatric New York, NY 10016 Contact: Nagamah Deygoo (212) 263-6426 OPEN 930824 ACTU: 4401. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 ACTU: 1801. NEW YORK Mount Sinai School of Medicine / Pediatrics One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940824 ACTU: 4301. NEW YORK Harlem Hospital 506 Lenox Avenue New York, NY 10037 Contact: Rick Urbano (212) 939-4040 Contact: (212) 939-4045 OPEN 931215 ACTU: 5006. NEW YORK Bronx Lebanon Hospital Center / Department of Pediatrics 1650 Selwyn Avenue Room 2C Bronx, NY 10457 Contact: Patrice Edwards-Cihak (718) 960-1015 OPEN 931022 ACTU: 6901. NEW YORK Montefiore Medical Center / Adolescent AIDS Program 111 East 210th Street / NW674 Bronx, NY 10467 Contact: Dina Monte (718) 882-0023 OPEN 930726 ACTU: 4903. NEW YORK Montefiore Medical Center Adolescent AIDS Program 111 East 210th Street Bronx, NY 10467-2490 Contact: Dina Monte (718) 882-0023 OPEN 930812 ACTU: 5049. NEW YORK Westchester Hospital / New York Medical College Munger Pavillion Room 134 Valhalla, NY 10595 Contact: Liz Ahern (914) 285-7898 Contact: (914) 993-4643 OPEN 940606 ACTU: 5005. NEW YORK Schneider Children's Hospital / Long Island Jewish Med Ctr 270-05 76th Avenue Room 235 / Div of Allergy and Immunology New Hyde Park, NY 11042 Contact: Debby Hickey (718) 470-3300 OPEN 930824 ACTU: 5001. NEW YORK King's County Hospital Center / SUNY HSCB 450 Clarkson Avenue Brooklyn, NY 11203 Contact: Helen Bergin (718) 245-3342 Contact: (718) 245-3341 Contact: (718) 245-4485 OPEN 940301 ACTU: 5035. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 940415 ACTU: 1102. NEW YORK Children's Hospital 219 Bryant Street Buffalo, NY 14222 Contact: Cynthia Kelly (716) 878-7908 OPEN 940303 ACTU: 1104. OHIO Children's Hospital 700 Children's Drive Columbus, OH 43205-2696 Contact: Jane Hunkler (614) 722-4460 Contact: (614) 722-6050 OPEN 940728 ACTU: 2302. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 940323 ACTU: 2401. OHIO Childrens Hospital of Cincinnati Eden and Bethesda Avenue Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 940330 ACTU: 2404. OTHER Ramon Ruiz Arnau University Hospital Laurel Avenue Bayamon, PR 00619 Contact: Leticia Diaz (809) 798-2733 OPEN 931028 ACTU: 5033. OTHER San Juan City Hospital / Puerto Rico Medical Center Department of Pediatrics Third Floor Hematology Rio Piedras, PR 00927 Contact: Esther Rosa (809) 764-3083 Contact: (809) 274-0904 OPEN 940317 ACTU: 5031. OTHER University of Puerto Rico / University Pediatric Hospital 4th Floor South Wing Room 4B-45 / GPO Box 365067 San Juan, PR 00936-5067 Contact: Carmen Rivera (809) 759-9595 Contact: (809) 765-1979 X 724OPEN 940308 ACTU: 6601. PENNSYLVANIA Milton S Hershey Medical Center / Hemophilia Cntr of W Penn 812 Fifth Avenue Pittsburgh, PA 15219 Contact: Dr Margaret V Ragni (412) 622-7270 OPEN 940513 ACTU: 9318. PENNSYLVANIA George Washington University(Hershey Satellite) 500 University Drive Post Office Box 850 Hershey, PA 17033-0850 Contact: Dr Fran Damianos (717) 531-7488 OPEN 940711. PENNSYLVANIA Children's Hospital of Philadelphia 34th Street & Civic Center Blvd Philadelphia, PA 19104-4399 Contact: Dr Deborah Schaible (215) 590-2097 Contact: Hospital Information (215) 590-1000 OPEN 931118 ACTU: 6701. SOUTH CAROLINA Medical University of South Carolina Clinical Science Building / 171 Ashley Avenue Charleston, SC 29425-3312 Contact: Genny Connelly (803) 792-2385 OPEN 931207 ACTU: 5037. 45 UNIQUE IDENTIFIER NIH/00554 PROTOCOL ID NUMBERS NIAID ACTG 219 PROTOCOL TITLE Pediatric Late Outcomes Protocol. VERSION NUMBER & DATE 1 (930121) TRIAL CATEGORY Epidemiology TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Oleske J PROTOCOL CHAIRS CO-CHAIR Fowler MG GENERAL DESCRIPTION PURPOSE: PRIMARY: To describe late outcomes (long-term consequences related to HIV disease progression, treatment effects, and interaction of HIV disease and therapy) in HIV-infected infants, children, and adolescents currently or previously enrolled in pediatric ACTG protocols; and to evaluate late treatment effects in these children. To determine whether infants born to HIV-infected women who were enrolled in ACTG protocols while pregnant demonstrate any late treatment effects (late consequences of antiretroviral therapy received in utero and/or in the newborn period). SECONDARY: To provide data describing the demographic, medical, and treatment characteristics of children enrolled in ACTG clinical trials. GENERAL DESCRIPTION RATIONALE: The potential long-term benefits, toxicities, and other adverse outcomes of new anti-HIV therapies cannot currently be assessed within the time frame of clinical trials underway. The need exists to better assess both positive and negative late outcomes and late treatment effects in children who are still growing. GENERAL DESCRIPTION METHODOLOGY: Children have a complete physical exam, history, Tanner staging growth, neurologic exam, and quality-of-life assessment every 6 months (if < 3 years of age) or every 12 months (if >= 3 years of age). Laboratory tests (hematology, chemistries, urinalysis, etc.) are also performed every 6 or 12 months (according to age) in infected individuals and every 6 months or 3 years in uninfected individuals. Audiometry is performed at ages 6 and 12. EKG and ophthalmic exams are performed at specified intervals. Participants are followed until age 21 or until lost to follow-up. PROTOCOL PHASE Epidemiology OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Participants must meet at least one of the following criteria: 1. Infant born to an HIV-infected woman who is currently enrolled or has been enrolled in an ACTG perinatal transmission or antiretroviral/immunomodulator therapy protocol while pregnant with this child. 2. HIV-infected infant, child, or adolescent who - has currently or previously enrolled in an ACTG treatment protocol OR - was discontinued from an ACTG treatment or perinatal transmission protocol because of toxicity OR - was enrolled in a protocol but never received study drug. ELIGIBILITY ASYM. ARC. AIDS. HIV Seronegative / OTHER. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Prospective PROTOCOL DETAILS STUDY INTENT: Epidemiology. PROTOCOL DETAILS PROJECTED ACCRUAL: 1200 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Until age 21 or lost to follow-up. PROTOCOL DETAILS ACTUAL ACCRUAL: 1076/1200 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 74 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Participants must meet at least one of the following criteria: 1. HIV-infected infant, child, or adolescent currently or previously enrolled in an ACTG treatment protocol. 2. Infant born to an HIV-infected woman who is currently enrolled or has been enrolled in an ACTG perinatal transmission or antiretroviral/immunomodulator therapy protocol while pregnant with this child. NOTE: Children and adolescents enrolled solely in ACTG 220 (pre-enrollment protocol) or other observational studies are not eligible for this protocol until they become enrolled in an ACTG treatment trial (adult, perinatal, or pediatric). [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: Non-applicable percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: Non-applicable g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: Non-applicable cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: Non-applicable platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CD4/CD8 RATION: Non-applicable. PATIENT INCLUSION CRIT. BILIRUBIN: Non-applicable mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): Non-applicable. PATIENT INCLUSION CRIT. SGPT(ALT): Non-applicable. PATIENT INCLUSION CRIT. CREATININE: Non-applicable. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: Non-applicable ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: Non-applicable. PATIENT AGE AGE: 01 Days - 18 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Non-applicable. OTHER TREATMENT INFO. END POINT: Patient late outcomes, including survival, growth, nutrition, quality of life, neurologic and neuropsychologic parameters, organ system toxicities, AIDS-defining opportunistic infections or cancer, and immunologic and virologic parameters. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*EPIDEMIOLOGY/ETIOLOGY MESH HEADING Acquired Immunodeficiency Syndrome/ *EPIDEMIOLOGY/ETIOLOGY MESH HEADING Adolescence MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Female MESH HEADING HIV Infections/*EPIDEMIOLOGY/ETIOLOGY MESH HEADING Human MESH HEADING Infant MESH HEADING Male LAST REVISION DATE 941207 ENTRY MONTH 9310 ALABAMA University of Alabama at Birmingham School of Medicine 751 CHT / University Station Birmingham, AL 35294 Contact: Michael Cooney (205) 939-9552 Contact: beeper (205) 869-9524 OPEN 930714 ACTU: 5046. CALIFORNIA Harbor General / UCLA Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 930824 ACTU: 3609. CALIFORNIA UCLA Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 930408 ACTU: 3601. CALIFORNIA Long Beach Memorial Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 930609 ACTU: 3606. CALIFORNIA Cedars Sinai Medical Center / Pediatrics 8700 Beverly Boulevard Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 930802 ACTU: 3603. CALIFORNIA Children's Hospital of Los Angeles 10833 Le Conte Avenue Los Angeles, CA 90024-1757 Contact: Leslie Spring (310) 206-6369 OPEN 940627 ACTU: 3602. CALIFORNIA Children's Hospital of Los Angeles / Children's AIDS Center 4650 Sunset Blvd / Mail Stop #54 Los Angeles, CA 90027 Contact: Antonieta Sosa (213) 669-2180 OPEN 940308 ACTU: 9916. CALIFORNIA Los Angeles County USC Medical Center 1129 North State Street Los Angeles, CA 90033 Contact: Janice Ono (213) 226-3945 OPEN 930430 ACTU: 5048. CALIFORNIA University of CA San Diego Medical Center / Pediatric 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 930616 ACTU: 4601. CALIFORNIA Fountain Valley Regional Hospital and Medical Center 17150 Euclid Avenue / Suite 322 Fountain Valley, CA 92708 Contact: Dr Douglas Cable (714) 432-0422 OPEN 931028. CALIFORNIA UCSF / Moffitt Hospital 602 / Pediatrics 505 Parnassus / Box 0105 San Francisco, CA 94143-0105 Contact: Debbie Trevithick (415) 476-6480 OPEN 930824 ACTU: 4501. CALIFORNIA San Francisco General Hospital (Pediatric) Box 0105 Moffitt Hospital 602 / 505 Parnassus San Francisco, CA 94143-0105 Contact: Debbie Trevithick (415) 476-6480 OPEN 930824 ACTU: 4502. CALIFORNIA Children's Hospital Oakland 747 Fifty Second Street Oakland, CA 94609-1809 Contact: Jim Riddel (510) 428-3000 X 282Contact: (510) 539-6311 X PagOPEN 930709 ACTU: 4504. COLORADO University of Colorado Hlth Sciences Ctr / Peds Infect Dis 1056 East 19Th Avenue B055 Denver, CO 80218-1088 Contact: Carol Salbenblatt (303) 861-6751 OPEN 930719 ACTU: 7001. CONNECTICUT Univ of Connecticut Farmington / Univ of CT Health Center 263 Farmington Avenue Farmington, CT 06032 Contact: Lorraine Wells (203) 679-2320 OPEN 940214 ACTU: 7303. CONNECTICUT Yale University School of Medicine PO Box 3333 / 333 Cedar Street New Haven, CT 06510-8064 Contact: Unspecified (203) 737-4040 OPEN 940119 ACTU: 5038. DISTRICT OF COLUMBIA Georgetown University Hospital / PC 3800 Reservoir Road NW / Second Floor Washington, DC 20007-2197 Contact: Maureen Dwyer (202) 687-5437 OPEN 931221 ACTU: 7104. DISTRICT OF COLUMBIA Children's National Medical Center / Special Immuno Svc Suite 2108 / 111 Michigan Avenue NW Washington, DC 20010-2970 Contact: Sandra Jones (202) 884-3682 OPEN 930607 ACTU: 7101. DISTRICT OF COLUMBIA Howard University Hospital 2041 Georgia Avenue NW Washington, DC 20060 Contact: Dr Helga Finke (202) 865-1248 OPEN 930729 ACTU: 5044. FLORIDA Univ of Miami School of Medicine / Pediatric Imm Infect Dis 1800 NW Tenth Avenue Miami, FL 33136 Contact: Janet Gourley (305) 548-4446 OPEN 930514 ACTU: 4201. GEORGIA Emory University Hospital 69 Butler Street SE Atlanta, GA 30303 Contact: Judy Sarver (404) 616-6227 Contact: clinic (404) 616-4390 Contact: beeper (404) 899-5290 OPEN 930430 ACTU: 5030. ILLINOIS University of Illinois at Chicago 840 S Wood Street Chicago, IL 60612 Contact: Patricia Naughton (312) 996-1778 OPEN 930910 ACTU: 5028. ILLINOIS Chicago Children's Memorial Hospital / Pediatric 2300 Childrens Plaza Box 20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 930520 ACTU: 4001. ILLINOIS Wyler Children's Hospital 5841 South Maryland Avenue Chicago, IL 60637-1470 Contact: Kim Stieglitz (312) 702-6176 OPEN 940718 ACTU: 4003. LOUISIANA Tulane University School of Medicine / Div of Ped Infect Dis 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 930831 ACTU: 7201. MASSACHUSETTS Baystate Medical Center / Department of Pediatrics 759 Chestnut Street / SHU-Main 3 Springfield, MA 01199 Contact: MaryPat Toye (413) 784-5399 OPEN 930609 ACTU: 7302. MASSACHUSETTS University of Massachusetts Medical School / Dept of Peds 55 Lake Avenue North Worcester, MA 01655-0001 Contact: Joanne Shepard (508) 856-1692 OPEN 931213 ACTU: 7301. MASSACHUSETTS Children's Hospital 300 Longwood Avenue / Carnegie 3 Boston, MA 02115 Contact: Robert Bishop (617) 735-8198 OPEN 930802 ACTU: 2901. MASSACHUSETTS Boston City Hospital / Ped Infect Dis / Finland Lab 774 Albany Street / Finland Lab Room 301 Boston, MA 02118 Contact: Anne Marie Reagan (617) 534-5813 OPEN 940304 ACTU: 2903. MARYLAND University of Maryland School of Medicine / Pediatrics 120 Penn Street Baltimore, MD 21201 Contact: Sue Lovelace (410) 706-8220 OPEN 940124 ACTU: 3702. MARYLAND The Johns Hopkins University ( Pediatrics ) 600 North Wolfe Street Baltimore, MD 21287 Contact: Laura J Belcher (410) 955-9749 OPEN 940405 ACTU: 3701. MICHIGAN Children's Hospital of Michigan 3901 Beaubien Boulevard Detroit, MI 48201 Contact: Charnell Cromer (313) 745-5565 OPEN 931118 ACTU: 5041. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 940124 ACTU: 3201. NORTH CAROLINA Duke University Medical Center / Pediatrics Box 3499 Durham, NC 27710 Contact: John Swetnam (919) 684-6335 OPEN 930708 ACTU: 4701. NEW JERSEY Children's Hospital of New Jersey 15 South 9th Street / CHAP Program 5 East Newark, NJ 07107 Contact: George Donovan Mcsherry (201) 268-8273 OPEN 930616 ACTU: 2801. NEW JERSEY Univ of Med & Dentistry of NJ / Univ Hospital 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan Mcsherry (201) 268-8273 OPEN 931227 ACTU: 2802. NEW JERSEY Children's Hospital of New Jersey 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan McSherry (201) 268-8273 OPEN 940304 ACTU: 2803. NEW JERSEY Robert Wood Johnson University Hospital / UMDNJ One Robert Wood Johnson Place CN19 New Brunswick, NJ 08903-0019 Contact: Ida Kechula (908) 937-7894 OPEN 940610 ACTU: 5032. NEW YORK Beth Israel Medical Center / Pediatrics First Avenue at 16th Street Dazian Pavilion Tenth Floor New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 930611 ACTU: 4302. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue / Pediatric New York, NY 10016 Contact: Nagamah Deygoo (212) 263-6426 OPEN 930412 ACTU: 4401. NEW YORK Cornell Medical Center N-834 / Pediatric Infectious Disease 1300 York Avenue New York, NY 10021 Contact: Tony Hinds (212) 746-3326 OPEN 940114 ACTU: 5019. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 ACTU: 1801. NEW YORK Mount Sinai School of Medicine / Pediatrics One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940114 ACTU: 4301. NEW YORK Mount Sinai / Hemophilia Treatment Center One Gustave Levy Place New York, NY 10029 Contact: Avril Gabriel (212) 241-0236 OPEN 940311 ACTU: 9210. NEW YORK Metropolitan Hospital Center / Pediatrics Department 1901 First Avenue New York, NY 10029 Contact: Mavis Dummit (212) 230-7103 Contact: message machine (212) 230-6841 Contact: beeper (212) 537-1589 OPEN 940815 ACTU: 5003. NEW YORK Incarnation Children's Ctr / c/o Columbia Presb Med Ctr 142 Audubon Avenue New York, NY 10032 Contact: Pam Clark (212) 928-2228 OPEN 930830 ACTU: 4103. NEW YORK The Columbia Presbyterian Medical Hosp (Pediatric) 622 West 168th St Room 1161 New York, NY 10032-3796 Contact: Kathy A Shea (212) 305-7222 OPEN 930830 ACTU: 4101. NEW YORK Harlem Hospital 506 Lenox Avenue New York, NY 10037 Contact: Rick Urbano (212) 939-4040 Contact: (212) 939-4045 OPEN 931215 ACTU: 5006. NEW YORK Lincoln Hospital Center / Department of Pediatrics 234 East 149th Street Bronx, NY 10451 Contact: Annie Villareal (718) 579-5329 Contact: (718) 579-5000 OPEN 940711 ACTU: 5004. NEW YORK Bronx Lebanon Hospital Center / Department of Pediatrics 1650 Selwyn Avenue Room 2C Bronx, NY 10457 Contact: Patrice Edwards-Cihak (718) 960-1015 OPEN 931022 ACTU: 6901. NEW YORK Montefiore Medical Center / Adolescent AIDS Program 111 East 210th Street / NW674 Bronx, NY 10467 Contact: Dina Monte (718) 882-0023 OPEN 930922 ACTU: 4903. NEW YORK North Shore University Hospital / Pediatric Immunology 350 Community Drive Manhasset, NY 11030 Contact: Cathy Macco (516) 773-7676 OPEN 930729 ACTU: 5010. NEW YORK Schneider Children's Hospital / Long Island Jewish Med Ctr 270-05 76th Avenue Room 235 / Div of Allergy and Immunology New Hyde Park, NY 11042 Contact: Debby Hickey (718) 470-3300 OPEN 930824 ACTU: 5001. NEW YORK King's County Hospital Center / SUNY HSCB 450 Clarkson Avenue Brooklyn, NY 11203 Contact: Helen Bergin (718) 245-3342 Contact: (718) 245-3341 Contact: (718) 245-4485 OPEN 940214 ACTU: 5035. NEW YORK SUNY at Brooklyn / Health Science Center / Pediatrics 450 Clarkson Avenue / Box 24 Brooklyn, NY 11203 Contact: Barbara Driscoll (718) 270-3081 OPEN 930402 ACTU: 5008. NEW YORK SUNY Health Science Center at Stony Brook HSC T 15 080 Stony Brook, NY 11794-8111 Contact: Peggy Melendez (516) 444-1313 Contact: (516) 444-7692 Contact: beeper (516) 282-8808 Contact: Jeannie Conner (516) 444-2724 OPEN 931013 ACTU: 5040. NEW YORK Children's Hospital at Albany Medical Center 22 New Scotland Avenue Albany, NY 12208 Contact: Mary Ellen Adams (518) 432-1501 OPEN 930601 ACTU: 5042. NEW YORK SUNY Health Science Center at Syracuse 750 East Adams Street Syracuse, NY 13210 Contact: Kathie Shea-Contello (315) 464-6331 OPEN 940405 ACTU: 5039. NEW YORK Children's Hospital 219 Bryant Street Buffalo, NY 14222 Contact: Cynthia Kelly (716) 878-7908 OPEN 940303 ACTU: 1104. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 930525 ACTU: 1101. OHIO Children's Hospital 700 Children's Drive Columbus, OH 43205-2696 Contact: Jane Hunkler (614) 722-4460 Contact: (614) 722-6050 OPEN 930602 ACTU: 2302. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 940610 ACTU: 2501. OHIO Childrens Hospital of Cincinnati Eden and Bethesda Avenue Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 931028 ACTU: 2404. OTHER Ramon Ruiz Arnau University Hospital Laurel Avenue Bayamon, PR 00619 Contact: Leticia Diaz (809) 798-2733 OPEN 930402 ACTU: 5033. OTHER San Juan City Hospital / Puerto Rico Medical Center Department of Pediatrics Third Floor Hematology Rio Piedras, PR 00927 Contact: Esther Rosa (809) 764-3083 Contact: (809) 274-0904 OPEN 930611 ACTU: 5031. OTHER University of Puerto Rico / University Pediatric Hospital 4th Floor South Wing Room 4B-45 / GPO Box 365067 San Juan, PR 00936-5067 Contact: Carmen Rivera (809) 759-9595 Contact: (809) 765-1979 X 724OPEN 930514 ACTU: 6601. PENNSYLVANIA Children's Hospital of Philadelphia 34th Street & Civic Center Blvd Philadelphia, PA 19104-4399 Contact: Dr Deborah Schaible (215) 590-2097 Contact: Hospital Information (215) 590-1000 OPEN 931206 ACTU: 6701. PENNSYLVANIA Saint Christopher's Hospital for Children / Sect Imm & Rheum Erie Avenue at Front Street Philadelphia, PA 19134-1095 Contact: Carole Treston (215) 427-5284 Contact: FAX (215) 427-5555 OPEN 931216 ACTU: 6704. SOUTH CAROLINA Medical University of South Carolina Clinical Science Building / 171 Ashley Avenue Charleston, SC 29425-3312 Contact: Genny Connelly (803) 792-2385 OPEN 930520 ACTU: 5037. 46 UNIQUE IDENTIFIER NIH/00485 PROTOCOL ID NUMBERS NIAID ACTG 216 PROTOCOL TITLE Chemoprevention of Anal Neoplasia Arising Secondary to Anogenital Human Papillomavirus Infection in Persons With HIV Infection. VERSION NUMBER & DATE 3 (940401) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: PRIMARY: In Phase I, to define a broadly tolerable dose of isotretinoin that can be used in combination with interferon alfa-2a (IFN alfa-2a). In Phase II, to determine trends in efficacy of isotretinoin alone or in combination with IFN alfa-2a as chemoprevention (preventing progression or recurrence) of anal intraepithelial neoplasia in patients with HIV infection. SECONDARY: To evaluate the effects of isotretinoin alone or in combination with IFN alfa-2a on immune function markers, human papillomavirus (HPV) type, and HPV DNA levels. GENERAL DESCRIPTION RATIONALE: Patients with HIV infection have a significant risk of recurrence following local ablation of intraepithelial neoplasia; thus, anogenital epithelial may become an increasingly important cause of morbidity, and possibly mortality, as the HIV epidemic matures. Clinical studies of non-HIV-infected subjects have established that synthetic retinoids inhibit the progression of epithelial preneoplastic conditions and some neoplastic states. GENERAL DESCRIPTION METHODOLOGY: In the Phase I portion of the study, 10 patients per site each receive isotretinoin in escalating doses, beginning with 0.25 mg/kg daily for weeks 1 and 2, followed by increases to 0.50 mg/kg for weeks 3 and 4 and 0.75 mg/kg for weeks 5 and 6. If a patient experiences grade 2 or worse toxicity, dose is reduced to the previously tolerated dose for the remainder of the 6 week period. Patients are then reassessed for anal neoplasia; those with no progression and no grade 2 or worse toxicity receive an additional 6 weeks of isotretinoin in combination with 1.5 MU interferon alfa-2a, thrice weekly. For Phase II of the study, a separate group of patients who have undergone ablative therapy are randomized to one of three arms (26 patients/arm): isotretinoin alone at the dose tolerated by at least 60 percent of patients in Phase I; isotretinoin plus 1.5 MU interferon alfa-2a; or observation only. Treatment continues for 48 weeks. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Anal intraepithelial neoplasia. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA and Western blot. 2. NO active opportunistic infection requiring treatment with prohibited drugs. 3. Current grade 1 anal intraepithelial neoplasia with histologic confirmation (for Phase I patients) OR prior histologically confirmed grade 2 or 3 anal intraepithelial neoplasia, with ablative therapy within the past 30-90 days (for Phase II patients). ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS IND 41,357 STUDY DESIGN Drug Combination; Dose Escalating; Drug Tolerance; Randomized; 3-Arm PROTOCOL DETAILS STUDY INTENT: Combination and single drug therapy, Drug efficacy, Drug tolerance, Secondary prophylaxis, Maximum tolerated dose (MTD). PROTOCOL DETAILS PROJECTED ACCRUAL: 182 patients. PROTOCOL DETAILS ACTUAL ACCRUAL: 6/182 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. NO active opportunistic infection requiring treatment with prohibited drugs. 3. Current grade 1 anal intraepithelial neoplasia with histologic confirmation (for Phase I patients) OR prior histologically confirmed grade 2 or 3 anal intraepithelial neoplasia, with ablative therapy within the past 30-90 days (for Phase II patients). 4. Capability of complying with study protocol. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 10.0 g/dl. (Transfusion not permitted within 2 weeks prior to study entry). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 2.5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 2.5 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. (If creatinine value not available). PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 1500 cells/mm3. Alkaline phosphatase <= 2.5 mg/dl. Serum triglyceride < 400 mg/dl. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or two effective methods of birth control / contraception during the study and for 90 days after. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. PCP prophylaxis (required for patients with CD4 count < 200 cells/mm3). 2. Chemoprophylaxis for candidiasis and herpes simplex. 3. Metronidazole for up to 14 days. 4. Erythropoietin. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of ventricular arrhythmias or myocardial infarction. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse or illegal drug use (alcohol consumption is strongly discouraged). PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within 20 days prior to study entry: Radiation therapy. Excluded within 14 days prior to study entry: Transfusion. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 20 days prior to study entry: 1. G-CSF. 2. Myelosuppressive antibiotics. 3. Corticosteroids. 4. Biologic response modifiers. 5. Cytotoxic chemotherapy. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. G-CSF. 2. Myelosuppressive antibiotics. 3. Corticosteroids. 4. Biologic response modifiers. 5. Cytotoxic chemotherapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active medical problems for which the patient is undergoing evaluations or for which prohibited therapy is required. 2. Other active malignancies requiring systemic therapy. NOTE: Patients with malignancies being managed with local therapy (e.g., Kaposi's sarcoma, basal cell carcinoma) may enroll at the discretion of the site investigator. 3. Significant symptomatic cardiac disease. SUBSTANCE IDENTIFICATION Drug 1 DRG-0034 Interferon Alfa-2a SUBSTANCE IDENTIFICATION Drug 2 DRG-0213 Isotretinoin TRADE NAME OF SUBSTANCE Drug 1‰ Roferon-A MANUFACTURERS Drug 1: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. MANUFACTURERS Drug 2: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Phase II: 1.5 MU administered MWF for 48 weeks. Drug 2: Phase I: 0.25, 0.50, and 0.75 mg/kg administered during1-2, 3-4, and 5-6, respectively. Phase II: Best tolerated dose as determined in Phase I, adminisMWF for 48 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 2: Phase I: 0.25, 0.50, and 0.75 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Subcutaneous, 18 MU vials. Drug 2: Oral, 20 and 40 mg capsules OTHER TREATMENT INFO. TREATMENT DURATION: Phase I: 12 weeks. Phase II: 48 weeks. OTHER TREATMENT INFO. END POINT: Phase I: Dose-limiting toxicity. Phase II: Recurrence of grade 2 or 3 anal intraepithelial neoplasia or progression to invasive cancer; unacceptable toxicity. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Attainment of study endpoint. 2. Development of major opportunistic infection. 3. Intercurrent illness that would affect assessment of clinical status or require discontinuation of study drugs. 4. Unacceptable toxicity. 5. Progressive Kaposi's sarcoma that requires systemic chemotherapy. 6. Development of other malignancies requiring radiation or systemic therapy. 7. Pregnancy. 8. Patient noncompliance or desire to withdraw from study. OTHER TREATMENT INFO. MODIFICATION: Phase II: For grade 3 toxicity, hold study drug until toxicity resolves to grade 1 or better, then restart at same dose. For grade 3 toxicity that does not resolve within 21 days or that recurs, or for any occurrence of grade 4 toxicity, discontinue drug permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Hoffmann-La Roche, Incorporated. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Anus Neoplasms/ETIOLOGY/*PREVENTION & CONTROL MESH HEADING Female MESH HEADING Human MESH HEADING Interferon Alfa-2a/*THERAPEUTIC USE MESH HEADING Isotretinoin/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Papillomavirus, Human MESH HEADING Papovaviridae Infections/COMPLICATIONS MESH HEADING Tumor Virus Infections/COMPLICATIONS CAS REGISTRY NUMBER 4759-48-2 (Isotretinoin) CAS REGISTRY NUMBER 76543-88-9 (Interferon Alfa-2a) LAST REVISION DATE 941207 ENTRY MONTH 9408 CALIFORNIA UCSF / AIDS Clinic Ambulatory Care Center 995 Potrero Avenue San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940706 ACTU: 0802. 47 UNIQUE IDENTIFIER NIH/00484 PROTOCOL ID NUMBERS NIAID ACTG 215 PROTOCOL TITLE A Phase I Study of TNP-470 in the Treatment of AIDS-Associated Kaposi's Sarcoma. VERSION NUMBER & DATE 5 (940819) TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Gill PS PROTOCOL CHAIRS CO-CHAIR Dezube B GENERAL DESCRIPTION PURPOSE: To assess toxicity and determine the MTD of intravenous TNP-470 administered weekly in patients with AIDS-related Kaposi's sarcoma. To assess pharmacokinetics and tumor response of the drug. GENERAL DESCRIPTION RATIONALE: Since evidence shows that neovascularization is important in the development of Kaposi's sarcoma, drugs that inhibit angiogenesis, such as TNP-470, may be of benefit in patients with the disease. GENERAL DESCRIPTION METHODOLOGY: Patients are entered at 4 escalating dose levels of TNP-470, ranging from 20-50 mg/m2. Four patients treated at a given dose level must receive at least 4 weeks of therapy before escalation in subsequent cohorts proceeds. If 50 percent of patients at a given dose level experience dose-limiting toxicity, the previous dose is defined as the MTD and an additional two patients are treated at the MTD. Patients receive treatment for 12 weeks, followed by 2 weeks of rest, followed by an additional 12 weeks of treatment. Patients are followed for 12 weeks post-treatment. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA confirmed by Western blot. 2. Biopsy-proven cutaneous Kaposi's sarcoma (KS) with 5 or more measurable lesions and no evidence of visceral disease. Pulmonary or symptomatic gastrointestinal KS or acutely life-threatening KS potentially responsive to other therapy is not permitted. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 41,244 STUDY DESIGN Pharmacokinetic; Dose Escalating; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Maximum tolerated dose (MTD), Pharmacokinetics, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 20 - 36 patients. (Up to 8 patients at each of 4 dose levels) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 36 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 20/20 - 36 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 10 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Cutaneous Kaposi's sarcoma. 3. Life expectancy of at least 3 months. 4. Consent of parent or guardian if under 18 years of age. NOTE: This protocol is considered suitable for prison populations. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9.0 g/dl. (No transfusion during the week prior to study entry). PATIENT INCLUSION CRIT. PLATELET COUNT: > 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 2.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: > 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 1000 cells/mm3. PTT or PT < 120 percent of control. PATIENT AGE AGE: 12 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study and for 60 days after. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. AZT, ddI, ddC, or d4T provided patients have received at least 2 weeks of this therapy prior to study entry. (Combination ddI/ddC is not permitted.) 2. MAI prophylaxis. Required in patients with CD4 count < 200 cells/mm3: Aerosolized pentamidine, trimethoprim/sulfamethoxazole, or dapsone as PCP prophylaxis. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of substanial non-iatrogenic bleeding disorders. 2. History of tumor or malignancies other than Kaposi's sarcoma, with the exception of completely resected basal cell skin carcinoma or in situ cervical carcinoma. 3. History of seizures within the past 10 years. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 11 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control during study and for 60 days after. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Unwilling to refrain from unprotected sexual contact or other activities that may result in HIV re-infection. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 4 weeks prior to study entry: 1. Steroids. 2. Antineoplastic drugs. 3. Interferons. 4. Systemic or topical anti-Kaposi's sarcoma agents or regimens. Excluded within 6 weeks prior to study entry: suramin. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Combination therapy with ddI/ddC (although these drugs may be administered alone or in combination with AZT). 2. Anticonvulsive medication. 3. Steroids. 4. Antineoplastic drugs. 5. Interferons. 6. Systemic or topical anti-Kaposi's sarcoma agents or regimens. 7. Suramin. 8. Aspirin. 9. Warfarin. 10. Heparin. 11. Nonsteroidal anti-inflammatory drugs. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Peripheral neuropathy (grade 2 or worse). 2. Underlying severe or life-threatening infection with bacterial, viral, fungal, or protozoal pathogens. 3. Known hypersensitivity to TNP-470, fumagillin, or known related compounds. SUBSTANCE IDENTIFICATION Drug 1 DRG-0148 TNP-470 MANUFACTURERS Drug 1: TAKEDA AMERICA Incorporated 101 Carnegie Center Princeton, NJ 08540 Contact: Dr Mikihiko Obayashi (609) 452-1113. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 20 - 50 mg/m2 weekly for a minimum of 4 and maximum of weeks, with a 2-week rest after the first 12 weeks SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous, 30 mg vials OTHER TREATMENT INFO. TREATMENT DURATION: 4-24 weeks. OTHER TREATMENT INFO. END POINT: Toxicity, disease progression, development of opportunisitic infection, response. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity, including recurrent grade 3 or 4 toxicity. 2. Development of major opportunistic infection that does not resolve within 6 weeks. 3. Intercurrent illness that would affect assessment of clinical status significantly or preclude use of TNP-470. 4. Progressive Kaposi's sarcoma. 5. Other malignancies that require radiation or systemic therapy. 6. Pregnancy. OTHER TREATMENT INFO. MODIFICATION: For grade 3 toxicity: Hold study drug until toxicity resolves to baseline, then resume at next lower dose level (or 50 percent of dose for first cohort). For grade 1 hematuria, grade 2 hemorrhage, or grade 2 or worse coagulation abnormalities: Hold study drug until complete resolution of symptoms, then resume. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antineoplastic Agents/*ADVERSE EFFECTS/ PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antineoplastic Agents) LAST REVISION DATE 941207 ENTRY MONTH 9305 CALIFORNIA Kenneth Norris Cancer Hospital / LAC-USC 2020 Zonal Avenue Room 309 Los Angeles, CA 90033 Contact: Luis Mendez (213) 343-8288 OPEN 930611 ACTU: 1203. CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 930611 ACTU: 1201. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 930520 ACTU: 2701. MASSACHUSETTS Beth Israel Hospital 330 Brookline Avenue Boston, MA 02115 Contact: Sheila Hussey (617) 735-4103 OPEN 930514 ACTU: 0102. MASSACHUSETTS Boston City Hospital / AIDS Research Office 818 Harrison Avenue ACC 5th Floor Room 5D11 Boston, MA 02118 Contact: Beverly Byam (617) 534-5160 OPEN 940930 ACTU: 0104. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 930915 ACTU: 2101. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 940721 ACTU: 1802. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940923 ACTU: 1801. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 940627 ACTU: 7401. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 940713 ACTU: 1103. 48 UNIQUE IDENTIFIER NIH/00476 PROTOCOL ID NUMBERS NIAID ACTG 211 PROTOCOL TITLE Phase I/II Study of Recombinant Human Interferon-gamma (rIFN-gamma) in HIV-Infected Children. VERSION NUMBER & DATE 2 (930219) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child PROTOCOL CHAIRS CHAIR Shearer WT PROTOCOL CHAIRS CO-CHAIR Abramson SL, Kline MW GENERAL DESCRIPTION PURPOSE: PRIMARY: To determine the safety and toxicity of recombinant interferon gamma-1b (rIFN-gamma) in HIV-infected children receiving ongoing zidovudine (AZT) therapy. To document HIV-associated defects in neutrophil and/or monocyte function that are improved with rIFN-gamma. SECONDARY: To determine whether a change in CD4 cell count occurs and to assess virologic status and effects on AZT pharmacokinetics. GENERAL DESCRIPTION RATIONALE: It is likely that infants and children severely immunocompromised by HIV infection would respond to immunomodulators that augment different portions of the host defense system. Interferon-gamma has been shown to benefit children with severely compromised nonspecific immunity and may thus be of benefit to those with HIV infection. GENERAL DESCRIPTION METHODOLOGY: Patients are treated with subcutaneous rIFN-gamma 3 times a week for 24 weeks and are then followed for an additional 12 weeks. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Class P-2 symptomatic HIV infection demonstrated as follows: o Children >= 15 months must have EITHER two positive HIV antibody tests by ELISA, with one test confirmed by Western blot OR a positive viral culture (blood or CSF). o Children < 15 months of age whose only laboratory evidence of HIV infection is a positive antibody test must also have a positive viral culture (blood or CSF). 2. Ongoing AZT therapy of 6 months or longer duration. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS IND BB4827 STUDY DESIGN Dose Escalating; Open Label; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug toxicity, Pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 30 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 36 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 11/30 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Class P-2 symptomatic HIV infection. 2. Ongoing AZT therapy of 6 months or longer duration. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: > 27 percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 2.6 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: BUN <= 40 mg/dl. White blood cell count > 1500 cells/mm3. Neutrophils > 750 cells/mm3. PATIENT AGE AGE: 01 Years - 17 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: 1. Ongoing AZT therapy of 6 weeks or longer duration. 2. Ongoing PCP prophylaxis for more than 6 weeks duration. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: 1. AZT therapy. 2. PCP prophylaxis. Allowed: 1. Antipyretics. 2. Antiemetics. 3. Antihistamines. 4. Decongestants. 5. Skin creams and lotions. 6. Immunizations according to current recommendations. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of congestive heart failure or arrhythmias. 2. History of congenital heart disease. 3. History of seizure disorder requiring anticonvulsant medication. (NOTE: History of uncomplicated febrile seizures does not exclude.) [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 11 Months. 18 Years - 99 Years. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Ongoing alcohol or drug use. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Red blood cell transfusion within 4 weeks prior to study entry. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 8 weeks prior to study entry: Other immunomodulators or IVIG. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antiretroviral therapy other than AZT. 2. Chemotherapy for active malignancy. 3. Amphotericin B for systemic fungal infections. PATIENT EXCLUSION CRIT. AVAILABILITY: Co-enrollment and treatment on other ACTG pediatric studies. SUBSTANCE IDENTIFICATION Drug 1 DRG-0020 Interferon-gamma MANUFACTURERS Drug 1: Genentech Incorporated 460 Point San Bruno Boulevard South San Francisco, CA 94080 Contact: Professional Services (800) 821-8590. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 50 mcg/m2 3 times a week (MWF) during weeks 1 through 1then 100 mcg/m2 3 times a week (MWF) during weeks 13 through 2 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Subcutaneous, 100 mcg (3 MU) vials OTHER TREATMENT INFO. TREATMENT DURATION: 24 weeks. OTHER TREATMENT INFO. END POINT: Primary: Toxicity, improvement in neutrophil and/or monocyte function. Secondary: Change in CD4 cell counts, virologic parameters, effects of study drug on AZT pharmacokinetics. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Grade 4 local or systemic reactions to study therapy or persistent or recurrent grade 3 toxicity at 50 percent dose. 2. Sustained increases in viral burden. 3. Patient noncompliance or at the request of the patient, parents or guardian, investigator, FDA, pharmaceutical company, or IND sponsor. OTHER TREATMENT INFO. MODIFICATION: For grade 3 toxicity: hold drug. If toxicity resolves to grade 2 or better within 14 days, resume drug at 50 percent dose. If toxicity persists after 14 days, discontinue drug permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Genentech Incorporated. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Female MESH HEADING Human MESH HEADING Infant MESH HEADING Interferon-gamma, Recombinant/*ADVERSE EFFECTS/PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Male CAS REGISTRY NUMBER 0 (Interferon-gamma, Recombinant) LAST REVISION DATE 941207 ENTRY MONTH 9306 PENNSYLVANIA Children's Hospital of Philadelphia 34th Street & Civic Center Blvd Philadelphia, PA 19104-4399 Contact: Dr Deborah Schaible (215) 590-2097 Contact: Hospital Information (215) 590-1000 OPEN 940531 ACTU: 6701. 49 UNIQUE IDENTIFIER NIH/00434 PROTOCOL ID NUMBERS NIAID ACTG 206 PROTOCOL TITLE A Randomized Phase II Trial to Determine the Safety, Tolerance, and Efficacy of Two Doses of Interferon Alfa-2b Combined With Didanosine in Patients With Kaposi's Sarcoma. VERSION NUMBER & DATE 3 (930318) TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Krown SE GENERAL DESCRIPTION PURPOSE: Primary: To evaluate the safety, toxicity, and antitumor activity of two doses of interferon alfa-2b (IFN-alpha) combined with a fixed dose of didanosine (ddI) in patients with Kaposi's sarcoma associated with HIV infection. Secondary: To evaluate the effects of combined IFN-alpha and ddI treatment on HIV expression and markers of immune function. GENERAL DESCRIPTION RATIONALE: Previous studies have shown that IFN-alpha can induce regression of Kaposi's sarcoma and suppression of HIV in some patients. Although various trials using IFN-alpha in combination with the nucleoside analog zidovudine have demonstrated a high degree of antitumor activity and evidence of HIV suppression, the overlapping toxicity (primarily neutropenia) of these two agents has proven dose-limiting. The toxicity profile of ddI suggests that this drug may be better tolerated than zidovudine when combined with IFN-alpha. GENERAL DESCRIPTION METHODOLOGY: Up to 90 patients are randomized to receive either low or high doses of IFN-alpha (1 or 10 million Units/day) in combination with a fixed dose of ddI. Fourteen patients are initially entered at each dose level. If no objective antitumor responses are observed among the first 14 patients at a given dose, no further patients are entered on that treatment arm. If one or more antitumor responses are seen at a given dose, up to 45 patients may be entered on that treatment arm. Patients must complete at least 4 weeks of study therapy to be considered evaluable for tumor response. Treatment is continued until tumor progression or unacceptable toxicity occurs. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. Positive antibody to HIV confirmed by any federally licensed ELISA test kit and Western blot. 2. Biopsy-proven Kaposi's sarcoma (at least 5 measurable lesions, with at least 1 measurable cutaneous lesion) involving the skin, lymph nodes, oral cavity, or asymptomatic lesions of the GI tract not requiring systemic chemotherapy. Lung involvement with Kaposi's sarcoma excludes. 3. CD4 count = or > 100 cells/mm3 on one occasion within 30 days prior to study entry. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 34,595 STUDY DESIGN Drug Combination; Multicenter; Open Label; Randomized; Unblinded PROTOCOL DETAILS STUDY INTENT: Combination drug therapy, Drug efficacy, Drug safety, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 90 patients. 45 patients per regimen) PROTOCOL DETAILS ACTUAL ACCRUAL: 42/90 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 22 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Positive antibody to HIV confirmed by any federally licensed ELISA test kit and Western blot. 2. Biopsy-proven Kaposi's sarcoma (at least 5 measurable lesions, with at least 1 measurable cutaneous lesion) involving the skin, lymph nodes, oral cavity, or asymptomatic lesions of the GI tract not requiring systemic chemotherapy. Lung involvement with Kaposi's sarcoma excludes. 3. CD4 count = or > 100 cells/mm3 on one occasion within 30 days prior to study entry. 4. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. (in the absence of transfusion in the preceding 2 weeks.) PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 100 cells/mm3. ( 100 - 200 - 300 - 400 - 500 - 600 - 700 - 800 plus). PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 70. PATIENT INCLUSION CRIT. OTHER: Neutrophil count >= 1000 cells/mm3. Serum amylase < 1.5 x ULN. Serum triglyceride <= 400 mg/dl. PT <= 1.3 x control. PATIENT AGE AGE: 12 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Negative pregnancy test within 14 days of study entry. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Chemoprophylaxis for candidiasis and herpes simplex. 2. Up to 14 days of metronidazole. 3. Recombinant erythropoietin. 4. G-CSF (for severe cases of neutropenia). 5. Isoniazid for treatment of TB if given in conjunction with pyridoxine. Required in patients with CD4 counts < 200 cells/mm3: Prophylaxis for PCP. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Opportunistic infection or B symptoms. 2. Prior grade 3 or 4 toxicity attributed to ddI therapy. 3. Prior history of peripheral neuropathy (= or > grade 1), pancreatitis, intractable diarrhea, or active seizure disorder not well controlled by anti-seizure medications. 4. History of myocardial infarction or ventricular arrhythmias. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 11 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. Positive pregnancy test within 14 days of study entry. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Alcohol consumption is strongly discouraged. Patients considered to be noncompliant should be excluded. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Radiation therapy within 30 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior IFN-alpha. 2. Corticosteroids, biological response modifiers, cytotoxic chemotherapy, or known neurotoxic drugs (other than ddI or ddC) within 30 days prior to study entry. 3. Therapy with antiretroviral drugs (other than ddI) within 7 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other investigational, antiviral, immunomodulating, or antitumor agents. 2. Drugs associated with peripheral neuropathy (other than ddI). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Concurrent opportunistic infection or B symptoms. 2. Visceral (non-nodal) Kaposi's sarcoma requiring cytotoxic chemotherapy. 3. Severe (> 2+) tumor-associated edema. 4. Concurrent neoplasia other than basal cell carcinoma, or anogenital intraepithelial neoplasia. 5. Current clinical evidence of peripheral neuropathy (= or > grade 1), pancreatitis, intractable diarrhea, or active seizure disorder not well controlled by anti-seizure medications. 6. Significant symptomatic cardiac disease. 7. Medical contraindication. SUBSTANCE IDENTIFICATION Drug 1 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 2 DRG-0035 Interferon Alfa-2b MANUFACTURERS Drug 1: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Colin McLaren (203) 284-6942. MANUFACTURERS Drug 2: Schering-Plough Corporation 2000 Galloping Hill Road Kenilworth, NJ 07033 Contact: Dr Janice Albrecht (908) 298-7985. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg (or 100 mg in patients weighing < 50 kg) q 12 hrDrug 2: 1 or 10 million U daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 400 mg (or 200 mg in patients weighing < 50 kg). Drug 2: 1 or 10 million U SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral; 25, 50, and 100 mg chewable, dispersible tablets.Drug 2: Subcutaneous, 10 million unit vials OTHER TREATMENT INFO. TREATMENT DURATION: Until tumor progression or unacceptable toxicity occurs. OTHER TREATMENT INFO. END POINT: Tumor response, dose-limiting toxicity. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Development of tumor progression, new visceral involvement, or new or increasing tumor-related edema. 2. Unacceptable toxicity. 3. Major opportunistic infection. 4. Other malignancies requiring radiation or systemic therapy. 5. Intercurrent illness that would affect assessments of clinical status to a significant degree or require discontinuation of drugs. 6. Pregnancy. 7. Patient noncompliance. OTHER TREATMENT INFO. MODIFICATION: For grade 2 peripheral neuropathy: hold ddI until return to grade 1 or better, then resume ddI at reduced dose. For a second occurrence of grade 2 or any occurrence of grade 3 peripheral neuropathy, discontinue study medication permanently. In general, for a first occurrence of grade 2 cardiac (excluding hemorrhage), stomatitis, renal, bladder, pulmonary, allergic (other than rash), or mucocutaneous toxicity, or a first occurrence of other grade 3 toxicities: hold study medication until toxicity returns to acceptable level, then resume IFN-alpha at 50 percent dose and ddI at either a reduced or full dose (depending on the specific toxicity). If these toxicities recur, study medication is permanently discontinued. Study medication is also discontinued for a first occurrence of grade 3 or higher cardiac (including hemorrhage), stomatitis, renal, bladder, pulmonary, allergic, or mucocutaneous toxicity or any grade 4 hematologic (including anemia), headache, constipation, or hepatic toxicity or grade 4 nausea or vomiting. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Bristol-Myers Squibb Company, Schering-Plough Research. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS/DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Didanosine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Interactions MESH HEADING Female MESH HEADING Human MESH HEADING Interferon-alpha/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Interferon-alpha) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 941207 ENTRY MONTH 9208 CALIFORNIA Kaiser Permanente Medical Group / Stanford University 2590 Geary Boulevard San Francisco, CA 94115 Contact: Gretchen Van Raalte (415) 202-3482 OPEN 920804 ACTU: 0502. COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 920811 ACTU: 6101. COLORADO Denver Department of Health and Hospitals / Univ of CO Colorado ACTU / Campus Box B 163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 930325 ACTU: 6102. COLORADO Rose Med Ctr / Univ of Colorado Hlth Sci Ctr / Colorado ACTU Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 941005 ACTU: 6104. COLORADO Kaiser Permanente Franklin Med Cntr / Univ Col Hlth Sci Cntr 4200 East Ninth Avenue / Colorado ACTU / Campus Box B-163 Denver, CO 80262 Contact: Graham Ray (303) 270-8551 Contact: FAX (303) 270-6102 OPEN 930624 ACTU: 6103. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 921001 ACTU: 2701. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940902 ACTU: 2702. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940502 ACTU: 2601. MASSACHUSETTS Bay State Medical Center 759 Chestnut Street Springfield, MA 01199 Contact: Deborah Naglieri-Prescod (413) 784-3046 OPEN 921007 ACTU: 3002. MASSACHUSETTS Boston City Hospital / AIDS Research Office 818 Harrison Avenue ACC 5th Floor Room 5D11 Boston, MA 02118 Contact: Beverly Byam (617) 534-5160 OPEN 930512 ACTU: 0104. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 920818 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 920818 ACTU: 2102. NEW YORK Memorial Hospital / Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021 Contact: Gloria Gilbert (212) 639-7169 OPEN 920729 ACTU: 2202. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 930630 ACTU: 1801. NEW YORK Harlem Hospital Center 506 Lenox Avenue / Room 3101A New York, NY 10037 Contact: Robin Flam (212) 939-3948 OPEN 940317 ACTU: 7502. NEW YORK Adirondack Medical Center at Saranac Lake 47 New Scotland Avenue Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930818 ACTU: 7403. NEW YORK Mid-Hudson Care Center / Albany Med College / Div Med Oncol 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930818 ACTU: 7402. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930818 ACTU: 7401. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 930610 ACTU: 1102. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 941102 ACTU: 2401. OTHER University of Puerto Rico / Schl of Med / Inf Dis Sec / ACTU G P O Box 365067 San Juan, PR 00936-5067 Contact: Maritza Cruz-Ortiz (809) 767-9192 Contact: (809) 767-9193 OPEN 930316 ACTU: 5401. PENNSYLVANIA University of Pennsylvania / Div of Infectious Diseases 549 Johnson Pavillion / 6073 / 36th and Hamilton Walk Philadelphia, PA 19104-6073 Contact: Debora Dunbar (215) 349-8092 OPEN 930518 ACTU: 6201. 50 UNIQUE IDENTIFIER NIH/00482 PROTOCOL ID NUMBERS NIAID ACTG 203P PROTOCOL TITLE A Phase I Pilot Study of the Safety and Efficacy of Interferon Alfa-2b (IFN alfa-2b) in Combination With Nucleoside Analogue Therapy in Patients With Combined Hepatitis C (HCV) and Advanced Human Immunodeficiency Virus (HIV) Infections. VERSION NUMBER & DATE 1 (921203) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To investigate the toxicity of interferon alfa-2b (IFN alfa-2b) in combination with nucleoside analogue therapy in HIV-positive patients with chronic hepatitis C. To determine the efficacy of treatment with IFN alfa-2b for chronic hepatitis C in patients with advanced HIV infections treated with nucleoside therapy. GENERAL DESCRIPTION RATIONALE: IFN alfa-2b has HIV inhibitory properties and has also been approved for treatment of chronic hepatitis C. Studies have shown that IFN alfa-2b is effective in asymptomatic HIV-positive patients with chronic hepatitis C, but the drug's benefit against hepatitis C in patients with advanced HIV infection has not been determined. GENERAL DESCRIPTION METHODOLOGY: Patients receive interferon alfa-2b subcutaneously at a dose of 3 million units 3 times weekly for 6 months. If no response is seen after 18 weeks of therapy or if an initial response is followed by relapse while on therapy, dose is increased to 5 million units. Patients who require a dose escalation should continue on IFN alfa-2b for an additional 6 months. All patients will also receive available nucleoside analogue therapy (zidovudine, didanosine, dideoxycytidine) at currently accepted doses as clinically appropriate. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Hepatitis C. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV positive by ELISA confirmed by Western blot or other confirmatory studies such as a positive HIV culture, positive HIV antigen, or plasma viremia. 2. Hepatitis C virus (HCV) infection documented by positive test for HCV RNA by PCR and HCV antibody by one of the more sensitive ELISA assays. 3. CD4 count <= 200 cells/mm3 on at least two determinations. NOTE: At least two patients will have CD4 count <= 50 cells/mm3. 4. No severe liver disease (Grade C Childs-Pugh classification) or chronic liver disease not caused by hepatitis C. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND BB4878 STUDY DESIGN Prospective; Drug Combination; Nonrandomized; Multicenter; Pilot Study PROTOCOL DETAILS STUDY INTENT: Drug toxicity, Drug efficacy, Combination drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 10 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: At least 6 months. PROTOCOL DETAILS ACTUAL ACCRUAL: 10/10 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 8 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV positivity. 2. Documented hepatitis C virus. 3. CD4 count <= 200 cells/mm3. 4. No severe liver disease (Grade C Childs-Pugh classification) or chronic liver disease not caused by hepatitis C. 5. Willingness to be followed for the duration of treatment and follow-up period. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 200 cells/mm3. ( 0 - 100 - 200 ). PATIENT INCLUSION CRIT. SGPT(ALT): >= 1.5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. KARNOFSKY: >= 50. PATIENT INCLUSION CRIT. OTHER: Neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior AZT, ddI, and ddC. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Treatment or suppression of opportunistic infections with standard drugs. 2. Pneumovax, HIB, tetanus, influenza, and hepatitis B vaccines. 3. Clinically indicated antibiotics. 4. Short courses of steroids (< 21 days) for acute problems not related to hepatitis C. 5. Other regularly prescribed medications such as analgesics, nonsteroidal anti-inflammatory agents, antipyretics, allergy medications, and oral contraceptives. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy other than local irradiation to the skin. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prednisone within 12 weeks prior to study entry (if patient has received prior daily doses for 1 month or longer duration). 2. Acute therapy for an infection within 2 weeks prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Nonnucleoside analogue therapy for HIV. 2. Biologic response modifiers. 3. Systemic cytotoxic chemotherapy. 4. Chronic systemic steroid use. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Hepatitis B (HBsAg positive). 2. Autoimmune hepatitis (FANA titer >= 1:160 and anti-smooth muscle antibody titer >= 1:160). 3. Wilson's disease. 4. alpha-1 antitrypsin deficiency. 5. Hemochromatosis. 6. Malignancy requiring systemic chemotherapy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0035 Interferon Alfa-2b SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 4 DRG-0015 Dideoxycytidine TRADE NAME OF SUBSTANCE Drug 1‰ Intron-A TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir TRADE NAME OF SUBSTANCE Drug 3‰ Videx TRADE NAME OF SUBSTANCE Drug 4‰ Hivid MANUFACTURERS Drug 1: Schering-Plough Corporation 2000 Galloping Hill Road Kenilworth, NJ 07033 Contact: Dr Janice Albrecht (908) 298-7985. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 3: Bristol-Myers Squibb Company 2400 West Lloyd Expressway Evansville, IN 47721-0001 Contact: DDI Information (800) 662-7999. MANUFACTURERS Drug 4: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 3 MIU thrice weekly (MWF) for 6 months. Drug 2: Administered at currently accepted doses. Drug 3: Administered at currently accepted doses. Drug 4: Administered at currently accepted doses SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Subcutaneous, 10 MIU vials OTHER TREATMENT INFO. TREATMENT DURATION: At least 6 months. OTHER TREATMENT INFO. END POINT: Toxicity, normalization of serum ALT, loss of serum hepatitis C virus RNA, survival, progression of liver disease. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Pregnancy. 3. Desire of patient to withdraw from study. 4. Treatment considered life-threatening to patient. OTHER TREATMENT INFO. MODIFICATION: For a first, second, or third occurrence of neutrophils < 500 cells/mm3: Hold IFN alfa-2b until count rises above 500, then resume at full dose (first occurrence) or reduced dose (second and third occurrences). For a fourth occurrence of neutrophils < 500 cell/mm3, discontinue study drug permanently. For recurrent grade 3 or 4 anemia: Hold IFN alfa-2b until toxicity resolves to grade 1 or better, then resume at 50 percent dose. For an additional occurrence within a 30-day period, discontinue study drug permanently. For direct hyperbilirubinemia > 3.5 to 5 x ULN: Hold IFN alfa-2b; if toxicity resolves within 4 weeks, resume study drug at reduced dose, but if toxicity does not resolve within 4 weeks or recurs at the reduced dose, discontinue study drug permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Schering-Plough Corporation. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS/DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Didanosine/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Hepatitis C/COMPLICATIONS/ETIOLOGY/*THERAPY MESH HEADING Human MESH HEADING Interferon Alfa-2b/ADMINISTRATION & DOSAGE/ *ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Opportunistic Infections/COMPLICATIONS/ ETIOLOGY/THERAPY MESH HEADING Zalcitabine/*THERAPEUTIC USE MESH HEADING Zidovudine/*THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) CAS REGISTRY NUMBER 7481-89-2 (Zalcitabine) CAS REGISTRY NUMBER 99210-65-8 (Interferon Alfa-2b) LAST REVISION DATE 941207 ENTRY MONTH 9307 INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 930702 ACTU: 2601. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 930702 ACTU: 0401. NEW YORK Harlem Hospital Center 506 Lenox Avenue / Room 3101A New York, NY 10037 Contact: Robin Flam (212) 939-3948 OPEN 940609 ACTU: 7502. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 940523 ACTU: 1902. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940523 ACTU: 1901. PENNSYLVANIA Milton S Hershey Medical Center / Hemophilia Cntr of W Penn 812 Fifth Avenue Pittsburgh, PA 15219 Contact: Dr Margaret V Ragni (412) 622-7270 OPEN 930702 ACTU: 9318. PENNSYLVANIA Pennsylvania State University / Hershey Medical Center 500 Univ Drive / PO Box 850 / Biomedical Rsrch Bldg C-6833 Hershey, PA 17033 Contact: Francine Damianos (717) 531-7488 OPEN 931216. 51 UNIQUE IDENTIFIER NIH/00516 PROTOCOL ID NUMBERS NIAID ACTG 202 PROTOCOL TITLE Dexamethasone in Cryptococcal Meningitis. VERSION NUMBER & DATE 4 (940802) TRIAL CATEGORY Opportunistic Infections PROTOCOL CHAIRS CHAIR Jacobson J GENERAL DESCRIPTION PURPOSE: To evaluate the effect of corticosteroids on reducing elevated intracranial pressure in cryptococcal meningitis. To evaluate the safety of corticosteroids in patients with cryptococcal meningitis and intracranial hypertension. GENERAL DESCRIPTION RATIONALE: In AIDS patients with cryptococcal meningitis, a correlation has been found between early death and elevated intracranial pressure. Since dexamethasone has been found to reduce intracranial pressure resulting from other forms of meningitis, it may be of benefit in AIDS patients with cryptococcal meningitis. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive dexamethasone or placebo every 6 hours for 72 hours (days 1 through 3). Additionally, standard antifungal therapy with amphotericin B and flucytosine is given for 2 weeks, followed by fluconazole for 8 weeks. Lumbar punctures will be performed daily on days 1 through 3, on days 7 and 14, and at week 10. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Cryptococcal meningitis. DISEASES STATUS Patients have the following symptoms and conditions: 1. Documented initial episode or relapse of acute cryptococcal meningitis. (NOTE: Patients must be untreated for this episode except for administration of a test dose of 1 g or less amphotericin B.) 2. Acute cryptococcal meningitis with cerebrospinal fluid opening pressure >= 250 mm H2O prior to receipt of antifungal therapy for this episode. 3. HIV infection documented by HIV antibody (by ELISA confirmed by Western blot), serum p24 antigen, or recovery of HIV in culture; OR a diagnosis of AIDS based on a documented AIDS-defining opportunistic infection. NOTE: Patients with a history of high-risk behavior for HIV infection (bisexual or homosexual men, intravenous drug abusers, recipients of blood or blood products prior to May 1985, or sexual partners of any of the above) may enroll pending receipt of HIV documentation. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 41,525 STUDY DESIGN Multicenter; Placebo-Controlled; Double-Blind; Randomized; Drug Combination PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Combination drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 36 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 10 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 5/36 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 13 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented initial episode or relapse of acute cryptococcal meningitis. (NOTE: Patients must be untreated for this episode except for administration of a test dose of 1 g or less amphotericin B.) 2. Acute cryptococcal meningitis with cerebrospinal fluid opening pressure >= 250 mm H2O prior to receipt of antifungal therapy for this episode. 3. Documented HIV infection OR a diagnosis of AIDS based on a documented AIDS-defining opportunistic infection. 4. Ability to begin therapy within 8 hours after the pre-entry lumbar puncture. 5. Consent of parent or guardian if less than 18 years of age. NOTE: Comatose patients eligible provided informed consent can be provided by guardian or next of kin. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 7.5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 7.5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2 x ULN. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Aerosolized pentamidine or systemic chemoprophylaxis for PCP. 2. Preventive therapy for steroid-associated ulcers and any other therapies required to manage steroid toxicity (e.g., insulin). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 7 days prior to study entry: Corticosteroids, mannitol, urea preparations, acetazolamide, or more than 24 hours of phenytoin. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Acetazolamide, mannitol, urea preparations, and other corticosteroids during the first 72 hours of the study. 2. Treatment or prophylaxis with other systemic antifungal agents at any time. 3. Antiretroviral therapy during the first 72 hours of the study. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Concurrent CNS disease such as another infection or neoplasm that would interfere with assessment of response. 2. Prison incarceration. SUBSTANCE IDENTIFICATION Drug 1 DRG-0013 Dexamethasone SUBSTANCE IDENTIFICATION Drug 2 DRG-0006 Amphotericin B SUBSTANCE IDENTIFICATION Drug 3 DRG-0049 Flucytosine SUBSTANCE IDENTIFICATION Drug 4 DRG-0005 Fluconazole MANUFACTURERS Drug 1: Merck and Company Incorporated Professional Services West Point, PA 19486 Contact: Professional Information (215) 661-7300 Contact: Prof Info / Call Collect (215) 652-3298. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. MANUFACTURERS Drug 4: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 10 mg (or placebo) loading dose followed by 4 mg (or placebo) q 6 hr for 72 hr. Drug 2: 0.7 mg/kg daily for at least 2 weeks. Drug 3: 100 mg/kg daily (in 4 divided doses) for at least 2 weeDrug 4: 400 mg daily for the first 2 days after completion of amphotericin B/flucytosine, then 200 mg daily for an additionalweeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 16 mg (after loading dose). Drug 2: 0.7 mg/kg. Drug 3: 100 mg/kg. Drug 4: 400 mg (for 2 days), then 200 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous, 4 mg vials. Drug 2: Intravenous. Drug 3: Intravenous (or if necessary, nasogastric). Drug 4: Intravenous OTHER TREATMENT INFO. TREATMENT DURATION: 72 hours for steroid phase of study; 10 weeks for antifungal therapy phase. OTHER TREATMENT INFO. END POINT: Primary: Change in opening cerebrospinal fluid pressure at 24 hours; serious adverse events. Secondary: Changes in opening cerebrospinal fluid pressure at 48 and 72 hours; survival; neurologic deficits; quantitative cryptococcal culture measurements; cryptococcal antigen titer; CSF leucocyte counts, glucose, and protein levels. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity attributed to study drug. 2. Requirement for treatment with prohibited or restricted medications. OTHER TREATMENT INFO. MODIFICATION: Flucytosine is held for grade 4 hepatic or hematologic toxicity and resumed at full dose or reduced dose, respectively, when toxicity resolves to grade 3 or better. For a second occurrence of grade 4 hepatic toxicity or for a third occurrence of grade 4 hematologic toxicity, flucytosine is discontinued permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Amphotericin B/*THERAPEUTIC USE MESH HEADING Brain Diseases/*DRUG THERAPY/ETIOLOGY MESH HEADING Cryptococcosis/*DRUG THERAPY/ETIOLOGY MESH HEADING Dexamethasone/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Fluconazole/*THERAPEUTIC USE MESH HEADING Flucytosine/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Meningitis/*DRUG THERAPY/ETIOLOGY MESH HEADING Middle Age MESH HEADING Opportunistic Infections/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 1397-89-3 (Amphotericin B) CAS REGISTRY NUMBER 2022-85-7 (Flucytosine) CAS REGISTRY NUMBER 50-02-2 (Dexamethasone) CAS REGISTRY NUMBER 86386-73-4 (Fluconazole) LAST REVISION DATE 941207 ENTRY MONTH 9306 ALABAMA University of Alabama at Birmingham 908 20th Street S / 1917 Research Clinic Room 135 Birmingham, AL 35294-2041 Contact: Susan Duncan (205) 934-3690 OPEN 940919 ACTU: 5801. DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 931014 ACTU: 5701. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 940408 ACTU: 0901. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 931215 ACTU: 2701. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 930813 ACTU: 1802. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 930825 ACTU: 1801. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 930621 ACTU: 1902. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 930621 ACTU: 1901. NEW YORK Bronx Veterans Administration Medical Center 130 West Kingsbridge Road Bronx, NY 10468 Contact: Nancy Ostrow (718) 584-9000 X 667Contact: (718) 584-9000 X 667OPEN 930527 ACTU: 1804. NEW YORK SUNY Health Sciences Center at Brooklyn ACTU Box 77 / 450 Clarkson Avenue Brooklyn, NY 11203-2098 Contact: Donald Smith (718) 270-3372 Contact: (718) 270-3370 OPEN 930712 ACTU: 5901. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 940706 ACTU: 1102. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 941004 ACTU: 2301. OTHER University of Puerto Rico / Schl of Med / Inf Dis Sec / ACTU G P O Box 365067 San Juan, PR 00936-5067 Contact: Maritza Cruz-Ortiz (809) 767-9192 Contact: (809) 767-9193 OPEN 931201 ACTU: 5401. 52 UNIQUE IDENTIFIER NIH/00425 PROTOCOL ID NUMBERS NIAID ACTG 201 PROTOCOL TITLE A Phase I, Dose-Escalating Safety and Tolerance Study of sCD4-PE40 in HIV-Infected Persons. VERSION NUMBER & DATE 7 (940422) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR van der Horst C GENERAL DESCRIPTION PURPOSE: To determine the safety and tolerance of sCD4-PE40 given at various dosing intervals and concentrations. To determine whether frequent dosing alters immunogenicity or toxicity. To obtain preliminary data to ascertain whether sCD4-PE40 has activity against HIV in human subjects. To determine whether there is any additive toxicity with combined use of sCD4-PE40 and zidovudine (AZT). GENERAL DESCRIPTION RATIONALE: There is some evidence that AZT and sCD4-PE40, an experimental drug with anti-HIV activity previously demonstrated in vitro, may produce increased benefit when used in combination in HIV-infected patients. GENERAL DESCRIPTION METHODOLOGY: Cohorts of six patients each receive escalating doses of 20-640 mcg/m2 sCD4-PE40 in a single IV weekly dose for 8 weeks. All six patients at a given dose must complete 2 weeks of therapy without dose-limiting toxicity before dose escalation in subsequent patient cohorts may occur. The MTD is defined as the dose of sCD4-PE40 immediately below that at which two or more of six patients experience grade 3 or higher toxicity or one or more of six patients experience grade 4 toxicity. After the MTD for the once-weekly schedule is reached, subsequent cohorts receive escalated doses of sCD4-PE40 on a 5x weekly schedule for approximately 4 weeks, in an attempt to establish the MTD for that schedule. When an MTD has been determined for the 5x weekly schedule, and if antiretroviral activity is observed, six additional patients receive this dose combined with AZT (100 mg 5x daily) for 4 weeks. PROTOCOL PHASE Phase I B OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Documented positive antibody to HIV by any federally licensed ELISA test kit, confirmed by another method such as Western blot, RIA, HIV culture, etc. If a prior diagnosis of AIDS has not been established by CDC criteria, a confirmatory test is required. 2. CD4 count = or < 300 cells/mm3 within 4 weeks prior to study entry. 3. Must be p24 antigen positive. Patients entering the AZT portion of the study only: Must be AZT naive or have had less than 2 months of AZT therapy. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS BB IND 4442 STUDY DESIGN Prospective; Dose Escalating; Open Label PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Drug dosing schedule, Maximum tolerated dose (MTD). PROTOCOL DETAILS PROJECTED ACCRUAL: 64 patients. 6 patients/dose PROTOCOL DETAILS ACTUAL ACCRUAL: 64/64 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 6 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection by ELISA confirmed by a second method. If a prior diagnosis of AIDS has not been established by CDC criteria, a confirmatory test is required. 2. CD4 count = or < 300 cells/mm3 within 4 weeks prior to study entry. 3. Positive p24 antigen. Patients entering the AZT portion of the study only: Must be AZT naive or have had less than 2 months of AZT therapy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. (Transfusion permitted.) PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 300 cells/mm3. ( 0 - 100 - 200 - 300 ). PATIENT INCLUSION CRIT. SGOT(AST): < 1.25 x ULN. (ULN = upper limit of normal.) PATIENT INCLUSION CRIT. SGPT(ALT): < 1.25 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: > 60. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase < 1.25 x ULN. Absolute neutrophil count >= 1000 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 7 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. PCP prophylaxis with aerosolized pentamidine, trimethoprim / sulfamethoxazole, or dapsone. 2. Clotrimazole troches or nystatin oral suspension for oral candidiasis. 3. Acyclovir (up to 1000 mg/day for 10 days) for herpes lesions. 4. Erythropoietin. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 7 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Current active alcoholism or active substance abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Other antiretroviral or immunomodulator agents (including but not limited to AZT, ddI, ddC, interferon, and steroids) within 4 weeks prior to study entry. 2. Ribavirin within 90 days prior to study entry. 3. Cytotoxic chemotherapy within one month prior to study entry. 4. Prior soluble CD4 or CD4-Ig. Excluded in patients entering the AZT portion of the study: more than 2 months of prior AZT therapy. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Hepatotoxic agents. 2. Other antiretroviral or immunomodulator agents (including but not limited to AZT, ddI, ddC, interferon, and steroids). 3. Other investigational drugs. 4. Systemic therapy for malignancy. 5. G-CSF and GM-CSF. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Hemophilia. 2. Acute medical problems (including active opportunistic infections such as active cryptococcosis, Pneumocystis carinii, herpes zoster, histoplasmosis, or CMV or nonopportunistic diseases including liver disease, renal disease, or orthostatic hypotension) at time of study entry. 2. Active pulmonary disease. 3. Chronic active hepatitis B surface antigenemia or unstable hepatitis C. 4. Current diagnosis of malignancy for which systemic therapy would be required during the study. 5. Inadequate intravenous access. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0118 sCD4-PE40 (Recombinant Soluble TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: The Upjohn Company 7000 Portage Road Kalamazoo, MI 49001 Contact: James VanSweden (616) 323-4696. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 100 mg 5x daily for 8 weeks (in selected patients). Drug 2: 20, 40, 80, 160, 320, and 640 mcg/m2 weekly administeresingle dose for 8 weeks, or divided into 5 equal doses per weekapproximately 4 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 500 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg capsules. Drug 2: Intravenous, 1330 mcg vials OTHER TREATMENT INFO. TREATMENT DURATION: 4 or 8 weeks. OTHER TREATMENT INFO. END POINT: MTD of sCD4-PE40 administered once a week and five times per week. HIV plasma and lymphocyte culture titers. Concentration of circulating HIV p24 antigen. Amount of HIV DNA by PCR in lymphocytes. CD4 lymphocyte count. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Major, unexpected, or life-threatening toxicity requiring drug discontinuation. 2. Development of intercurrent illness such as opportunistic infection. 3. Generalized debilitation or mental incapacity that would preclude informed consent. 4. Indication for systemic cytotoxic therapy for a newly diagnosed malignancy. 5. Pregnancy. 6. Further participation is deemed detrimental to patient's health or well-being. 7. Administrative reasons such as patient noncompliance or a major protocol violation. OTHER TREATMENT INFO. MODIFICATION: For grade 3 cutaneous or hematologic toxicity, grade 3 headache, constipation, or diarrhea, grade 4 nausea or vomiting, or grade 2 hemorrhagic, other gastrointestinal, renal, bladder, pulmonary, allergic (except skin rashes), cardiac, neurologic, or other pain-related toxicities: hold study drug until return to pretherapy or grade 1, then resume at 50 percent dose. For persistent grade 3 hepatic toxicity, hold study drug until return to grade 1, then resume at 50 percent dose. Study drug is permanently discontinued for the following: persistent grade 4 hepatic toxicity in patients receiving once-weekly doses or an initial unresolved occurrence of grade 4 hepatic toxicity in all other patients; grade 4 hematologic toxicity, or grade 3 or 4 hemorrhagic, gastrointestinal (except grade 3 nausea or vomiting), renal, bladder, pulmonary, febrile, allergic, cutaneous, cardiac, neurologic, or pain-related toxicities. Study drug is also permanently discontinued for recurrent toxicity at a 50 percent dose. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), The Upjohn Company / Antiretrovirals, Burroughs Wellcome. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Antigens, CD4/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Recombinant Proteins/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Zidovudine/*ADVERSE EFFECTS/THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Recombinant Proteins) CAS REGISTRY NUMBER 0 (Antigens, CD4) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 941207 ENTRY MONTH 9206 CALIFORNIA University of California at Los Angeles School of Medicine 60051 CHS / 10833 Le Conte Avenue Los Angeles, CA 90024-1793 Contact: Susan G McCarthy (310) 825-1301 OPEN 920610 ACTU: 0601. DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 930427 ACTU: 5701. LOUISIANA Tulane U School of Medicine \ General Clinical Research Ctr 1430 Tulane Avenue New Orleans, LA 70112-2699 Contact: Dana Wineski (504) 585-4020 OPEN 920807. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 920610 ACTU: 0201. MARYLAND State of Maryland Div of Corrections c/o Johns Hopkins Hosp 1830 East Monument Street / Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 920610 ACTU: 0202. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 920522 ACTU: 3201. 53 UNIQUE IDENTIFIER NIH/00461 PROTOCOL ID NUMBERS NIAID ACTG 200 PROTOCOL TITLE A Phase III Randomized Trial of Topical Vaginal Fluorouracil (5-Fluorouracil, 5-FU) Maintenance Therapy Versus Observation After Standard Treatment for High-Grade Cervical Dysplasia in HIV-Infected Women. VERSION NUMBER & DATE 2 (941012) TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Maiman M PROTOCOL CHAIRS CO-CHAIR Watts DH GENERAL DESCRIPTION PURPOSE: To determine the efficacy and safety of intravaginal fluorouracil administered as prophylaxis in HIV-infected women who have received standard ablative therapy (surgery) for high-grade cervical dysplasia (pre-cancer of the cervix; cervical intraepithelial neoplasia). To correlate time to recurrence of cervical dysplasia with T-cell function. GENERAL DESCRIPTION RATIONALE: Women with HIV infection are at greater risk for cervical dysplasia. Because of the likelihood that untreated or recurrent cervical dysplasia may progress to invasive cancer, there is an urgent need to develop appropriate therapies. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either intravaginal fluorouracil or no treatment (observation only). Fluorouracil cream is self-administered via applicator at biweekly intervals for 6 months. Patients are evaluated for recurrent cervical dysplasia by cytology and colposcopy with or without biopsy. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Dysplasia, Cervical. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA confirmed by Western blot. 2. History of histologically diagnosed grade II or III cervical intraepithelial neoplasia (CIN) that was successfully treated by laser therapy, cryotherapy, loop excision, or cone biopsy within the past 12 weeks. Mild cervical dysplasia (grade I CIN) is not eligible. 3. History of vaginal intraepithelial neoplasia (VAIN) or vulvar intraepithelial neoplasia (VIN) is permitted. Patients with vaginal or vulvar warts are eligible, but such lesions must be biopsied to prove absence of dysplasia. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS IND 40,765 STUDY DESIGN Randomized; Open Label; Multicenter; 2-Arm PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Secondary prophylaxis. PROTOCOL DETAILS PROJECTED ACCRUAL: 158 patients. (79 patients per treatment arm) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 6 months. PROTOCOL DETAILS ACTUAL ACCRUAL: 38/158 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 26 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Prior cervical dysplasia (grade II or III cervical intraepithelial neoplasia) successfully treated with an ablative procedure within the past 12 weeks. 3. Patients less than 18 years of age must have consent of parent or guardian. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 7 days of study entry. Abstinence or effective method of birth control / contraception during the study and for 30 days after. OTHER PATIENT INCL. CH. PRIOR TREATMENT: Required: Ablative therapy for cervical dysplasia within the past 8 weeks. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antiretrovirals (AZT, ddI, ddC) and immunomodulators (interferon and interleukin). 2. Prophylaxis or treatment for opportunistic infections. 3. Vaginal antifungal agents or other indicated vaginal medications (although not permitted on day of fluorouracil application). 4. Contraceptives. 5. Acyclovir (prophylaxis or treatment) in patients with a history of primary or recurrent genital herpes. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Malignancy requiring cytotoxic chemotherapy within the 3 months prior to study entry. 2. Prior hysterectomy. 3. History of allergic reaction or severe hypersensitivity to fluorouracil. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. SEX: MALE PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 7 days of study entry. No abstinence or no agreement to use effective method of birth control during study and for 30 days after. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Fluorouracil (systemic or topical) within 3 months prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Cytotoxic chemotherapy for malignancy. 2. High-dose steroids (> 10 mg/day prednisone or its steroid equivalent). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Untreated or persistent vaginal or vulvar dysplasia. 2. Colposcopy or biopsy inconclusive or positive for dysplasia. 3. Active genital ulcerative disease such as syphilitic chancre or herpes ulcer. 4. Adenocarcinoma in situ. SUBSTANCE IDENTIFICATION Drug 1 DRG-0161 Fluorouracil (Topical) TRADE NAME OF SUBSTANCE Drug 1‰ Efudex MANUFACTURERS Drug 1: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 2 g biweekly for 6 months SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravaginal, 5% cream OTHER TREATMENT INFO. TREATMENT DURATION: 6 months. OTHER TREATMENT INFO. END POINT: Time to development of recurrent dysplasia; frequency of recurrence of dysplasia as a function of CD4 and CD8 counts; dose-limiting toxicity. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Recurrence of cervical dysplasia. 2. Pregnancy. 3. Third occurrence of grade 3 or 4 toxicity. OTHER TREATMENT INFO. MODIFICATION: For grade 3 or 4 toxicity: hold fluorouracil until 4 weeks after toxicity resolves, then resume with regular schedule. For a second occurrence of grade 3 or 4 toxicity, hold fluorouracil until 4 weeks after toxicity resolves, then resume on a 4-week schedule. For a third occurrence of grade 3 or 4 toxicity, discontinue treatment permanently. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Hoffmann-La Roche Pharmaceutical Company. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Cervix Diseases/COMPLICATIONS/*PREVENTION & CONTROL MESH HEADING Cervix Dysplasia/COMPLICATIONS/*PREVENTION & CONTROL MESH HEADING Female MESH HEADING Fluorouracil/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Middle Age CAS REGISTRY NUMBER 51-21-8 (Fluorouracil) LAST REVISION DATE 941207 ENTRY MONTH 9301 DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 930527 ACTU: 5701. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 930318 ACTU: 0901. ILLINOIS Children's Memorial Hospital Family Clinic 303 East Superior Passavant Pavilion Room 823 Chicago, IL 60611 Contact: Baiba L Berzins RN (312) 908-9636 OPEN 930121 ACTU: 2704. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 930121 ACTU: 2701. LOUISIANA Tulane University School of Medicine / Div of Ped Infect Dis 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 940502 ACTU: 7201. MASSACHUSETTS Boston City Hospital / AIDS Research Office 818 Harrison Avenue ACC 5th Floor Room 5D11 Boston, MA 02118 Contact: Beverly Byam (617) 534-5160 OPEN 940308 ACTU: 0104. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 930402 ACTU: 0201. MICHIGAN Children's Hospital of Michigan 3901 Beaubien Boulevard Detroit, MI 48201 Contact: Dr Paula Shuman (313) 745-1941 OPEN 931227. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 940919 ACTU: 3201. NEW JERSEY Univ of Med & Dentistry of NJ / Univ Hospital 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan Mcsherry (201) 268-8273 CLOSED 940513 ACTU: 2802. NEW YORK St Clare's Hospital and Health Center 415 West 51st Street New York, NY 10019 Contact: Phyllis Ristau (212) 459-8449 OPEN 930607 ACTU: 2204. NEW YORK Memorial Hospital / Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021 Contact: Gloria Gilbert (212) 639-7169 OPEN 930723 ACTU: 2202. NEW YORK Harlem Hospital Center 506 Lenox Avenue / Room 3101A New York, NY 10037 Contact: Robin Flam (212) 939-3948 OPEN 930923 ACTU: 7502. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 930301 ACTU: 1902. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 930202 ACTU: 1901. NEW YORK Montefiore Medical Center Adolescent AIDS Program 111 East 210th Street Bronx, NY 10467-2490 Contact: Dina Monte (718) 882-0023 OPEN 931026 ACTU: 5049. NEW YORK SUNY Health Sciences Center at Brooklyn ACTU Box 77 / 450 Clarkson Avenue Brooklyn, NY 11203-2098 Contact: Donald Smith (718) 270-3372 Contact: (718) 270-3370 OPEN 930121 ACTU: 5901. NEW YORK Adirondack Medical Center at Saranac Lake 47 New Scotland Avenue Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930818 ACTU: 7403. NEW YORK Mid-Hudson Care Center / Albany Med College / Div Med Oncol 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930818 ACTU: 7402. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930818 ACTU: 7401. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 930602 ACTU: 1102. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 930426 ACTU: 2401. OTHER San Juan City Hospital / Puerto Rico Medical Center Department of Pediatrics Third Floor Hematology Rio Piedras, PR 00927 Contact: Esther Rosa (809) 764-3083 Contact: (809) 274-0904 OPEN 930607 ACTU: 5031. OTHER University of Puerto Rico / Schl of Med / Inf Dis Sec / ACTU G P O Box 365067 San Juan, PR 00936-5067 Contact: Maritza Cruz-Ortiz (809) 767-9192 Contact: (809) 767-9193 OPEN 930618 ACTU: 5401. 54 UNIQUE IDENTIFIER NIH/00531 PROTOCOL ID NUMBERS NIAID ACTG 193A PROTOCOL TITLE A Randomized, Double-Blind, Four-Arm Study Comparing Combination Nucleoside, Alternating Nucleoside, and Triple-Drug Therapy for the Treatment of Advanced HIV Disease (CD4 <= 50/mm3). VERSION NUMBER & DATE 6 (941101) TRIAL CATEGORY HIV Infection PROTOCOL CHAIRS CHAIR Henry WK PROTOCOL CHAIRS CO-CHAIR Kahn JO, Balfour HH GENERAL DESCRIPTION PURPOSE: To determine the relative clinical efficacy of zidovudine (AZT) plus didanosine (ddI), AZT plus dideoxycytidine (ddC), AZT alternating monthly with ddI, and AZT/ddI plus nevirapine in HIV-infected patients with advanced disease. GENERAL DESCRIPTION RATIONALE: The rapid emergence of resistant HIV strains has been observed in patients receiving monotherapy with a nucleoside analog or non-nucleoside reverse transcriptase inhibitor. Use of combination therapy with two nucleoside drugs or convergent combination therapy with two nucleosides and a non-nucleoside RT inhibitor may minimize the evolution of these resistant HIV strains. Since toxicity is a major problem in patients with advanced disease who are receiving combination nucleoside therapy, alternating the two drugs may provide a way of retaining several benefits of combination therapy while minimizing the increased toxicity. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either AZT/ddC, AZT/ddI, AZT alternating monthly with ddI, or AZT/ddI/nevirapine. Patients are evaluated at week 0 and every 4 weeks thereafter for 2 years. Pharmacologic, virologic, and macroneurologic substudies will be conducted. Patients who are already enrolled on protocol ACTG 193 will be given the option of continuing on their originally assigned ACTG 193 therapy for an additional 6 months or undergoing re-randomization to one of the four treatment arms on ACTG 193A. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Serodiagnosis of HIV infection by ELISA confirmed by an FDA-approved confirmatory test such as Western blot. 2. CD4 count <= 50 cells/mm3 (documented by an ACTG-certified laboratory within 90 days prior to study entry). 3. Either no prior nucleoside therapy OR a history of prior nucleoside therapy in the absence of high-grade intolerance. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 42,003 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; 4-Arm; Drug Combination; Comparative PROTOCOL DETAILS STUDY INTENT: Combination drug therapy, Drug efficacy, Drug dosing schedule. PROTOCOL DETAILS PROJECTED ACCRUAL: 1292 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 2 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 908/1292 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 90 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. CD4 count <= 50 cells/mm3. 3. Either no prior nucleoside therapy OR a history of prior nucleoside therapy in the absence of high-grade intolerance. 4. Life expectancy of at least 6 months. 5. Consent of parent or guardian if < 18 years of age. NOTE: Patients who withdrew from protocol ACTG 193 therapy prior to activation of ACTG 193A are not eligible. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 25000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 50 cells/mm3. ( 0 ). PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. Serum amylase <= 2 x ULN. (If serum amylase > 2 x ULN, then pancreatic amylase <= 2 x ULN or normal lipase may be substituted.) PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception during the study and for 90 days after. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: 1. Radiation therapy for cutaneous Kaposi's sarcoma. 2. Acupuncture. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: PCP prophylaxis. Allowed: 1. Erythropoietin maintenance. 2. G-CSF and GM-CSF. 3. Prophylaxis for Mycobacterium avium intracellulare. 4. Antifungal prophylaxis or treatment with specific drugs. 5. Maintenance therapy for opportunistic infection. 6. Over-the-counter medications or alternative therapies such as vitamins and herbs. 7. Antibiotics as clinically indicated. 8. Steroids for < 21 days for acute problems. 9. Antipyretics, analgesics, allergy medication, antidepressants, sleep medications, oral contraceptives, or other appropriate medications. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of recurrent grade 3 or greater toxicity to AZT, ddI, or ddC on two or more occasions. 2. Evidence of active pulmonary disease within 6 months prior to study entry. 3. History of grade 3 or worse peripheral neuropathy. 4. History of acute or chronic pancreatitis. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active alcohol or drug abuse. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: More than 4 units of blood in a 30-day period. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior nevirapine. Excluded within 7 days prior to study entry: 1. Acute therapy for opportunistic infection (maintenance therapy is permitted). 2. Acute systemic therapy for a nonopportunistic infection or other medical condition. 3. Antiretroviral drugs other than AZT, ddI, or ddC. 4. Biological response modifiers. 5. d4T therapy. 6. Nucleosides other than those used in the study. 7. Antibiotics containing clavulanate potassium. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Systemic chemotherapy for malignancy. 2. Acute or induction therapy for opportunistic infection. 3. Antiretroviral drugs other than study drugs. 4. Biological response modifiers. 5. Erythromycin, phenytoin, phenobarbital, warfarin, or coumadin. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Abnormal baseline chest x-ray. 2. New pulmonary or cardiac symptoms. 3. Psychological or emotional problems sufficient to prevent compliance with study medication. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 3 DRG-0015 Dideoxycytidine SUBSTANCE IDENTIFICATION Drug 4 DRG-0116 Nevirapine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir TRADE NAME OF SUBSTANCE Drug 2‰ Videx TRADE NAME OF SUBSTANCE Drug 3‰ Hivid TRADE NAME OF SUBSTANCE Drug 4‰ BI-RG-587 MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: Bristol-Myers Squibb Company 5 Research Parkway / PO Box 5100 Wallingford, CT 06492-7600 Contact: Colin McLaren (203) 284-6942. MANUFACTURERS Drug 3: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. MANUFACTURERS Drug 4: Boehringer Ingelheim Pharmaceuticals Incorporated 900 Ridgebury Road Ridgefield, CT 06877 Contact: Susannah Cort (203) 791-6063 Contact: Maureen Myers (203) 798-5583. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg (or placebo) TID. Drug 2: 200 mg (or placebo) BID. (125 mg BID in patients weighi60 kg). Drug 3: 0.75 mg (or placebo) TID. Drug 4: 200 mg (or placebo) BID SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 600 mg. Drug 2: 400 mg (250 mg in patients weighing < 60 kg). Drug 3: 2.25 mg. Drug 4: 400 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 100 mg capsules. Drug 2: Oral; 25, 50, and 100 mg chewable/dispersible tablets. Drug 3: Oral, 0.375 and 0.75 mg scored tablets. Drug 4: Oral, 200 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 2 years. OTHER TREATMENT INFO. END POINT: Primary: Survival. Secondary: Changes in clinical status; development of HIV/AIDS-related complications; changes in CD4 and CD8 counts, virologic markers, and neurologic impairment. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Intercurrent event or requirement for therapy that precludes further use of study drugs. 3. Development of a malignancy treated with systemic chemotherapy. 4. Pregnancy. 5. Study treatment has ceased for 90 or more days. 6. Poor compliance rate. 7. Termination of the study arm. OTHER TREATMENT INFO. MODIFICATION: Dose is held or reduced for specific toxicities. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Burroughs Wellcome, Bristol-Myers Squibb Company. MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Didanosine/ADMINISTRATION & DOSAGE/ *THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zalcitabine/*THERAPEUTIC USE MESH HEADING Zidovudine/ADMINISTRATION & DOSAGE/ *THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) CAS REGISTRY NUMBER 7481-89-2 (Zalcitabine) LAST REVISION DATE 941207 ENTRY MONTH 9306 ALABAMA University of Alabama at Birmingham 908 20th Street S / 1917 Research Clinic Room 135 Birmingham, AL 35294-2041 Contact: Susan Duncan (205) 934-3690 OPEN 940714 ACTU: 5801. CALIFORNIA Children's Hospital at Los Angeles/ Children's AIDS Center 4650 Sunset Blvd / Mail Stop #54 Los Angeles, CA 90027 Contact: Antonieta Sosa (213) 669-2180 OPEN 940714 ACTU: 9927. CALIFORNIA Children's Hospital of Los Angeles / Children's AIDS Center 4650 Sunset Blvd / Mail Stop #54 Los Angeles, CA 90027 Contact: Antonieta Sosa (213) 669-2180 OPEN 940719 ACTU: 9916. CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 940714 ACTU: 1201. CALIFORNIA Harbor General / REI Lab / UCLA 1124 West Carson Street Torrance, CA 90502 Contact: Sally Kruger (310) 222-3848 Contact: Rick Johnson OPEN 940714 ACTU: 0603. CALIFORNIA Olive View Medical Center / Department of Medicine 14445 Olive View Drive / 2B182 Olive View Medical Center Sylmar, CA 91342 Contact: Betsy Manchester (818) 364-3205 OPEN 940714 ACTU: 0602. CALIFORNIA University of California San Diego 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 940714 ACTU: 0701. CALIFORNIA AIDS Community Research Consortium 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harris (415) 364-5653 OPEN 940714 ACTU: 0505. CALIFORNIA Santa Clara Valley Med Ctr / ACRC 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harriss (415) 364-5653 OPEN 940714 ACTU: 0506. CALIFORNIA San Francisco General Hospital / UCSF 995 Potrero Avenue / Building 80 Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940714 ACTU: 0801. CALIFORNIA UCSF / AIDS Clinic Ambulatory Care Center 995 Potrero Avenue San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 940714 ACTU: 0802. CALIFORNIA Kaiser Permanente Medical Group / Stanford University 2590 Geary Boulevard San Francisco, CA 94115 Contact: Gretchen Van Raalte (415) 202-3482 OPEN 940714 ACTU: 0502. CALIFORNIA Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Contact: Virginia Tallman (415) 723-2804 Contact: Dr Rami Ramachandran (415) 723-6231 OPEN 940714 ACTU: 0501. COLORADO University of Colorado c/o Mountain States Reg Hemo Center 4200 East Ninth Avenue / Box C 222 Denver, CO 80262 Contact: Sheryl Giambartolomei (303) 372-1750 OPEN 940714 ACTU: 9813. COLORADO Denver Department of Health and Hospitals / Univ of CO Colorado ACTU / Campus Box B 163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 940714 ACTU: 6102. COLORADO Rose Med Ctr / Univ of Colorado Hlth Sci Ctr / Colorado ACTU Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M Graham Ray (303) 270-8551 OPEN 941004 ACTU: 6104. COLORADO University of Colorado Health Science Center Colorado ACTU / Campus Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: M. Graham Ray (303) 270-8551 OPEN 940714 ACTU: 6101. CONNECTICUT Yale University School of Medicine / Sect of Infectious Dis 135 College Street New Haven, CT 06510-2483 Contact: Laurie Andrews (203) 737-4040 OPEN 940714 ACTU: 6401. DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 940714 ACTU: 5701. DISTRICT OF COLUMBIA HIV Center - DC General Hospital / Georgetown Univ Med Ctr Kober-Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 Contact: Fax (202) 687-6476 OPEN 940714 ACTU: 5703. DISTRICT OF COLUMBIA Whitman-Walker Clinic / Georgetown Univ Medical Center Kober-Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 Contact: Fax (202) 687-6476 OPEN 940714 ACTU: 5702. DISTRICT OF COLUMBIA Howard U Coll of Med / AIDS Minority Infrastructure Program 2112 Georgia Avenue NW Washington, DC 20059 Contact: Victoria Holly -Trimmer (202) 806-4700 Contact: (202) 806-4755 OPEN 940714 ACTU: 5301. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 940714 ACTU: 0901. FLORIDA University of South Florida / Division of Infectious Disease 12901 North 30th St / Box 19 Tampa, FL 33612 Contact: Pat Seeley (813) 974-5378 OPEN 940714. HAWAII Hawaii Aids Clinical Trails Unit Leahi Hospital / Young Bldg / 3675 Kilauea Avenue / 6th Flr Honolulu, HI 96816 Contact: Debra M Ogata Arakaki (808) 737-2751 OPEN 940714 ACTU: 5201. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 940714 ACTU: 2701. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940714 ACTU: 2702. ILLINOIS Louis A Weiss Memorial Hospital / Northwestern Univ Med Schl 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941205 ACTU: 2708. ILLINOIS Cook County Hospital Passavant Pavilion / Room 823 / 303 East Superior Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940714 ACTU: 2705. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940714 ACTU: 2601. INDIANA Methodist Hospital Of Indiana 550 North University Boulevard Room 5550 Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940714 ACTU: 2602. MASSACHUSETTS New England Hemophilia Center / Med Ctr of Central Mass-Mem 119 Belmont Street Worcester, MA 01605 Contact: Pat Forand (508) 793-6276 OPEN 940714 ACTU: 9110. MASSACHUSETTS Dartmouth-Hitchcock Med Ctr / c/o Med Ctr Cntrl Mass-Mem 119 Belmont Street Worcester, MA 01605 Contact: Pat Forand (508) 793-6276 OPEN 940714 ACTU: 9116. MASSACHUSETTS Massachusetts General Hospital / Harvard 55 Fruit Street Gray 5 Boston, MA 02114 Contact: Ellen Godfrey (617) 726-5598 OPEN 940714 ACTU: 0101. MASSACHUSETTS Boston City Hospital / AIDS Research Office 818 Harrison Avenue ACC 5th Floor Room 5D11 Boston, MA 02118 Contact: Beverly Byam (617) 534-5160 OPEN 940714 ACTU: 0104. MINNESOTA St Paul-Ramsey Medical Center 640 Jackson Street St Paul, MN 55101 Contact: Ray Nelson (612) 221-1280 OPEN 940714 ACTU: 1503. MINNESOTA Hennepin County Med Clinic / Univ of Minnesota Hosp Clinic 420 Delaware Street SE / Room G255 Mayo Building Minneapolis, MN 55415 Contact: Renee St Jacques (612) 373-1810 OPEN 940714 ACTU: 1502. MINNESOTA University of Minnesota Hospital and Clinic PO Box 437 / UMHC / Harvard Street & East River Road Minneapolis, MN 55455 Contact: Nancy Reed (612) 625-1462 OPEN 940714 ACTU: 1501. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 940714 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 940714 ACTU: 2102. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 940714 ACTU: 3201. NEBRASKA University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-5130 Contact: Frances Tennant (402) 559-5750 OPEN 940714 ACTU: 1505. NEW JERSEY Univ of Med & Dentistry of NJ / Univ Hospital 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan Mcsherry (201) 268-8273 OPEN 940714 ACTU: 2802. NEW JERSEY Robert Wood Johnson University of Medicine One Robert Wood Johnson Place / CN-19 Room 378C New Brunswick, NJ 08903-0019 Contact: Dr Hugh Kim (908) 937-7680 OPEN 940714 ACTU: 9218. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 940714 ACTU: 1802. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 940714 ACTU: 0401. NEW YORK St Clare's Hospital and Health Center 415 West 51st Street New York, NY 10019 Contact: Phyllis Ristau (212) 459-8449 OPEN 940714 ACTU: 2204. NEW YORK Memorial Hospital / Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021 Contact: Gloria Gilbert (212) 639-7169 OPEN 940714 ACTU: 2202. NEW YORK Cornell University Medical Center 525 East 68th Street / Room 2434 New York, NY 10021 Contact: Brenda Greenhill (212) 746-4177 OPEN 940714 ACTU: 2201. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940714 ACTU: 1801. NEW YORK Mount Sinai / Hemophilia Treatment Center One Gustave Levy Place New York, NY 10029 Contact: Avril Gabriel (212) 241-0236 OPEN 940714 ACTU: 9210. NEW YORK Columbia Presbyterian Medical Center 622 West 168 Street / Harkness Pavilion 5 Room 516 New York, NY 10032-3784 Contact: Mykyelle Wade (212) 305-8507 OPEN 940714 ACTU: 7501. NEW YORK Harlem Hospital Center 506 Lenox Avenue / Room 3101A New York, NY 10037 Contact: Robin Flam (212) 939-3948 OPEN 940714 ACTU: 7502. NEW YORK Montefiore Drug Treatment Center 418 Forchheimer-ID / 1300 Morris Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3639 Contact: (718) 920-5344 OPEN 940714 ACTU: 1905. NEW YORK North Central Bronx Hospital / Montefiore Family Health Cntr 418 Forchheimer-ID/1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940714 ACTU: 1906. NEW YORK North Central Bronx Hospital / Samaritan Village Inc 418 Forchheimer ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940714 ACTU: 1907. NEW YORK Comprehensive Health Care Center 418 Forchheimer-ID / 1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940714 ACTU: 1908. NEW YORK Albert Einstein College of Medicine 418 Forcheimer / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940714 ACTU: 1904. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940714 ACTU: 1903. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940714 ACTU: 1901. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 940714 ACTU: 1902. NEW YORK Montefiore Medical Center / Adolescent AIDS Program 111 East 210th Street / NW674 Bronx, NY 10467 Contact: Dina Monte (718) 882-0023 OPEN 940714 ACTU: 4903. NEW YORK Bronx Veterans Administration Medical Center 130 West Kingsbridge Road Bronx, NY 10468 Contact: Nancy Ostrow (718) 584-9000 X 667Contact: (718) 584-9000 X 667OPEN 940714 ACTU: 1804. NEW YORK North Shore University Hospital 300 Community Drive Manhasset, NY 11030 Contact: Patricia Gemma (516) 562-1528 OPEN 940714 ACTU: 2203. NEW YORK SUNY Health Sciences Center at Brooklyn ACTU Box 77 / 450 Clarkson Avenue Brooklyn, NY 11203-2098 Contact: Donald Smith (718) 270-3372 Contact: (718) 270-3370 OPEN 940714 ACTU: 5901. NEW YORK City Hospital at Elmhurst / Mt Sinai 79-01 Broadway Room D1-29 Elmhurst, NY 11373 Contact: Dinah Reitman (718) 334-3963 OPEN 940714 ACTU: 1803. NEW YORK Adirondack Medical Center at Saranac Lake 47 New Scotland Avenue Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 940714 ACTU: 7403. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 940714 ACTU: 7401. NEW YORK Mid-Hudson Care Center / Albany Med College / Div Med Oncol 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 940714 ACTU: 7402. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 940714 ACTU: 1103. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 940714 ACTU: 1102. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 940714 ACTU: 1101. OHIO Children's Hospital 700 Children's Drive Columbus, OH 43205-2696 Contact: Jane Hunkler (614) 722-4460 Contact: (614) 722-6050 OPEN 940714 ACTU: 2302. OHIO Medical College of Ohio / Department of Medicine 3000 Arlington Avenue Toledo, OH 43699 Contact: Lynn Lipton (419) 381-3729 Contact: (419) 381-4328 OPEN 940714 ACTU: 2502. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 940714 ACTU: 2501. OHIO Metrohealth Medical Center / Case Western Reserve Univ 2500 MetroHealth Drive Cleveland, OH 44109-1998 Contact: Nancy Frantz (216) 459-5136 OPEN 940714 ACTU: 2503. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 940714 ACTU: 2401. OTHER University of Puerto Rico / Schl of Med / Inf Dis Sec / ACTU G P O Box 365067 San Juan, PR 00936-5067 Contact: Maritza Cruz-Ortiz (809) 767-9192 Contact: (809) 767-9193 OPEN 940714 ACTU: 5401. PENNSYLVANIA George Washington University (Hershey Satellite) 812 Fifth Avenue Pittsburgh, PA 15219 Contact: Elaine Carfagna (412) 622-7271 OPEN 940714. PENNSYLVANIA University of Pennsylvania / Div of Infectious Diseases 549 Johnson Pavillion / 6073 / 36th and Hamilton Walk Philadelphia, PA 19104-6073 Contact: Debora Dunbar (215) 349-8092 OPEN 940714 ACTU: 6201. PENNSYLVANIA University of Pennsylvania / Girard Medical Center 549 Johnson Pavillion/6073 / 36th and Hamilton Walk Philadelphia, PA 19104-6073 Contact: Debora Dunbar (215) 349-8092 OPEN 940714 ACTU: 6203. PENNSYLVANIA Thomas Jefferson Unversity 1015 Chestnut Street Philadelphia, PA 19107 Contact: Lyle Jew (215) 955-7785 OPEN 940714 ACTU: 6202. SOUTH CAROLINA Medical University of SC / Infect Diseases Division 807 CSB 171 Ashley Avenue Charleston, SC 29425 Contact: Denise Taylor (803) 782-6174 OPEN 940714 ACTU: 3205. 55 UNIQUE IDENTIFIER NIH/00459 PROTOCOL ID NUMBERS NIAID ACTG 192 PROTOCOL TITLE A Double-Blind, Placebo-Controlled Trial of Paromomycin for Treatment of Cryptosporidiosis in Patients With Advanced HIV Disease and CD4 Counts Under 150 Cells/mm3. VERSION NUMBER & DATE 3 (941013) TRIAL CATEGORY Opportunistic Infections PROTOCOL CHAIRS CHAIR Carey J GENERAL DESCRIPTION PURPOSE: To determine the effectiveness of oral paromomycin at an initial dose of 2000 mg/day for 21 days compared to placebo in the treatment of cryptosporidiosis in patients with HIV infection. To evaluate the safety of oral paromomycin at two different doses. To explore whether paromomycin administered over a longer period provides additional benefit. GENERAL DESCRIPTION RATIONALE: In previous studies, patients with cryptosporidiosis demonstrated dramatic improvement with paromomycin therapy. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either placebo or paromomycin (2000 mg/day) for 3 weeks. After the initial double-blind phase, all patients receive open-label paromomycin (2000 mg/day) for 3 weeks. Following 6 weeks of therapy, patients who do not achieve a complete response receive 4000 mg/day for an additional 3 weeks, while complete responders continue receiving 2000 mg/day for an additional 3 weeks. Complete or partial responders after 9 weeks may receive 16 additional weeks of optional maintenance therapy at the dose at which their response was achieved. Treatment continues for up to 25 weeks total. Patients are followed at weeks 1, 3, 4, 6, 7, and 9, and then at 2-4 week intervals. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Cryptosporidiosis / diarrhea. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive. 2. CD4 count <= 150 cells/mm3. 3. Cryptosporidial diarrhea for at least 4 of 7 days prior to study entry, defined by four or more loose stools per day. 4. Cryptosporidium oocysts documented in 2 consecutive stool samples within 21 days prior to study entry. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS IND 40,711 STUDY DESIGN Multicenter; Double-Blind; Placebo-Controlled; Randomized; 2-Arm PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 68 patients. (34 per treatment arm) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 25 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 27/68 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 20 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Advanced HIV disease. 2. Diarrhea presumptively caused by Cryptosporidia. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 150 cells/mm3. PATIENT INCLUSION CRIT. CREATININE: < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. KARNOFSKY: >= 40. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antiretroviral therapy. 2. Macrolides for disseminated Mycobacterium avium. 3. Atovaquone for toxoplasmosis. 4. Other antimicrobials for concurrent infections. 5. Lomotil, Imodium, or deodorized opium tincture in a standardized regimen for diarrhea. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Paromomycin at > 1 g/day for >= 14 days prior to study entry. Excluded within 14 days prior to study entry: 1. Agents with putative anticryptosporidial activity (such as spiramycin, diclazuril, letrazuril, or bovine colostrum), with the exception of macrolides that are permitted for other indications. 2. Octreotide acetate (Sandostatin). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded during the first 9 weeks of study: 1. Agents with putative anticryptosporidial activity (such as spiramycin, diclazuril, letrazuril, or bovine colostrum). 2. Octreotide acetate (Sandostatin). 3. Antidiarrheals other than those specifically allowed. 4. Clarithromycin if initiated at 500 mg or higher or azithromycin if initiated at 600 mg or higher. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Hypersensitivity to aminoglycosides. 2. Inability to swallow capsules. 3. Active infection due to other enteric pathogens. Previous diagnosis of CMV or MAC infection permitted if patient is currently stabilized on a therapeutic regimen (clarithromycin up to 500 mg BID or azithromycin up to 600 mg daily). 4. Other known causes for diarrhea (e.g., malabsorption syndrome, gastrointestinal Kaposi's sarcoma). SUBSTANCE IDENTIFICATION Drug 1 DRG-0188 Paromomycin TRADE NAME OF SUBSTANCE Drug 1‰ Humatin MANUFACTURERS Drug 1: Warner Lambert Company / Parke-Davis Research 2800 Plymouth Road Ann Arbor, MI 48105 Contact: John Bender (313) 996-7297. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 500 mg (or placebo) QID during weeks 1 through 3, followed by 500 mg QID for all patients during weeks 4 through followed by either 500 mg QID (in patients with a complete respafter 6 weeks) or 1000 mg QID (in patients without a complete response after 6 weeks) during weeks 7 through 9; followed by optional maintenance (in patients with a complete or partial response) during weeks 10 through 25, at the dose at which the response was achieved SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 2000 - 4000 mg, depending on response SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 250 mg capsules OTHER TREATMENT INFO. TREATMENT DURATION: Up to 9 weeks, with possible continuation for 16 additional weeks. OTHER TREATMENT INFO. END POINT: Response rate, drug tolerance, parasitologic response. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Clinically significant adverse experiences (e.g., ototoxicity). 2. Lack of efficacy. 3. Progressive rise in serum creatinine to 2 X baseline for > 4 days, or serum creatinine > 1.5 mg/dl despite adequate hydration. 4. Continuation would jeopardize patient's health. OTHER TREATMENT INFO. MODIFICATION: Patients on 4000 mg/day study drug who experience increased diarrhea, nausea, or vomiting decrease dose to 2000 mg/day. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Cryptosporidiosis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Paromomycin/*THERAPEUTIC USE CAS REGISTRY NUMBER 7542-37-2 (Paromomycin) LAST REVISION DATE 941207 ENTRY MONTH 9309 CALIFORNIA Kaiser Permanente Medical Group / Stanford University 2590 Geary Boulevard San Francisco, CA 94115 Contact: Gretchen Van Raalte (415) 202-3482 OPEN 931020 ACTU: 0502. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 931006 ACTU: 0901. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 931223 ACTU: 2701. ILLINOIS Louis A Weiss Memorial Hospital / Northwestern Univ Med Schl 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941017 ACTU: 2708. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940201 ACTU: 2702. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940513 ACTU: 2601. INDIANA Methodist Hospital Of Indiana 550 North University Boulevard Room 5550 Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940523 ACTU: 2602. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 931109 ACTU: 2101. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 930916 ACTU: 0401. NEW YORK Cornell University Medical Center 525 East 68th Street / Room 2434 New York, NY 10021 Contact: Brenda Greenhill (212) 746-4177 OPEN 931006 ACTU: 2201. NEW YORK Columbia Presbyterian Medical Center 622 West 168 Street / Harkness Pavilion 5 Room 516 New York, NY 10032-3784 Contact: Mykyelle Wade (212) 305-8507 OPEN 931227 ACTU: 7501. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 931101 ACTU: 1902. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 931101 ACTU: 1901. NEW YORK Montefiore Medical Center Adolescent AIDS Program 111 East 210th Street Bronx, NY 10467-2490 Contact: Dina Monte (718) 882-0023 OPEN 930916 ACTU: 5049. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 940825 ACTU: 1103. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 940214 ACTU: 1102. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 931006 ACTU: 2301. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 931006 ACTU: 2501. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 940113 ACTU: 2401. OTHER University of Puerto Rico / Schl of Med / Inf Dis Sec / ACTU G P O Box 365067 San Juan, PR 00936-5067 Contact: Maritza Cruz-Ortiz (809) 767-9192 Contact: (809) 767-9193 OPEN 941004 ACTU: 5401. 56 UNIQUE IDENTIFIER NIH/00467 PROTOCOL ID NUMBERS NIAID ACTG 188 PROTOCOL TITLE Neurodevelopmental and Neurological Study of Infants and Children With HIV-1 Infection and AIDS in Clinical Trials. VERSION NUMBER & DATE 1 (920925) TRIAL CATEGORY Epidemiology TRIAL CATEGORY Child PROTOCOL CHAIRS CHAIR Wilson B PROTOCOL CHAIRS CO-CHAIR Fletcher J, Belman A GENERAL DESCRIPTION PURPOSE: To establish the validity of the NIMH Neurodevelopmental and Neurological Assessment Battery. To evaluate neurodevelopment in infants and children with HIV-related CNS disease. To evaluate multicultural assessment issues in multisite studies. To describe the nature of impaired developmental abilities and the different course of HIV disease in infants and children. GENERAL DESCRIPTION RATIONALE: The assessment of children who sustain CNS insult requires approaches that differ in several ways from adult-based assessment. The rapid changes that occur in the developing CNS as well as in behavior reflect underlying processes of growth and development. GENERAL DESCRIPTION METHODOLOGY: This study will be conducted as a nested substudy within ACTG 152. It will include 225 HIV-infected patients from ACTG 152, as well as an additional 450 non-infected participants recruited for two comparison groups, one consisting of seronegative infants and children with perinatal exposure to HIV and a second group without perinatal exposure to HIV. A neurological assessment battery will evaluate the following domains: growth, sensory, tone, motor, posture, locomotion, hand use, deep tendon reflexes, abnormal movements, language, and behavior. Participants will be asked to do different kinds of activities such as talking, listening, and drawing, and to play games that involve walking, jumping, concentration, and memory. Spanish-speaking children will be evaluated using the Spanish translations of the battery. All participants will be assessed at clinic visits and followed for a minimum of 2 years. PROTOCOL PHASE Epidemiology OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Participants must meet the following criteria. 1. Belong to one of the following categories: o Infants and children enrolled on ACTG 152; o Other infants and children who are HIV seronegative WITHOUT perinatal HIV exposure; o Other infants and children who are HIV seronegative WITH perinatal HIV exposure. NOTE: Infants < 15 months of age with perinatal HIV exposure may have a positive serological test for HIV antibody at enrollment, but a negative test must be obtained once the child reaches the age of 15 months. 2. Recruited at sites designated to conduct this observational study. ELIGIBILITY ARC. AIDS. HIV Seronegative. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Nested Study PROTOCOL DETAILS STUDY INTENT: Epidemiology. PROTOCOL DETAILS PROJECTED ACCRUAL: 675 patients. (225 patients from ACTG 152; 450 other participants for comparison) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 2 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 141/675 (941207). PROTOCOL DETAILS STUDY DURATION: 2 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Participants must meet the following criteria: 1. Infants and children on ACTG 152 OR other infants and children who are HIV seronegative without perinatal HIV exposure OR other infants and children who are HIV seronegative with perinatal HIV exposure. NOTE: Infants < 15 months of age with perinatal HIV exposure may have a positive serological test for HIV antibody at enrollment, but a negative test must be obtained once the child reaches the age of 15 months. 2. Recruited at sites designated to conduct this observational study. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: Non-applicable percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: Non-applicable g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: Non-applicable cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: Non-applicable platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CD4/CD8 RATION: Non-applicable. PATIENT INCLUSION CRIT. BILIRUBIN: Non-applicable mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): Non-applicable. PATIENT INCLUSION CRIT. SGPT(ALT): Non-applicable. PATIENT INCLUSION CRIT. CREATININE: Non-applicable. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: Non-applicable ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: Non-applicable. PATIENT AGE AGE: 03 Months - 18 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Excluded in participants enrolled in ACTG 152: History of pancreatitis within one year prior to study entry associated with compatible symptoms. Excluded in ALL participants: History of uncontrolled seizure disorder. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 02 Months. 19 Years - 99 Years. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Ongoing drug or alcohol use. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded in participants in comparison groups: Chemotherapy for malignancy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Excluded in participants enrolled in ACTG 152: 1. Active malignancy. 2. Grade 3 or higher peripheral neuropathy. 3. Cardiomyopathy. 4. Blindness or deafness. 5. Pancreatitis. Excluded in participants in the comparison groups: 1. Active malignancy. 2. Peripheral neuropathy defined by absent deep tendon reflexes, severe motor weakness, paralysis, severe paresthesia, or sensory loss. PATIENT EXCLUSION CRIT. AVAILABILITY: Inablilty to be followed at the site of enrollment or another ACTU for 104 weeks. OTHER TREATMENT INFO. END POINT: Neurodevelopmental and neurological status. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING AIDS-Related Complex/*COMPLICATIONS/ETIOLOGY MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS/ETIOLOGY MESH HEADING Adolescence MESH HEADING Central Nervous System Diseases/ *COMPLICATIONS/EPIDEMIOLOGY/ETIOLOGY MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Human MESH HEADING Infant MESH HEADING Peripheral Nervous System Diseases/ *COMPLICATIONS/EPIDEMIOLOGY/ETIOLOGY LAST REVISION DATE 941207 ENTRY MONTH 9402 NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940105 ACTU: 1801. 57 UNIQUE IDENTIFIER NIH/00446 PROTOCOL ID NUMBERS NIAID ACTG 185 PROTOCOL TITLE A Phase III Randomized, Double-Blind, Controlled Study of the Use of Anti-HIV Immune Serum Globulin (HIVIG) for the Prevention of Maternal-Fetal HIV Transmission in Pregnant Women and Newborns Receiving Zidovudine (AZT). VERSION NUMBER & DATE 2 (930712) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Pregnancy TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the effect of anti-HIV immune serum globulin (HIVIG) versus immune globulin (IVIG) administered during pregnancy and to the newborn, in combination with zidovudine (AZT) administered intrapartum and to the newborn, on incidence of HIV infection in infants born to HIV-infected women who received AZT during pregnancy for medical indications. GENERAL DESCRIPTION RATIONALE: Vertical transmission of HIV from mother to child may occur before, during, or after parturition (via breast-feeding). It is believed that therapy administered both during pregnancy and intrapartum may help prevent vertical transmission. Additionally, adjunctive short-term antiretroviral therapy for the newborn, following the intensive viral exposure presumed to occur at birth, may be necessary. GENERAL DESCRIPTION METHODOLOGY: Pregnant women who are currently receiving AZT are randomized at 20-30 weeks of gestation to begin receiving either HIVIG or IVIG every 28 days up to delivery. Within 12 hours after birth, the infant receives an infusion of matching study drug. During labor, all women receive an intravenous loading dose of AZT administered over 1 hour, followed by continuous infusion during the intrapartum period until the umbilical cord is clamped. All infants receive AZT syrup every 6 hours, beginning as soon as oral fluids are tolerated but within 8-12 hours after birth and continuing for 6 weeks. Women are followed until 26 weeks postpartum. Infants are followed at weeks 1, 2, 4, and then every 4 weeks through week 24, every 12 weeks through week 60, at week 78 (18 months), and at week 104 (24 months). PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by ELISA, with appropriate confirmatory test, positive p24 antigen, or positive viral culture (blood or CSF). 2. Receiving AZT during current pregnancy for any of the following medical indications: o CD4 count <= 500 cells/mm3 at study entry o CD4 count <= 500 cells/mm3 at time AZT was initiated o History of AIDS-defining illness. 3. Gestational age between 20 and 30 weeks based on sonogram or menstrual history confirmed by first pelvic exam. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS BB-IND 4293 STUDY DESIGN Randomized; Controlled; Multicenter; Drug Combination; 2-Arm; Double-Blind PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance, Combination drug therapy, Immunotherapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 800 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Women: Until 6 months postpartum. Infants: 2 years. PROTOCOL DETAILS ACTUAL ACCRUAL: 118/800 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 5 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. Been receiving AZT during current pregnancy for medical indications. 3. Gestational age between 20 and 30 weeks. 4. Intention to carry pregnancy to term. 5. Available venous access (placement of central line or Hickman catheter not indicated for study purposes). 6. Willingness to be followed by a participating site for study duration. NOTE: Father of fetus (if available after a reasonable attempt to contact him) must also provide informed consent. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 70 ml/min. (if creatinine value not available). PATIENT INCLUSION CRIT. OTHER: Urine protein < 2+ by dipstick or < 4 g protein in 24-hour urine collection. PATIENT AGE AGE: 13 Years - 60 Years. PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Pregnant. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Women - Medications as required for obstetrical management of HIV infection (e.g., acyclovir, ketoconazole, isoniazid, antibiotics, or other antiretroviral therapy if intolerant or failing on AZT), unless specifically excluded. 2. Infants - Drug treatment for signs of drug withdrawal (phenobarbital, chlorpromazine, tincture of opium, paregoric or Valium). 3. Infants - Medications as indicated for management of an HIV-exposed infant (e.g., hepatitis B vaccine, syphilis treatment, Pneumocystis carinii pneumonia prophylaxis). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Evidence of pre-existing fetal anomalies (e.g., anencephaly, renal agenesis, or Potter's syndrome) that may result in a high probability that the fetus-infant would not survive to the end of the study period. 2. Chorionic villus sampling (CVS) or percutaneous umbilical blood sampling (PUBS) occurring in this pregnancy prior to study entry. 3. Illness associated with excessive protein loss, e.g., chronic diarrhea with no documented weight gain in a 3-month period during pregnancy. 4. Pre-existing conditions such as hypogammaglobulinemia or immune thrombocytopenia that are felt to require IVIG therapy. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. SEX: MALE PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Not pregnant. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Receipt of anti-HIV vaccines or passive immunotherapy with HIVIG or IVIG during this pregnancy prior to study entry. 2. Receipt of antiretroviral agents other than AZT during this pregnancy prior to study entry (e.g., rCD4, CD4-IgG, d4T, ddC, ddI). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Illness associated with excessive protein loss, e.g., severe proteinuria (protein >= 4 g protein in a 24-hour urine collection). SUBSTANCE IDENTIFICATION Drug 1 DRG-0087 Anti-HIV immune serum globulin (Human) SUBSTANCE IDENTIFICATION Drug 2 DRG-0022 Globulin, immune SUBSTANCE IDENTIFICATION Drug 3 DRG-0004 Zidovudine TRADE NAME OF SUBSTANCE Drug 1‰ HIVIG TRADE NAME OF SUBSTANCE Drug 2‰ IVIG TRADE NAME OF SUBSTANCE Drug 3‰ Retrovir MANUFACTURERS Drug 1: North American Biologicals Incorporated 16500 NW 15th Avenue Miami, FL 33169 Contact: Dr Christine Sapan (305) 625-5303. MANUFACTURERS Drug 2: Cutter Biological Miles Incorporated 4th & Parker Streets PO Box 1986 Berkeley, CA 94701 Contact: Dr Ralph Rousell (510) 420-5120. MANUFACTURERS Drug 3: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: During pregnancy: 200 mg/kg q 28 days beginning betweengestational weeks 20 and 30 and continuing until delivery. Infant: 200 mg/kg within 12 h after birth. Drug 2: During pregnancy: 200 mg/kg q 28 days beginning betweengestational weeks 20 and 30 and continuing until delivery. Infant: 200 mg/kg within 12 h after birth. Drug 3: Intrapartum: 2.0 mg/kg IV (loading dose) followed by 1.mg/kg/hr continuous infusion until umbilical cord is clamped. Infant: 2.0 mg/kg PO q 6 h (beginning as soon as infant can toloral fluids within 8-12 h after birth) until week 6 SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 3: Infant: 8.0 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV); 500, 2000, 2500, and 12500 mg vials. Drug 2: Intravenous (IV); 500, 2500, and 12500 mg vials. Drug 3: Intravenous - 200 mg vials; oral - 2400 mg bottles OTHER TREATMENT INFO. END POINT: Definitive HIV infection in the infant. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue HIVIG or IVIG treatment for the following reasons: 1. Severe allergic reaction to infusion such as exfoliative erythroderma, anaphylaxis, or vascular collapse. 2. A clinical condition that is considered incompatible with life. 3. At the request of the patient, parent or guardian, investigator, FDA, pharmaceutical company, or IND sponsor. Infants discontinue AZT treatment for the following reasons: 1. Immediate life-threatening or clinical condition that is considered incompatible with life. 2. Grade 3 toxicity or unacceptable laboratory values. 3. Severe allergic reaction such as exfoliative erythroderma, anaphylaxis, or vascular collapse. 4. Evidence of HIV infection. 5. At the request of the parent or guardian, investigator, FDA, pharmaceutical company, or IND sponsor. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), National Institute of Child Health and Development. MESH HEADING AIDS-Related Complex/*THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*THERAPY/TRANSMISSION MESH HEADING Human MESH HEADING Immunization, Passive MESH HEADING Immunoglobulins, Intravenous/*THERAPEUTIC USE MESH HEADING Infant MESH HEADING Middle Age MESH HEADING Pregnancy MESH HEADING Pregnancy Complications, Infectious MESH HEADING Zidovudine/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Immunoglobulins, Intravenous) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 941207 ENTRY MONTH 9311 CALIFORNIA UCLA Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 940804 ACTU: 3601. CALIFORNIA University of Southern California Medical Center Pediatric Pavillion / Room 3D14 / 1129 North State Street Los Angeles, CA 90033 Contact: Janice Ono (213) 226-3945 OPEN 940804. MICHIGAN Children's Hospital of Michigan 3901 Beaubien Boulevard Detroit, MI 48201 Contact: Sheri Jo Smith (Adults) (313) 993-2681 Contact: Charnell Cromer (Pediatrics) (313) 745-5565 OPEN 940804. OTHER University of Puerto Rico / University Pediatric Hospital 4th Floor South Wing Room 4B-45 / GPO Box 365067 San Juan, PR 00936-5067 Contact: Carmen Rivera (809) 759-9595 Contact: (809) 765-1979 X 724OPEN 940804 ACTU: 6601. 58 UNIQUE IDENTIFIER NIH/00389 PROTOCOL ID NUMBERS NIAID ACTG 180 PROTOCOL TITLE Pharmacokinetics, Safety, Tolerance, and Activity of Nevirapine (BI-RG-587) Alone and in Combination With AZT in Mildly to Moderately Symptomatic HIV-I Infected Children. VERSION NUMBER & DATE 1 (910821) Final TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic TRIAL CATEGORY Child PROTOCOL CHAIRS CHAIR Sullivan J PROTOCOL CHAIRS CO-CHAIR Luzuriaga K GENERAL DESCRIPTION PURPOSE: Monotherapy phase: To evaluate and compare the safety, tolerance, pharmacokinetics, and preliminary activity of nevirapine administered alone in mildly to moderately symptomatic HIV-infected children ages 2 months to less than 18 years; to evaluate and compare the safety, tolerance, and pharmacokinetics of nevirapine in HIV-infected children ages 1 day to less than 2 months. Combination therapy phase: To evaluate and compare the safety, tolerance, pharmacokinetics, and preliminary activity of nevirapine administered in combination with zidovudine (AZT) in mildly to moderately symptomatic HIV-infected children ages 2 months to less than 18 years. GENERAL DESCRIPTION RATIONALE: Compounds with reverse transcriptase inhibitory activity that are more potent and less toxic than the nucleoside analogs are needed. Nevirapine (BI-RG-587) has shown in vitro inhibitory activity against HIV-1 reverse transcriptase and has shown a synergistic inhibition of HIV-1 replication when combined with zidovudine (AZT) in a plaque reduction assay. GENERAL DESCRIPTION METHODOLOGY: Sixty mildly to moderately symptomatic HIV-infected children (five patients in each of four age groups) will receive oral nevirapine at 7.5, 30, or 120 mg/m2 daily for 168 days. If preliminary activity is demonstrated and toxicity is acceptable after 84 days of treatment in the three oldest age groups (ages 2 months - less than 2 years, ages 2 years - less than 13 years, and ages 13 years - less than 18 years), children ages 1 day - less than 2 months will receive one of the three doses of nevirapine. Additionally, 15 additional patients (five in each of three age groups) will receive 180 mg/m2 zidovudine in combination with 120 mg/m2 nevirapine. At the end of 24 weeks of combination therapy, patients discontinue zidovudine for 2 weeks while remaining on nevirapine, in order for pharmacokinetic sampling to be done. Children will be enrolled sequentially by decreasing age and increasing nevirapine dose. PROTOCOL PHASE Unspecified OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Evidence of HIV-1 infection as follows: o Children younger than 15 months must have one positive peripheral blood viral isolation OR one detectable serum p24 antigen test (at least 30 pg/ml). o Children older than 15 months must have Either of the above criteria OR Two positive tests for serum HIV antibodies (at least 72 hours apart), both determined by ELISA or one of the two determined by Western blot. 2. Children ages 1 day to less than 2 months may be enrolled regardless of CD4 count and symptoms. 3. Children ages 2 months to less than 18 years must have absolute CD4 cell counts within 28-42 days prior to entry as follows: o Ages 2-11 months - < 1500/mm3 o Ages 12-23 months - < 750/mm3 o Ages 24 months and over - < 500/mm3 AND/OR Have one or more of the following symptoms: o HIV encephalopathy o Lymphocytic interstitial pneumonitis (provided patient is not on steroids or requires supplemental oxygen or has a pretreatment paO2 < 70 mm Hg) o Hepatitis considered secondary to HIV (patients with hemophilia cannot have hepatitis as the sole inclusion criteria) o Cardiomyopathy o Nephropathy (defined as persistent proteinuria, i.e., > 500 mg/24 hours in children 12 years and older and > 300 mg/24 hours in children younger than 12 years), with a normal creatinine clearance o Hematologic disorders including absolute neutrophil count < 1500/mm3 but > 800/mm3 or platelet count < 150000 on 2 occasions more than one week apart or hemolytic anemia o Dermatologic disease considered secondary to HIV o One or more episodes of herpes zoster or herpes simplex during the patient's life that occur simultaneously with HIV positivity o Diarrhea defined as more than 4 watery stools per day for > 4 weeks in the absence of a defined infection or 2 or more episodes of severe diarrhea within 2 months requiring hospitalization for rehydration o Parotitis (chronic parotid enlargement for 8 weeks or longer after diagnosis of HIV o Organomegaly (hepatomegaly or splenomegaly) o History of recurrent bacterial infections (6 or more episodes within 2 years) other than serious bacterial infections (bacteremia, meningitis, pneumonia, abscess of internal organ, bone/joint infections). ELIGIBILITY AIDS. p24+. HIV Seropositive. ARC. ASYM. OTHER PROTOCOL NUMBERS 882 STUDY DESIGN Multicenter; Open Label; Drug Tolerance; Drug Combination PROTOCOL DETAILS STUDY INTENT: Combination and single drug therapy, Combination and single pharmacokinetics, Drug efficacy, Drug safety, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 35 patients. PROTOCOL DETAILS ACTUAL ACCRUAL: 29/35 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 7 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. A positive Polymerase Chain Reaction (PCR) is not acceptable as the sole evidence of HIV infection. Three out of five children in each age and dose group must have a serum p24 antigen level of 70 pg/ml or greater and/or a plasma viral titer of 50 TCID/ml or greater prior to study entry. 2. Ability to be followed by their original trial center for the duration of the trial. 3. Consent of parent or guardian. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: > 24 percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: > 8 g/dl. Transfusion permitted. PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. Exclusion: HIV-associated thrombocytopenia. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 3 x ULN mg/dl. ULN = upper limit of normal. PATIENT INCLUSION CRIT. SGPT(ALT): < 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 2.0 mg/dl. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophil count > 750 cells/mm3 PATIENT AGE AGE: 01 Days - 17 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Abstinence or agree to use barrier methods of birth control / contraception during the study. Negative pregnancy test. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. IV gammaglobulin therapy. 2. Medications for PCP prophylaxis (e.g., TMP / SMX, dapsone, aerosolized and iv pentamidine). 3. Fluconazole. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with prior participation in this trial are excluded. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: No abstinence or no agreement to use barrier methods of birth control / contraception during the study. Pregnant. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active alcohol or drug abuse to impair compliance with the protocol. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: More than 6 weeks of prior zidovudine (AZT) therapy or more than 6 weeks of any other antiretroviral therapy. Excluded within 7 days prior to study entry: AZT (in monotherapy groups only). Excluded within 4 weeks prior to study entry: 1. Other approved or investigational antiretroviral agents. 2. All other investigational agents. 3. Glucocorticoids and steroid hormones. 4. Dicumarol, warfarin, and other anticoagulants. 5. Digitoxin. 6. Valproic acid. 7. Tolbutamide. 8. Doxycycline. 9. Chloramphenicol. 10. Isoniazid. 11. Phenobarbital and other barbiturates. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other approved or investigational antiretroviral agents. 2. All other investigational agents (except fluconazole). 3. Glucocorticoids and steroid hormones. 4. Dicumarol, warfarin, and other anticoagulants. 5. Digitoxin. 6. Valproic acid. 7. Tolbutamide. 8. Doxycycline. 9. Chloramphenicol. 10. Isoniazid. 11. Phenobarbital and other barbiturates. 12. Hepatotoxic drugs. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Lymphocytic interstitial pneumonitis if steroid-dependent or requiring supplemental oxygen or with a pretreatment paO2 < 70 mm Hg. 2. Opportunistic or serious bacterial infections within 28 days prior to entry. 3. Demonstrated intolerance to zidovudine prior to administration of nevirapine (in patients enrolled in the combination therapy phase of the study). 4. CDC classification of P-2D (secondary infectious diseases) and/or P-2E (secondary cancers). 5. Pre-existing malignancies. PATIENT EXCLUSION CRIT. AVAILABILITY: Unable to be followed by their original trial center for the duration of the study. SUBSTANCE IDENTIFICATION Drug 1 DRG-0116 Nevirapine SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine TRADE NAME OF SUBSTANCE Drug 1‰ BI-RG-587 TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir MANUFACTURERS Drug 1: Boehringer Ingelheim Pharmaceuticals Incorporated 900 Ridgebury Road Ridgefield, CT 06877 Contact: Susannah Cort (203) 791-6063 Contact: Maureen Myers (203) 798-5583. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 7.5, 30, or 120 mg/m2 daily for 168 days. Drug 2: 180 mg/m2 q 6 hr for 168 days SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 7.5, 30, or 120 mg/m2. Drug 2: 720 mg/m2 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 5 mg/ml suspension and 2.5, 12.5, and 50 mg tablets. Drug 2: Oral, 10 mg/ml syrup or 100 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 24 weeks. OTHER TREATMENT INFO. END POINT: Safety, tolerance, pharmacokinetics, and preliminary activity of nevirapine alone and in combination with zidovudine. OTHER TREATMENT INFO. DISCONTINUE: Patients will be discontinued from treatment for the following reasons: 1. Occurrence of an intolerable adverse event. 2. Recurrent grade 3 or 4 toxicity despite maximal dose reductions. 3. Significant noncompliance with protocol requirements. OTHER TREATMENT INFO. MODIFICATION: Monotherapy: For grade 3 or 4 toxicity, hold nevirapine until return to grade 2 or better, then resume at 50% dose. Combination therapy: For recognizable grade 3 or 4 toxicity or intolerable grade 2 toxicity to either neveripine or AZT, hold that drug until return to grade 1 or baseline, then resume at 50% dose; continue the other study drug. If toxicity cannot be attributed to either drug, discontinue both medications until resolution to grade 1 or baseline, then resume both drugs. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Boehringer Ingelheim Pharmaceutical Incorporated. MESH HEADING AIDS-Related Complex/DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY/METABOLISM MESH HEADING Adolescence MESH HEADING Antiviral Agents/PHARMACOKINETICS/ *THERAPEUTIC USE MESH HEADING Child MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY/METABOLISM MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Pyridines/PHARMACOKINETICS/*THERAPEUTIC USE MESH HEADING Reverse Transcriptase/ANTAGONISTS & INHIB MESH HEADING Zidovudine/PHARMACOKINETICS/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 129618-40-2 (BI-RG 587) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER EC 2 LAST REVISION DATE 941207 ENTRY MONTH 9112 CALIFORNIA UCLA School of Medicine / Department of Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024 Contact: Dr Yvonne J Bryson (310) 825-5235 OPEN 940804. CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 940804 ACTU: 1201. CONNECTICUT University of Connecticut Health Center / Dept of Pediatrics 263 Farmington Avenue Farmington, CT 06032 Contact: Dr James Robinson (203) 679-2221 OPEN 940804. FLORIDA Univ of Miami School of Medicine / Pediatric Imm Infect Dis 1800 NW Tenth Avenue Miami, FL 33136 Contact: Janet Gourley (305) 548-4446 OPEN 940804 ACTU: 4201. MASSACHUSETTS Baystate Medical Center / Department of Pediatrics 759 Chestnut Street Springfield, MA 01199 Contact: Dr Barbara Stechenberg (413) 784-5379 OPEN 940804. MASSACHUSETTS University of Massachusetts Medical Center / Biotech II 373 Plantation Street Room 318 Worcester, MA 01605 Contact: John Sullivan (508) 856-6282 OPEN 940804. NEW JERSEY Children's Hospital of New Jersey 15 South 9th Street / CHAP Program 5 East Newark, NJ 07107 Contact: George Donovan Mcsherry (201) 268-8273 OPEN 940804 ACTU: 2801. 59 UNIQUE IDENTIFIER NIH/00413 PROTOCOL ID NUMBERS NIAID ACTG 179 PROTOCOL TITLE Comparison of Two Dosage Regimens of Oral Dapsone for Prophylaxis of Pneumocystis Carinii Pneumonia in Pediatric HIV Infection. VERSION NUMBER & DATE 3 (931129) TRIAL CATEGORY Child TRIAL CATEGORY Opportunistic Infections PROTOCOL CHAIRS CHAIR McIntosh K PROTOCOL CHAIRS CO-CHAIR Cooper E GENERAL DESCRIPTION PURPOSE: Primary: To compare the toxicity of daily versus weekly dapsone in HIV-infected infants and children; to study the pharmacokinetics of orally administered dapsone in HIV-infected infants and children. Secondary: To obtain information on the rate of Pneumocystis carinii pneumonia ( PCP ) breakthrough in children receiving two different dose regimens of dapsone. GENERAL DESCRIPTION RATIONALE: Prophylaxis for Pneumocystis carinii pneumonia ( PCP ) is recommended for all HIV-infected children considered to be at high risk. Approximately 15 percent of children are intolerant to trimethoprim / sulfamethoxazole, the first choice drug for PCP prophylaxis. Since many children are also unable to take or tolerate aerosolized pentamidine, dapsone is a second choice for PCP prophylaxis. The most favorable dose regimen for dapsone has not been established. GENERAL DESCRIPTION METHODOLOGY: Ninety-six HIV-infected infants and children who are intolerant to trimethoprim / sulfamethoxazole ( TMP / SMX ) are randomized to receive oral dapsone either at 2 mg/kg once daily or at 4 mg/kg once weekly. Treatment continues until the last patient enrolled has received at least 3 months of therapy. Blood samples are drawn between weeks 4 and 8, at weeks 12 and 24, and every 3 months thereafter during dapsone administration. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Pneumocystis carinii pneumonia ( PCP ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Evidence of HIV infection. o Children 15 months of age and older must have a positive viral culture (blood or CSF) OR serum p24 antigen = or > 30 pg/ml OR two positive tests for HIV antibody by ELISA, with one test confirmed by Western blot. o Children younger than 15 months whose only laboratory evidence of HIV infection is a positive antibody test must also have a positive viral culture (blood or CSF) OR an AIDS-defining illness by CDC criteria. 2. Risk of developing PCP with prophylaxis requirement as defined in MMWR guidelines. 3. Known intolerance to TMP / SMX, such as occurrence of leukopenia, thrombocytopenia, or cutaneous reaction. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS IND 38,841 STUDY DESIGN Dose Comparison; Randomized; Open Label; 2-Arm PROTOCOL DETAILS STUDY INTENT: Drug prophylaxis, Drug safety, Pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 96 patients. PROTOCOL DETAILS ACTUAL ACCRUAL: 61/96 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 50 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Evidence of HIV infection. 2. Risk of developing PCP. 3. Known intolerance to TMP / SMX. 4. Consent of parent or guardian. Patients entering this study may be co-enrolled in other ACTG pediatric studies. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 8.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 5 x ULN mg/dl. (ULN = upper limit of normal.) PATIENT INCLUSION CRIT. SGPT(ALT): < 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophil count > 750 cells/mm3. Methemoglobin < 15 percent. PATIENT AGE AGE: 01 Months - 12 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Rifampin and rifampin derivatives for up to 1 week during the study. 2. Rifabutin or other drugs that could alter dapsone metabolism (if prescribed by the child's primary care physician). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: Serious or life-threatening reactions to TMP / SMX (e.g., anaphylaxis, Stevens-Johnson syndrome, hypotension) that would contraindicate therapy with sulfa drugs. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 29 Days. 13 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: RBC transfusion within 4 weeks prior to study entry. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior dapsone. 2. Rifampin, rifampin derivatives, or oxidant drugs within 1 week prior to study entry. 3. TMP / SMX within 7 days prior to study entry (and toxicity must be clearly resolving). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Rifampin, rifampin derivatives, or oxidant drugs for more than 1 week. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Glucose-6-phosphate dehydrogenase deficiency. 2. Known allergy to dapsone. SUBSTANCE IDENTIFICATION Drug 1 DRG-0036 Dapsone MANUFACTURERS Drug 1: Jacobus Pharmaceutical Company PO Box 5290 / 37 Cleveland Lane Princeton, NJ 08540 Contact: Dr David Jacobus (609) 921-7447 Contact: Dr Neil Lewis (609) 921-7447. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 2 mg/kg (maximum 100 mg/dose) once daily or 4 mg/kg (maximum 200 mg/dose) once weekly, for a minimum of 3 months SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral; 10 mg/5 ml syrup and 25 and 100 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: Minimum of 3 months. OTHER TREATMENT INFO. END POINT: Hematologic and dermatologic toxicity to dapsone. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Unacceptable toxicity. 2. Patient noncompliance related to failure to take study drug or keep scheduled appointments. 3. At the request of parent or guardian or at the discretion of ACTG, NIAID, FDA, investigator, or pharmaceutical sponsor. OTHER TREATMENT INFO. MODIFICATION: Special criteria have been determined for evaluation of hematologic, hepatic, allergic, and neurologic toxicities. Alternative explanations for clinical and laboratory toxicities should be sought prior to withholding study drug. If study drug is discontinued for toxicities attributed to other drugs, the study drug must be restarted within 14 days (for daily dose) or 18 days (for weekly dose), provided there is no contraindication. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Jacobus Pharmaceutical Company. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Child MESH HEADING Dapsone/*ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Drug Administration Schedule MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Pneumonia, Pneumocystis carinii/COMPLICATIONS/ *PREVENTION & CONTROL CAS REGISTRY NUMBER 80-08-0 (Dapsone) LAST REVISION DATE 941207 ENTRY MONTH 9207 ALABAMA University of Alabama at Birmingham School of Medicine 751 CHT / University Station Birmingham, AL 35294 Contact: Michael Cooney (205) 939-9552 Contact: beeper (205) 869-9524 OPEN 930203 ACTU: 5046. CALIFORNIA UCLA Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 930430 ACTU: 3601. CALIFORNIA Long Beach Memorial Medical Center / Pediatrics 10833 Le Conte Avenue Los Angeles, CA 90024-1752 Contact: Leslie Spring (310) 206-6369 OPEN 940513 ACTU: 3606. CALIFORNIA Los Angeles County USC Medical Center 1129 North State Street Los Angeles, CA 90033 Contact: Janice Ono (213) 226-3945 OPEN 931020 ACTU: 5048. CALIFORNIA University of CA San Diego Medical Center / Pediatric 9500 Gilman Drive / Clinical Sciences Bldg LaJolla, CA 92093-0672 Contact: Candace McIvor (619) 534-7170 OPEN 920702 ACTU: 4601. CALIFORNIA Children's Hospital Oakland 747 Fifty Second Street Oakland, CA 94609-1809 Contact: Jim Riddel (510) 428-3000 X 282Contact: (510) 539-6311 X PagOPEN 930402 ACTU: 4504. COLORADO University of Colorado Hlth Sciences Ctr / Peds Infect Dis 1056 East 19Th Avenue B055 Denver, CO 80218-1088 Contact: Carol Salbenblatt (303) 861-6751 OPEN 930408 ACTU: 7001. DISTRICT OF COLUMBIA Children's National Medical Center / Special Immuno Svc Suite 2108 / 111 Michigan Avenue NW Washington, DC 20010-2970 Contact: Sandra Jones (202) 884-3682 OPEN 930601 ACTU: 7101. DISTRICT OF COLUMBIA Howard University Hospital 2041 Georgia Avenue NW Washington, DC 20060 Contact: Dr Helga Finke (202) 865-1248 OPEN 921106 ACTU: 5044. FLORIDA Northeast Florida AIDS Program / Div of Pediatric Inf Dis/Im 653-1 W 8th Street Jacksonville, FL 32209 Contact: Michelle Eagle (904) 549-3051 OPEN 940909 ACTU: 5051. FLORIDA Univ of Miami School of Medicine / Pediatric Imm Infect Dis 1800 NW Tenth Avenue Miami, FL 33136 Contact: Janet Gourley (305) 548-4446 OPEN 940524 ACTU: 4201. GEORGIA Emory University Hospital 69 Butler Street SE Atlanta, GA 30303 Contact: Judy Sarver (404) 616-6227 Contact: clinic (404) 616-4390 Contact: beeper (404) 899-5290 OPEN 921021 ACTU: 5030. ILLINOIS University of Illinois at Chicago 840 S Wood Street Chicago, IL 60612 Contact: Patricia Naughton (312) 996-1778 OPEN 930727 ACTU: 5028. ILLINOIS Chicago Children's Memorial Hospital / Pediatric 2300 Childrens Plaza Box 20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 920702 ACTU: 4001. ILLINOIS Cook County Hospital / Childrens Memorial 2300 Childrens Plaza Box #20 Chicago, IL 60614-3394 Contact: Debbie Fonken (312) 880-4757 OPEN 921027 ACTU: 4002. ILLINOIS Wyler Children's Hospital 5841 South Maryland Avenue Chicago, IL 60637-1470 Contact: Kim Stieglitz (312) 702-6176 OPEN 940131 ACTU: 4003. LOUISIANA Tulane University School of Medicine / Div of Ped Infect Dis 1430 Tulane Avenue / PO Box SL37 New Orleans, LA 70112-2699 Contact: Jane Price (504) 585-7153 OPEN 920630 ACTU: 7201. MASSACHUSETTS Baystate Medical Center / Department of Pediatrics 759 Chestnut Street / SHU-Main 3 Springfield, MA 01199 Contact: MaryPat Toye (413) 784-5399 OPEN 920827 ACTU: 7302. MASSACHUSETTS University of Massachusetts Medical School / Dept of Peds 55 Lake Avenue North Worcester, MA 01655-0001 Contact: Joanne Shepard (508) 856-1692 OPEN 921022 ACTU: 7301. MASSACHUSETTS Children's Hospital 300 Longwood Avenue / Carnegie 3 Boston, MA 02115 Contact: Robert Bishop (617) 735-8198 OPEN 920630 ACTU: 2901. MASSACHUSETTS Boston City Hospital / Ped Infect Dis / Finland Lab 774 Albany Street / Finland Lab Room 301 Boston, MA 02118 Contact: Anne Marie Reagan (617) 534-5813 OPEN 920910 ACTU: 2903. MICHIGAN Children's Hospital of Michigan 3901 Beaubien Boulevard Detroit, MI 48201 Contact: Charnell Cromer (313) 745-5565 OPEN 930318 ACTU: 5041. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 930727 ACTU: 3201. NORTH CAROLINA Duke University Medical Center / Pediatrics Box 3499 Durham, NC 27710 Contact: John Swetnam (919) 684-6335 OPEN 930624 ACTU: 4701. NEW JERSEY Children's Hospital of New Jersey 15 South 9th Street / CHAP Program 5 East Newark, NJ 07107 Contact: George Donovan Mcsherry (201) 268-8273 OPEN 921215 ACTU: 2801. NEW JERSEY Children's Hospital of New Jersey 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan McSherry (201) 268-8273 OPEN 930420 ACTU: 2803. NEW JERSEY Robert Wood Johnson University Hospital / UMDNJ One Robert Wood Johnson Place CN19 New Brunswick, NJ 08903-0019 Contact: Ida Kechula (908) 937-7894 OPEN 930923 ACTU: 5032. NEW YORK Beth Israel Medical Center / Pediatrics First Avenue at 16th Street Dazian Pavilion Tenth Floor New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 920818 ACTU: 4302. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue / Pediatric New York, NY 10016 Contact: Nagamah Deygoo (212) 263-6426 OPEN 930128 ACTU: 4401. NEW YORK Memorial Hospital / Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021 Contact: Gloria Gilbert (212) 639-7169 OPEN 930727 ACTU: 2202. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 920818 ACTU: 1801. NEW YORK Mount Sinai School of Medicine / Pediatrics One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 940301 ACTU: 4301. NEW YORK Incarnation Children's Ctr / c/o Columbia Presb Med Ctr 142 Audubon Avenue New York, NY 10032 Contact: Pam Clark (212) 928-2228 OPEN 921222 ACTU: 4103. NEW YORK The Columbia Presbyterian Medical Hosp (Pediatric) 622 West 168th St Room 1161 New York, NY 10032-3796 Contact: Kathy A Shea (212) 305-7222 OPEN 921222 ACTU: 4101. NEW YORK Harlem Hospital 506 Lenox Avenue New York, NY 10037 Contact: Rick Urbano (212) 939-4040 Contact: (212) 939-4045 OPEN 920714 ACTU: 5006. NEW YORK Albert Einstein College of Medicine / Pediatrics 1300 Morris Park Avenue / Mazer Room 219 Bronx, NY 10461 Contact: Sarah Patterson (718) 430-2940 Contact: Clin (718) 918-5462 OPEN 920902 ACTU: 4901. NEW YORK North Shore University Hospital / Pediatric Immunology 350 Community Drive Manhasset, NY 11030 Contact: Cathy Macco (516) 773-7676 OPEN 930518 ACTU: 5010. NEW YORK Schneider Children's Hospital / Long Island Jewish Med Ctr 270-05 76th Avenue Room 235 / Div of Allergy and Immunology New Hyde Park, NY 11042 Contact: Debby Hickey (718) 470-3300 OPEN 920706 ACTU: 5001. NEW YORK King's County Hospital Center / SUNY HSCB 450 Clarkson Avenue Brooklyn, NY 11203 Contact: Helen Bergin (718) 245-3342 Contact: (718) 245-3341 Contact: (718) 245-4485 OPEN 930216 ACTU: 5035. NEW YORK SUNY Health Science Center at Stony Brook HSC T 15 080 Stony Brook, NY 11794-8111 Contact: Peggy Melendez (516) 444-1313 Contact: (516) 444-7692 Contact: beeper (516) 282-8808 Contact: Jeannie Conner (516) 444-2724 OPEN 920729 ACTU: 5040. NEW YORK SUNY Health Science Center at Syracuse 750 East Adams Street Syracuse, NY 13210 Contact: Kathie Shea-Contello (315) 464-6331 OPEN 921215 ACTU: 5039. NEW YORK University of Rochester Medical Center Box 689 / 601 Elmwood Avenue Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 921009 ACTU: 1101. OHIO Childrens Hospital of Cincinnati Eden and Bethesda Avenue Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 931021 ACTU: 2404. OTHER San Juan City Hospital / Puerto Rico Medical Center Department of Pediatrics Third Floor Hematology Rio Piedras, PR 00927 Contact: Esther Rosa (809) 764-3083 Contact: (809) 274-0904 OPEN 930216 ACTU: 5031. PENNSYLVANIA Children's Hospital of Philadelphia 34th Street & Civic Center Blvd Philadelphia, PA 19104-4399 Contact: Dr Deborah Schaible (215) 590-2097 Contact: Hospital Information (215) 590-1000 OPEN 921029 ACTU: 6701. PENNSYLVANIA Saint Christopher's Hospital for Children / Sect Imm & Rheum Erie Avenue at Front Street Philadelphia, PA 19134-1095 Contact: Carole Treston (215) 427-5284 Contact: FAX (215) 427-5555 OPEN 930805 ACTU: 6704. SOUTH CAROLINA Medical University of South Carolina Clinical Science Building / 171 Ashley Avenue Charleston, SC 29425-3312 Contact: Genny Connelly (803) 792-2385 OPEN 921112 ACTU: 5037. 60 UNIQUE IDENTIFIER NIH/00239 PROTOCOL ID NUMBERS NIAID ACTG 177 PROTOCOL TITLE Prophylaxis Against Mycobacterium Tuberculosis (MTb) in Patients Who Are Infected With the Human Immunodeficiency Virus (HIV) and Suspected or Confirmed Latent MTb Infection. VERSION NUMBER & DATE 4 (940630) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Chaisson R GENERAL DESCRIPTION PURPOSE: To evaluate and compare the safety and effectiveness of a one-year course of isoniazid (INH) versus a two-month course of rifampin plus pyrazinamide for the prevention of reactivation tuberculosis in individuals infected with both HIV and latent (inactive) Mycobacterium tuberculosis. GENERAL DESCRIPTION RATIONALE: Current guidelines from the American Thoracic Society and the Centers for Disease Control recommend 6 to 12 months of INH for PPD (purified protein derivative)-positive individuals. Although the effectiveness of this treatment is not known for HIV-infected individuals, several studies using INH to prevent tuberculosis in presumably normal hosts have shown 60 to 80 percent effectiveness. Problems with this treatment include compliance, adverse reaction, and the possibility of not preventing disease due to tuberculosis organisms being resistant to INH. A two-month preventive treatment plan should help in increasing compliance. In addition, the use of two drugs (rifampin / pyrazinamide) may help overcome problems with drug resistance. If this study shows equal or greater effectiveness of the two month rifampin / pyrazinamide treatment, it could alter the approach to tuberculosis prevention for both HIV-positive and HIV-negative individuals. GENERAL DESCRIPTION METHODOLOGY: Patients are chosen by a random selection process to either the INH or the rifampin / pyrazinamide arm of the dose. Patients on the INH arm receive 300 mg INH plus 50 mg vitamin B6 (pyridoxine) per day for 12 months. Patients on the other arm receive rifampin (450 - 600 mg/day) plus pyrazinamide (500 - 3000 mg/day) for 60 days. Dosage of rifampin and pyrazinamide depends on weight of patient. PROTOCOL PHASE Unspecified OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Tuberculosis. DISEASES STATUS Patients have the following symptoms and conditions: 1. Written documentation of positive antibody to HIV by federally licensed ELISA, confirmed by another method, such as Western blot, RIA, HIV culture. (If a prior diagnosis of AIDS has been established by CDC criteria, confirmatory test is not required.) 2. Positive PPD skin test (defined as = or > 5 mm induration to 5-TU of PPD using Mantoux method, to be read between 48 and 72 hours after application) but without evidence of active clinical tuberculosis: OR Documented history of a positive PPD skin test without subsequent treatment or prophylaxis with > 2 months of any antimycobacterial medication. (Note: While the optimal time for reading the PPD is between 48 and 72 hours, positive reactions beyond 72 hours are acceptable.) ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Prospective; Randomized; Comparative; Dose Comparison; Multicenter; Open Label; 2-Arm PROTOCOL DETAILS STUDY INTENT: Comparative drug therapy, Combination and single drug therapy, Drug efficacy, Drug safety, Drug prophylaxis. PROTOCOL DETAILS PROJECTED ACCRUAL: 2000 patients. This study is part of a larger collaborative CPCRA / ACTG study; total required is 2000 patients. Analysis is based on total 2000; ACTG PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Minimum of 24 months. PROTOCOL DETAILS ACTUAL ACCRUAL: 388/2000 (941207). PROTOCOL DETAILS STUDY DURATION: 72 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 73 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Current or documented history of positive PPD skin test. 3. Life expectancy of at least 6 months or, in the physician's opinion, patient has a reasonable chance of survival to end of study. Allowed: Participation in other clinical trials as long as there is no potential activity of other study drugs against Mycobacterium tuberculosis (MTb), additive toxicities between study agents, or known possible drug interactions between study drugs. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 8 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. ULN = upper limit of normal. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophil count > 750 cells/mm3. Alkaline phosphatase <= 5 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Abstinence or effective method of birth control / contraception including oral contraceptives during the study. Not pregnant. Negative pregnancy test within 30 days of study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Antiretroviral treatment. Pneumocystis carinii pneumonia prophylaxis. Treatment for acute opportunistic infection. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients may not have the following prior conditions: History of sensitivity / intolerance to any study medication. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Positive pregnancy test within 30 days of study entry. Pregnant. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Unwilling or unable to comply with the follow-up requirements of the protocol. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: More than 2 months of continuous treatment, after documentation of a positive PPD skin test, with agents that have known or potential antituberculous activity OR any antimycobacterial medication for > 1 month. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Treatment with quinolones, fluoroquinolones, aminoglycosides, or other agents that have activity against Mycobacterium tuberculosis. Excluded as ongoing (i.e., continuous, chronic and/or recurring) treatment: Aminoglycosides such as amikacin. Aminosalicylic acid salts (PAS). Capreomycin. Clofazimine. Cycloserine. Ethambutol. Ethionamide. Isoniazid (INH) if randomized to rifampin/pyrazinamide arm of study. Kanamycin. Pyrazinamide if randomized to INH arm of study. Quinolones and fluoroquinolones including but not limited to rifabutin, rifampin (if randomized to INH arm of study), ciprofloxacin, levofloxacin, ofloxacin, streptomycin, thiacetazone. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following conditions or symptoms are excluded: 1. Current active clinical tuberculosis, confirmed or suspected. 2. History of sensitivity / intolerance to any study medication. 3. Evidence of peripheral neuropathy, i.e., signs or symptoms of paresis, paresthesias, neuromotor abnormalities, or neurosensory deficits of grade 3 or worse. 4. Unwilling or unable to have current therapy and/or concomitant medication changed to avoid serious interaction with study medication. 5. Acute hepatitis. 6. Unable to comply with the follow-up requirements of the protocol. SUBSTANCE IDENTIFICATION Drug 1 DRG-0109 Rifampin SUBSTANCE IDENTIFICATION Drug 2 DRG-0125 Pyridoxine SUBSTANCE IDENTIFICATION Drug 3 DRG-0124 Pyrazinamide SUBSTANCE IDENTIFICATION Drug 4 DRG-0123 Isoniazid MANUFACTURERS Drug 1: Marion Merrell Dow Medical Information / PO Box 9627 Kansas City, MO 64134-0627 Contact: Medical Information (800) 633-1610. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Lederle Laboratories North Middletown Road Pearl River, NY 10965 Contact: Dr Amy Baim (914) 732-2147 Contact: Dr John Riefler (914) 732-2035. MANUFACTURERS Drug 4: Lannett Company Incorporated 9000 State Road Philadelphia, PA 19136 Contact: Vlad Mikijanic (215) 333-9000. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 450 - 600 mg/day for 60 days. Drug 2: 50 mg/day for 12 months. Drug 3: 500 - 3000 mg/day for 60 days. Drug 4: 300 mg daily for 12 months SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 450 - 600 mg. Drug 2: 50 mg. Drug 3: 500 - 3000 mg. Drug 4: 300 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 150 or 300 mg capsules. Drug 2: Oral, 50 mg tablets. Drug 3: Oral, 500 mg scored tablets. Drug 4: Oral, 300 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: Sixty days (rifampin + pyrazinamide) or 12 months (isoniazid + pyridoxine). OTHER TREATMENT INFO. END POINT: Primary end point: Time to development of confirmed active tuberculosis. Secondary end point: Combined end points of death and confirmed or probable clinical tuberculosis, toxicity from treatment, and laboratory findings. OTHER TREATMENT INFO. DISCONTINUE: Study drugs will be discontinued for the following: 1. Development of any confirmed or probable active pulmonary or extrapulmonary tuberculosis. 2. Development of severe clinical hepatitis due to study drug. 3. Development of Mycobacterium avium infection requiring continuous, chronic, or recurrent treatment with agents active in the treatment of tuberculosis, at the investigator's discretion. 4. Persistent or recurring severe study drug toxicity despite temporary drug discontinuation. OTHER TREATMENT INFO. MODIFICATION: For grade 3 hepatic toxicity: withhold study drug until toxicity resolves to baseline. For grade 4 hepatic toxicity: discontinue study drug. For grade 3 or 4 peripheral neuropathy: withhold study drug until toxicity resolves to grade 2 or lower. Restart study drug at investigator's discretion. For grade 2 rash: withhold study drug at the discretion of the investigator. For grade 3 or 4 rash: discontinue study drug. For grade 2 nausea or vomiting toxicity: withhold study drug until symptoms subside to grade 1 or lower. For grade 2 nausea or vomiting toxicity with laboratory evidence of transaminitis: withhold study drug and monitor symptoms and laboratory data. If signs and symptoms appear to be due to drug-induced hepatitis, discontinue study drug. For recurrent grade 2 nausea and vomiting: discontinue study drug. For grade 3 or 4 nausea or vomiting toxicity: withhold study drug until symptoms subside or resolve to baseline. For grade 3 or 4 nausea/vomiting related to drug-induced hepatitis, discontinue study drug permanently. For grade 2 or higher fever: withhold study drug until etiology of fever has been determined. If isoniazid (INH) is interrupted due to toxicity or other reasons, every effort should be made to have patient on the INH receive at least 6 reasonably continuous months of study drug. Multiple interruptions are permissible, and patients may receive INH beyond the first 12 months after randomization if this is required to complete 6 reasonably continuous months of study drug. If rifampin / pyrazinamide treatment is interrupted due to toxicity or other reasons, every effort should be made to have patients receive 60 days of study drug. Multiple interruptions are permissible and patients may receive rifampin / pyrazinamide beyond the first 2 months after randomization if necessary. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Lederle Laboratories, Marion Merrell Dow Research Institute. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antitubercular Agents/ADMINISTRATION & DOSAGE/ *THERAPEUTIC USE MESH HEADING Comparative Study MESH HEADING Drug Evaluation MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Isoniazid/ADMINISTRATION & DOSAGE/THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Multicenter Studies MESH HEADING Mycobacterium tuberculosis/DRUG EFFECTS MESH HEADING Opportunistic Infections/COMPLICATIONS/ PREVENTION & CONTROL MESH HEADING Pyrazinamide/ADMINISTRATION & DOSAGE/ THERAPEUTIC USE MESH HEADING Pyridoxine/ADMINISTRATION & DOSAGE/ THERAPEUTIC USE MESH HEADING Rifampin/ADMINISTRATION & DOSAGE/THERAPEUTIC USE MESH HEADING Tuberculosis/COMPLICATIONS/*PREVENTION & CONTROL CAS REGISTRY NUMBER 0 (Antitubercular Agents) CAS REGISTRY NUMBER 13292-46-1 (Rifampin) CAS REGISTRY NUMBER 54-85-3 (Isoniazid) CAS REGISTRY NUMBER 65-23-6 (Pyridoxine) CAS REGISTRY NUMBER 98-96-4 (Pyrazinamide) LAST REVISION DATE 941207 ENTRY MONTH 9112 ALABAMA University of Alabama at Birmingham 908 20th Street S / 1917 Research Clinic Room 135 Birmingham, AL 35294-2041 Contact: Susan Duncan (205) 934-3690 OPEN 940711 ACTU: 5801. CALIFORNIA Children's Hospital of Los Angeles / Children's AIDS Center 4650 Sunset Blvd / Mail Stop #54 Los Angeles, CA 90027 Contact: Antonieta Sosa (213) 669-2180 OPEN 941110 ACTU: 9916. CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 930427 ACTU: 1201. CALIFORNIA Harbor General / REI Lab / UCLA 1124 West Carson Street Torrance, CA 90502 Contact: Sally Kruger (310) 222-3848 Contact: Rick Johnson OPEN 911031 ACTU: 0603. CALIFORNIA Olive View Medical Center / Department of Medicine 14445 Olive View Drive / 2B182 Olive View Medical Center Sylmar, CA 91342 Contact: Betsy Manchester (818) 364-3205 OPEN 940513 ACTU: 0602. CALIFORNIA AIDS Community Research Consortium 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harris (415) 364-5653 OPEN 920902 ACTU: 0505. CALIFORNIA Santa Clara Valley Med Ctr / ACRC 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harriss (415) 364-5653 OPEN 920902 ACTU: 0506. CALIFORNIA San Francisco General Hospital / UCSF 995 Potrero Avenue / Building 80 Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 840OPEN 920911 ACTU: 0801. CALIFORNIA General Hospital / AIDS Clinical Trials Unit 995 Potrero Avenue / Bldg 80 / Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 846OPEN 920914 ACTU: 0808. CALIFORNIA Kaiser Permanente Medical Group / Stanford University 2590 Geary Boulevard San Francisco, CA 94115 Contact: Gretchen Van Raalte (415) 202-3482 OPEN 911031 ACTU: 0502. CALIFORNIA Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Contact: Virginia Tallman (415) 723-2804 Contact: Dr Rami Ramachandran (415) 723-6231 OPEN 920702 ACTU: 0501. CONNECTICUT Yale University School of Medicine / Sect of Infectious Dis 135 College Street New Haven, CT 06510-2483 Contact: Laurie Andrews (203) 737-4040 OPEN 920824 ACTU: 6401. DISTRICT OF COLUMBIA Georgetown University Medical Center Kober Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 OPEN 921224 ACTU: 5701. DISTRICT OF COLUMBIA HIV Center - DC General Hospital / Georgetown Univ Med Ctr Kober-Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 Contact: Fax (202) 687-6476 OPEN 930126 ACTU: 5703. DISTRICT OF COLUMBIA Whitman-Walker Clinic / Georgetown Univ Medical Center Kober-Cogan 110 / 3800 Reservoir Road NW Washington, DC 20007-2197 Contact: Karen Gammon (202) 687-1079 Contact: Fax (202) 687-6476 OPEN 931008 ACTU: 5702. DISTRICT OF COLUMBIA Howard U Coll of Med / AIDS Minority Infrastructure Program 2112 Georgia Avenue NW Washington, DC 20059 Contact: Victoria Holly -Trimmer (202) 806-4700 Contact: (202) 806-4755 OPEN 921215 ACTU: 5301. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue / Elliot Building First Floor Miami, FL 33136 Contact: Janie Reese (305) 547-3840 Contact: (305) 547-3838 OPEN 920506 ACTU: 0901. HAWAII Hawaii Aids Clinical Trails Unit Leahi Hospital / Young Bldg / 3675 Kilauea Avenue / 6th Flr Honolulu, HI 96816 Contact: Debra M Ogata Arakaki (808) 737-2751 OPEN 921215 ACTU: 5201. ILLINOIS Children's Memorial Hospital Family Clinic 303 East Superior Passavant Pavilion Room 823 Chicago, IL 60611 Contact: Baiba L Berzins RN (312) 908-9636 OPEN 911107 ACTU: 2704. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 911031 ACTU: 2701. ILLINOIS Louis A Weiss Memorial Hospital / Northwestern Univ Med Schl 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 941017 ACTU: 2708. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 920805 ACTU: 2702. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 940721 ACTU: 2601. MASSACHUSETTS Bay State Medical Center 759 Chestnut Street Springfield, MA 01199 Contact: Deborah Naglieri-Prescod (413) 784-3046 OPEN 920106 ACTU: 3002. MASSACHUSETTS New England Deaconess Hospital 185 Pilgrim Road Boston, MA 02215 Contact: Helen Fitch (617) 735-0785 OPEN 941020 ACTU: 0103. MARYLAND Johns Hopkins University / Infectious Diseases 1830 East Monument Street Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 911210 ACTU: 0201. MARYLAND State of Maryland Div of Corrections c/o Johns Hopkins Hosp 1830 East Monument Street / Room 8071 Baltimore, MD 21205 Contact: Becky Becker (410) 955-2898 OPEN 920304 ACTU: 0202. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 920313 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 920313 ACTU: 2102. NORTH CAROLINA Moses H Cone Memorial Hospital / University North Carolina 1200 North Elm Street Greensboro, NC 27401 Contact: Pam Mentley (910) 574-7888 OPEN 920228 ACTU: 3203. NORTH CAROLINA University of North Carolina at Chapel Hill 516 Burnett-Womack Building / CB #7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-6712 Contact: (919) 966-7883 OPEN 911126 ACTU: 3201. NORTH CAROLINA Wake County Department of Health Hosp South Room 0207 Box 3284 Durham, NC 27710 Contact: Kelley Rayle (919) 250-1035 OPEN 930607 ACTU: 3206. NEBRASKA University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-5130 Contact: Frances Tennant (402) 559-5750 OPEN 930720 ACTU: 1505. NEW JERSEY Children's Hospital of New Jersey 15 South 9th Street / CHAP Program 5 East Newark, NJ 07107 Contact: George Donovan Mcsherry (201) 268-8273 OPEN 930414 ACTU: 2801. NEW JERSEY Univ of Med & Dentistry of NJ / Univ Hospital 15 South Ninth Street Newark, NJ 07107-2198 Contact: George Donavan Mcsherry (201) 268-8273 OPEN 911202 ACTU: 2802. NEW YORK Beth Israel Medical Center ( Mount Sinai ) 16th Street at 1st Ave / 10Th Floor Dazian Pavilion New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 911202 ACTU: 1802. NEW YORK Bellevue Hospital / New York University Medical Center 550 First Avenue New York, NY 10016 Contact: Mary Ann Kiernan (212) 263-6565 OPEN 911031 ACTU: 0401. NEW YORK Saint Luke's Roosevelt Hospital 432 West 58th Street Antenucchi Building Lobby Level ANT 1 New York, NY 10019 Contact: Julie Linksman Rivera (212) 523-6743 CLOSED 930317 ACTU: 3401. NEW YORK St Clare's Hospital and Health Center 415 West 51st Street New York, NY 10019 Contact: Phyllis Ristau (212) 459-8449 OPEN 920729 ACTU: 2204. NEW YORK Cornell University Medical Center 525 East 68th Street / Room 2434 New York, NY 10021 Contact: Brenda Greenhill (212) 746-4177 OPEN 911031 ACTU: 2201. NEW YORK Memorial Hospital / Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021 Contact: Glennon Stutterer (212) 639-7161 OPEN 921221. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 911202 ACTU: 1801. NEW YORK Columbia Presbyterian Medical Center 622 West 168 Street / Harkness Pavilion 5 Room 516 New York, NY 10032-3784 Contact: Mykyelle Wade (212) 305-8507 OPEN 940311 ACTU: 7501. NEW YORK Montefiore Drug Treatment Center 418 Forchheimer-ID / 1300 Morris Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3639 Contact: (718) 920-5344 OPEN 911113 ACTU: 1905. NEW YORK North Central Bronx Hospital / Montefiore Family Health Cntr 418 Forchheimer-ID/1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 911113 ACTU: 1906. NEW YORK North Central Bronx Hospital / Samaritan Village Inc 418 Forchheimer ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 911113 ACTU: 1907. NEW YORK Comprehensive Health Care Center 418 Forchheimer-ID / 1300 Morris Park Ave Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 940418 ACTU: 1908. NEW YORK Albert Einstein College of Medicine 418 Forcheimer / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 911113 ACTU: 1904. NEW YORK Montefiore Medical Center / Albert Einstein College of Med 418 Forchheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 911113 ACTU: 1903. NEW YORK Bronx Municipal Hospital / Albert Einstein College of Med Forchheimer 418 / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 Contact: (718) 920-5344 OPEN 911107 ACTU: 1901. NEW YORK Jack Weiler Hospital / Albert Einstein College of Med 418 Fochheimer-ID / 1300 Morris Park Avenue Bronx, NY 10461 Contact: Nahla Mohamed (718) 430-3659 OPEN 911031 ACTU: 1902. NEW YORK Montefiore Medical Center / Adolescent AIDS Program 111 East 210th Street / NW674 Bronx, NY 10467 Contact: Dina Monte (718) 882-0023 OPEN 921224 ACTU: 4903. NEW YORK North Shore University Hospital 300 Community Drive Manhasset, NY 11030 Contact: Patricia Gemma (516) 562-1528 OPEN 930329 ACTU: 2203. NEW YORK SUNY Health Sciences Center at Brooklyn ACTU Box 77 / 450 Clarkson Avenue Brooklyn, NY 11203-2098 Contact: Donald Smith (718) 270-3372 Contact: (718) 270-3370 OPEN 920603 ACTU: 5901. NEW YORK City Hospital at Elmhurst / Mt Sinai 79-01 Broadway Room D1-29 Elmhurst, NY 11373 Contact: Dinah Reitman (718) 334-3963 OPEN 920310 ACTU: 1803. NEW YORK Nassau County Medical Center 2201 Hempstead Turnpike East Meadow, NY 11554 Contact: Ann M Gardner (516) 542-5707 Contact: (516) 542-5414 OPEN 911031 ACTU: 3302. NEW YORK SUNY at Stony Brook Health Sciences Center T 15 080 Stony Brook, NY 11794-8153 Contact: Ruth Ann Burk (516) 444-1658 Contact: Dr Roy Steigbigel (516) 444-1660 Contact: Dr Benjamin Luft (516) 444-1660 OPEN 911105 ACTU: 3301. NEW YORK Adirondack Medical Center at Saranac Lake 47 New Scotland Avenue Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930819 ACTU: 7403. NEW YORK Mid-Hudson Care Center / Albany Med College / Div Med Oncol 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930819 ACTU: 7402. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 930727 ACTU: 7401. NEW YORK SUNY Health Science Center / Dept of Medicine 750 East Adams Street / Rm 1254-WH Syracuse, NY 13210 Contact: Linda Brasington (315) 464-5533 OPEN 920122 ACTU: 1103. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 920805 ACTU: 1102. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 911031 ACTU: 2301. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 921009 ACTU: 2501. OHIO Metrohealth Medical Center / Case Western Reserve Univ 2500 MetroHealth Drive Cleveland, OH 44109-1998 Contact: Nancy Frantz (216) 459-5136 OPEN 930603 ACTU: 2503. OHIO University of Cincinnati School of Medicine Eden and Bethesda Avenue / AIDS Clinical Trials Cincinnati, OH 45267-0405 Contact: Jill Leonard (513) 558-6977 OPEN 930301 ACTU: 2401. OTHER University of Puerto Rico / Schl of Med / Inf Dis Sec / ACTU G P O Box 365067 San Juan, PR 00936-5067 Contact: Maritza Cruz-Ortiz (809) 767-9192 Contact: (809) 767-9193 OPEN 930618 ACTU: 5401. PENNSYLVANIA University of Pennsylvania / Div of Infectious Diseases 549 Johnson Pavillion / 6073 / 36th and Hamilton Walk Philadelphia, PA 19104-6073 Contact: Debora Dunbar (215) 349-8092 OPEN 920603 ACTU: 6201. PENNSYLVANIA University of Pennsylvania / Girard Medical Center 549 Johnson Pavillion/6073 / 36th and Hamilton Walk Philadelphia, PA 19104-6073 Contact: Debora Dunbar (215) 349-8092 OPEN 921113 ACTU: 6203. PENNSYLVANIA Thomas Jefferson Unversity 1015 Chestnut Street Philadelphia, PA 19107 Contact: Lyle Jew (215) 955-7785 OPEN 920721 ACTU: 6202. SOUTH CAROLINA Medical University of SC / Infect Diseases Division 807 CSB 171 Ashley Avenue Charleston, SC 29425 Contact: Denise Taylor (803) 782-6174 OPEN 921215 ACTU: 3205. 61 UNIQUE IDENTIFIER NIH/00403 PROTOCOL ID NUMBERS NIAID ACTG 149 PROTOCOL TITLE Phase II Study of G-CSF Plus ABVD (Adriamycin / Bleomycin / Vinblastine / Dacarbazine) in the Treatment of HIV-Associated Hodgkin's Disease. VERSION NUMBER & DATE 3 (940419) Final TRIAL CATEGORY AIDS-Related Malignancies TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Levine A GENERAL DESCRIPTION PURPOSE: Primary: To assess the toxicity of chemotherapy with ABVD (doxorubicin / bleomycin / vinblastine / dacarbazine) when given with granulocyte colony-stimulating factor (G-CSF) in patients with underlying HIV infection and Hodgkin's disease; to observe the efficacy of ABVD and G-CSF in reducing tumor burden in HIV-infected patients with Hodgkin's disease. Secondary: To determine the durability of tumor response to ABVD plus G-CSF over the 2-year study period; to observe the incidence of bacterial and opportunistic infections in HIV-infected patients with Hodgkin's disease receiving this regimen; to document quality of life of patients receiving this regimen. GENERAL DESCRIPTION RATIONALE: Addition of granulocyte colony-stimulating factor may prevent neutropenia caused by chemotherapy, allowing more timely administration of chemotherapy and improved response. GENERAL DESCRIPTION METHODOLOGY: Study drugs are administered in 28-day cycles to twenty-seven HIV-infected patients with Hodgkin's disease. ABVD (doxorubicin / bleomycin / vinblastine / dacarbazine) is administered on days 1 and 15 of each cycle, and granulocyte colony-stimulating factor (G-CSF) is given on days 2 through 14 and 16 through 28 of each cycle. All patients receive four cycles of treatment and are then restaged. Patients with a complete response (CR) following the initial four cycles receive two additional cycles of ABVD / G-CSF. Patients with a partial response following the initial four cycles receive two additional cycles of ABVD / G-CSF and are again restaged; those who have achieved a CR at that point then receive two more cycles, while those without CR discontinue study therapy. Patients with disease progression following the initial four cycles of therapy discontinue treatment on the study. Concomitant PCP prophylaxis is administered. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941207) DISEASE STUDIED Hodgkin's Disease. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by ELISA, HIV culture, or p24 antigen capture assay, or prior diagnosis of AIDS by 1987 CDC definition documented by medical records. 2. Pathologic diagnosis of measurable Hodgkin's disease (any stage) previously untreated by chemotherapy or radiotherapy. ELIGIBILITY ASYM / OTHER. AIDS / OTHER. ARC / OTHER. OTHER PROTOCOL NUMBERS BB IND 4220 STUDY DESIGN Multicenter; Open Label; Nonrandomized PROTOCOL DETAILS STUDY INTENT: Combination drug therapy, Drug efficacy, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 27 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Minimum 4 months. PROTOCOL DETAILS ACTUAL ACCRUAL: 15/27 (941207). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 13 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection or diagnosis of AIDS. 2. Hodgkin's disease. 3. Consent of parent or guardian and have care directly supervised by a pediatric oncologist if under 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. GRANULOCYTES: > 1000 cells/mm3. (No hematologic criteria applicable if bone marrow involvement with tumor). PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. (No hematologic criteria applicable if bone marrow involvement with tumor). PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE: < 2.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 60 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: LVEF > 50 (in patients who undergo MUGA scan). PATIENT AGE AGE: 12 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. Not breast-feeding. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Cranial irradiation (2400 rads) for patients with CNS involvement. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Maintenance therapy for opportunistic infections. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: PCP prophylaxis consisting of Bactrim, aerosolized pentamidine, or dapsone. Recommended: Antiemetic therapy within 30 minutes of chemotherapy. Allowed: 1. Antiretroviral medication after two cycles of chemotherapy, provided the patient has not experienced grade 3 neutropenia while on chemotherapy or on previous antiretroviral therapy. 2. Acetaminophen and/or nonsteroidal anti-inflammatory agents. 3. Bone marrow-suppressive agents, such as ganciclovir, Fansidar, Bactrim, and dapsone. 4. Maintenance therapy for chronic opportunistic infection. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 11 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. No abstinence or no agreement to use effective method of birth control / contraception during the study. Breast-feeding. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Prior radiotherapy for Hodgkin's disease. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior chemotherapy for Hodgkin's disease. 2. Antiretroviral therapy within 2 weeks prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Second primary cancer other than Kaposi's sarcoma that does not require systemic therapy, nonmelanomatous skin cancer, Bowen's disease, or carcinoma in situ of the cervix. 2. Acute, active bacterial or opportunistic infection requiring ongoing therapy if such therapy has been initiated within the past 2 weeks. 3. Known hypersensitivity (e.g., anaphylactoid reaction, brochospasm) to E. coli-derived proteins. PATIENT EXCLUSION CRIT. AVAILABILITY: Not accessible for scheduled treatment or follow-up visits. SUBSTANCE IDENTIFICATION Drug 1 DRG-0047 Doxorubicin SUBSTANCE IDENTIFICATION Drug 2 DRG-0045 Bleomycin SUBSTANCE IDENTIFICATION Drug 3 DRG-0134 Vinblastine SUBSTANCE IDENTIFICATION Drug 4 DRG-0135 Dacarbazine SUBSTANCE IDENTIFICATION Drug 5 DRG-0086 Granulocyte colony-stimulating factor TRADE NAME OF SUBSTANCE Drug 1‰ Adriamycin TRADE NAME OF SUBSTANCE Drug 2‰ Blenoxane TRADE NAME OF SUBSTANCE Drug 3‰ Velban TRADE NAME OF SUBSTANCE Drug 4‰ DTIC TRADE NAME OF SUBSTANCE Drug 5‰ Neupogen MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. MANUFACTURERS Drug 4: Drugs are provided by each participating unit site. MANUFACTURERS Drug 5: Amgen Incorporated 1840 DeHavilland Drive Thousand Oaks, CA 91320-1789 Contact: Mark Davis (805) 499-5725 X 4142. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 25 mg/m2 on days 1 and 15 for four cycles. Drug 2: 10 mg/m2 (10 units/m2) on days 1 and 15 for four cyclesDrug 3: 6 mg/m2 on days 1 and 15 for four cycles. Drug 4: 375 mg/m2 on days 1 and 15 for four cycles. Drug 5: 5 mcg/kg on days 2 through 14 and 16 through 28 for foucycles SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 25 mg/m2. Drug 2: 10 mg/m2 (10 units/m2). Drug 3: 6 mg/m2. Drug 4: 375 mg/m2. Drug 5: 5 mcg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: IV, 10 and 50 mg vials. Drug 2: IV, 15-unit vials. Drug 3: IV, 10 mg vials. Drug 4: IV, 100 and 200 mg vials. Drug 5: SC OTHER TREATMENT INFO. TREATMENT DURATION: Minimum 4 months. OTHER TREATMENT INFO. END POINT: Primary: Dose-limiting toxicity; degree of response to chemotherapy. Secondary: Durability of response or disease progression; rate of bacterial and opportunistic infection. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for any of the following reasons: 1. Unacceptable toxicity. 2. Documented complete response followed by two cycles of study treatment. 3. Documented partial response after six cycles of study treatment. 4. Disease progression at any time. 5. Clinical congestive heart failure or a decrease in left ventricular ejection fraction of 0.20 or to < 0.45. 6. Pregnancy. 7. Desire of patient to withdraw. OTHER TREATMENT INFO. MODIFICATION: Patients with bone marrow involvement should receive no more than 75 percent of the full chemotherapy dose during the first cycle. Hematologic toxicity: For ANC < 1000/mm3 on day 1 of a cycle, hold chemotherapy 1 week and continue G-CSF. For ANC < 1000/mm3 on day 15, hold chemotherapy 1 week and begin G-CSF at 10 mcg/kg/day. G-CSF may be increased to 15 - 20 mcg/kg/day, at the discretion of the investigator, if ANC remains < 1000/mm3. Discontinue G-CSF when ANC > 10000/mm3. For platelets < 100000/mm3, hold chemotherapy for 1 week unless values are caused by bone marrow involvement; if platelets are 75000 to < 100000/mm3 after 1 week, resume doxorubicin and vinblastine at 75 percent dose for the next cycle. If platelets are 50000 - < 75000/mm3 after 1 week, resume doxorubicin and vinblastine at 50 percent dose for the next cycle. When platelets are 100000 or higher, resume chemotherapy at full dose. Hepatic toxicity: For bilirubin 1.5 to < 3.0 mg/dl, reduce doxorubicin and vinblastine doses to 50 percent of previous dose. For bilirubin 3.0 mg/dl or higher, reduce doxorubicin and vinblastine to 25 percent of original dose; if toxicity does not resolve in 1 week, discontinue study medications. Renal toxicity: If creatinine increases to 2.5 mg/dl or higher or creatinine clearance decreases to 60 ml/min or less, discontinue study medications. Discontinue study medications for any of the following conditions: Grade 3 or worse peripheral neuropathy, pulmonary symptoms thought to be caused by toxicity, and grade 3 cardiac toxicity. SUPPORTING AGENCY National Institute of Allergy & Infectious Diseases (ACTG), Amgen Incorporated. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antineoplastic Agents, Combined/*THERAPEUTIC USE MESH HEADING Bleomycins/*THERAPEUTIC USE MESH HEADING Dacarbazine/*THERAPEUTIC USE MESH HEADING Doxorubicin/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Granulocyte Colony-Stimulating Factor/ *THERAPEUTIC USE MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Hodgkin's Disease/COMPLICATIONS/*DRUG THERAPY/ THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Vincristine/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antineoplastic Agents, Combined) CAS REGISTRY NUMBER 0 (ABVD protocol) CAS REGISTRY NUMBER 62683-29-8 (Granulocyte Colony-Stimulating Factor) LAST REVISION DATE 941207 ENTRY MONTH 9202 CALIFORNIA Kenneth Norris Cancer Hospital / LAC-USC 2020 Zonal Avenue Room 309 Los Angeles, CA 90033 Contact: Luis Mendez (213) 343-8288 OPEN 920625 ACTU: 1203. CALIFORNIA University of Southern California / LAC-USC Medical Center Bldg 5P21 / 1175 N Cummings Street / Room 349 Los Angeles, CA 90033-1079 Contact: Luis Mendez (213) 343-8288 OPEN 920508 ACTU: 1201. ILLINOIS Northwestern University Medical School / ACTG Studies 303 East Superior Street Passavant 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 920702 ACTU: 2701. ILLINOIS Illinois Masonic Med Ctr / Northwestern Univ Med Schl Passavant Pavilion Room 823 / 303 East Superior Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 941125 ACTU: 2707. INDIANA Indiana University Hospital 550 North University Boulevard Indianapolis, IN 46202-5250 Contact: Beth Zwickl (317) 274-8456 OPEN 930518 ACTU: 2601. MASSACHUSETTS Boston City Hospital / AIDS Research Office 818 Harrison Avenue ACC 5th Floor Room 5D11 Boston, MA 02118 Contact: Beverly Byam (617) 534-5160 CLOSED 930730 ACTU: 0104. MISSOURI Washington University School of Medicine 4511 Forest Park Pkwy Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0538 Contact: (314) 454-0058 OPEN 920218 ACTU: 2101. MISSOURI St Louis Regional Hospital 5535 Del Mar / 6Th Floor West Annex St Louis, MO 63112 Contact: Michael Conklin (314) 879-6411 OPEN 920218 ACTU: 2102. NEW YORK Saint Luke's Roosevelt Hospital 432 West 58th Street Antenucchi Building Lobby Level ANT 1 New York, NY 10019 Contact: Julie Linksman Rivera (212) 523-6743 CLOSED 930317 ACTU: 3401. NEW YORK Mount Sinai School of Medicine / Clinical Trials PO Box 1042 One Gustave L Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: (212) 241-7856 OPEN 920508 ACTU: 1801. NEW YORK SUNY at Buffalo 462 Grider Street / BB109 Buffalo, NY 14215 Contact: Michelle Lewis (716) 898-3932 Contact: (716) 898-3933 OPEN 921009 ACTU: 1102. OHIO Children's Hospital 700 Children's Drive Columbus, OH 43205-2696 Contact: Jane Hunkler (614) 722-4460 Contact: (614) 722-6050 OPEN 940106 ACTU: 2302. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN ACTU: 2301. 62 UNIQUE IDENTIFIER NIH/00137 PROTOCOL ID NUMBERS NIAID ACTG 103 PROTOCOL TITLE A Randomized Trial To Evaluate the Impact of Maintaining Steady-State Concentrations of Azidothymidine (AZT) Versus an Intermittent Schedule of AZT Delivery in Children With Symptomatic HIV Infection. AMENDED: ddI Arm Removed, Open Only to Children With Encephalopathy. VERSION NUMBER & DATE 2 (930707) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Nationwide Access TRIAL CATEGORY Child TRIAL CATEGORY Neurologic Manifestations PROTOCOL CHAIRS CHAIR Pizzo PA GENERAL DESCRIPTION PURPOSE: AMENDED 07/07/93: To evaluate whether continuous infusion AZT will impact neurodevelopmental deficits associated with HIV infection or alter rate of encephalopathy progression in children who have failed to improve or shown progression of these deficits despite optimal AZT therapy. AMENDED: To assess whether didanosine (ddI) will be better tolerated than AZT administered by either continuous intravenous deliver or oral administration (ddI arm removed per amended version). To determine whether ddI will achieve comparable clinical efficacy as the continuous intravenous route of delivery of AZT, and to assess whether either or both of these regimens are superior to that achieved with an intermittent AZT dosage schedule. To determine whether there are differences in patient or parent (guardian) compliance between the three treatment regimens. Original design: To determine whether the pharmacokinetic profile (bloodstream levels) of zidovudine (AZT) influences its effectiveness on HIV infection in children. That is, the study seeks to find out whether there is a difference in the effect of AZT when given as a continuous intravenous infusion (and, if available, an oral sustained release dose) compared to an intermittent (not continuous) dose given orally every 6 hours. The study also plans to determine (1) whether there are differences in the tolerance and side effects associated with AZT when given on an intermittent schedule as opposed to a steady-state schedule; (2) the extent of variation from patient to patient in AZT levels and whether the plasma and cerebrospinal fluid levels of AZT are related to the degree of therapeutic effectiveness; and (3) whether there are differences in the response of children who acquired HIV infection perinatally (just before, during, or just after the time of birth) versus those who acquired HIV infection by transfusion. GENERAL DESCRIPTION RATIONALE: One of the most serious effects of HIV disease in children is neuropsychological deterioration (relating to mental and nervous system functioning). This complication affects the vast majority of HIV infected children. A previous study of continuous intravenous administration of AZT in pediatric patients with HIV infection showed consistent and dramatic improvements of symptoms in all patients that had shown neurodevelopmental deficits or abnormalities. These improvements were seen within 3 to 4 weeks after AZT treatment was started. Neurodevelopmental improvements have been sustained on AZT, usually showing steady improvement which, in some patients, was associated with restoration of pre-HIV intellectual and neurological function. This study also showed an increase in the IQ scores of children receiving continuous infusion of AZT who did not have overt clinical evidence of encephalopathy (disease of the brain). Thus changes in cognitive function may be among the earliest signs of AIDS encephalopathy and underscores the need to start therapies that will treat the central nervous system in patients who appear to be clinically intact. A study comparing continuous infusion to intermittent dosing of AZT showed a significant increase in IQ scores for those children receiving the continuous dose compared to those treated with the intermittent schedule. Although a portable infusion pump allows patients to receive continuous infusion of AZT, a sustained release oral formulation that could provide a continuous release of AZT into the bloodstream would be highly desirable. GENERAL DESCRIPTION METHODOLOGY: AMENDED 07/07/93: Children with progressive encephalopathy who have received a minimum of 3 months of oral or intermittent AZT or who have failed to improve following 6 months of optimal AZT will receive continuous infusion AZT via a protable infusion pump. AMENDED: The oral sustained relase has been dropped and is now oral ddI 90 mg/m2 q8h. Added has been a planned stratification for randomization for patients who received any antiretroviral therapy 4 or more weeks prior to study entry. The informed consent was modified to reflect ddI toxicities from adult studies. Computerized Tomography radiation dosimetry is now included. AMENDED: DROPPING the DDI component and open only to CHILDREN WITH ENCEPHALOPATHY meaning they are losing milestones, this is equal to a P2 CDC rating . Testing the difference in INTERMEDIATE VS CONTINUOUS AZT. 12/1990. Original design: Children are first evaluated for randomization according to whether they have or do not have evidence of neurodevelopmental deficits at the time of the initial pretreatment evaluation. Patients are assigned to one of three groups, to receive AZT (1) by continuous infusion; (2) by oral, intermittent (every 6 hours) dosing; or (3) by oral sustained-release dosing. If the oral sustained-release formulation is not available when this study begins, it will begin with only the first two groups. The sustained release preparation will be evaluated as soon as it is available. Patients will be tested to measure physical or biological improvement in neurodevelopmental function. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940425) DISEASE STUDIED Primary HIV infection, Encephalopathy. DISEASES STATUS AMENDED 07/07/93: Only HIV-related encephalopathy patients eligible (i.e., children with progressive encephalopathy who have received a minimum of 3 months of oral or intermittent AZT or who have failed to improve following 6 months of optimal AZT). ORIGINAL DESIGN: AIDS: Children must have clinical evidence of HIV infection as demonstrated by the presence of one or more of the definitively or presumptively diagnosed indicator diseases as defined in the CDC Surveillance definition of AIDS. Children with lymphocytic interstitial pneumonitis are included if they meet at least one of the following conditions: (1) an additional AIDS-defining opportunistic infection; (2) recurrent serious bacterial infections; (3) evidence of HIV encephalopathy; (4) a wasting syndrome; or (5) meet the definition of AIDS-related complex (ARC) as follows: ARC: At least one of the first three clinical findings and any other listed below within 2 months of study entry (or with two of the first three findings): 1. Failure to thrive defined as child who crosses (falls) two percentile lines on the growth chart, or a child who is in less than the fifth percentile for height and weight and does not follow their growth curve. 2. Persistent (= or > 2 months) or recurrent oral candidiasis despite appropriate therapy. 3. CD4+ = or < 500 cells. Additional clinical findings: o Diarrhea (= or > 3 loose stools/day) that is either persistent (> 3 months) or recurrent (= or > 2 episodes resulting in dehydration within a 2-month period). o Hepatomegaly. o Splenomegaly. o Cardiomyopathy. o Nephropathy manifested by nephrotic syndrome without evidence of renal failure. o Two or more episodes of herpes stomatitis within a 1-year period. o Two or more episodes of recurrent herpes zoster or chronic zoster defined at = or > 30 days duration regardless of therapy. Children < 15 months of age, who are thought to have acquired HIV through perinatal transmission and whose only laboratory evidence of HIV infection is a positive antibody test, must also have increased immunoglobulin levels or decreased absolute number of CD4 cells or a decreased helper/suppressor ratio. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS NCI 89 C-102C STUDY DESIGN Open Label; Prospective; Randomized PROTOCOL DETAILS STUDY INTENT: Drug therapy, Administration route comparison. PROTOCOL DETAILS PROJECTED ACCRUAL: 75 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 52 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 4/75 (931027). PROTOCOL DETAILS DATE OF FIRST ENROLLMENT: 900321 PROTOCOL DETAILS STUDY DURATION: 52 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 7 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: AMENDED 07/07/93: Only HIV-related encephalopathy patients eligible (i.e., children with progressive encephalopathy who have received a minimum of 3 months of oral or intermittent AZT or who have failed to improve following 6 months of optimal AZT). ORIGINAL DESIGN: Eligibility criteria used are similar to those being used in the Multicenter Trial to Evaluate Oral Retrovir in the Treatment of Children with Symptomatic HIV Infection, currently Protocol 88 C-92a. Children are included: With overt encephalopathy as well as those who may have a subclinical cognitive impairment. Children must have laboratory evidence of HIV infection as demonstrated by either a positive viral culture (blood or cerebrospinal fluid) or detectable serum P24 antigen or repeatedly positive test for HIV antibody. HIV antibody must be determined by federally licensed ELISA test and confirmed by Western blot. Children with AIDS or ARC must have at least one of the following laboratory criteria indicative of immunologic abnormality: o Hypergammaglobulinemia (IgG or IgA) defined as immunoglobulin values > upper limit of the age-adjusted normal. o Hypogammaglobulinemia (IgG or IgA) defined as immunoglobulin levels < lower limit of the age-adjusted normal. o Absolute depression in CD4+ cells to = or < 500 cells/mm3. o Decreased helper/suppressor ratio to = or < 1.0. o Depressed in vitro mitogen response to at least one antigen (pokeweed, phytohemagglutinin, concanavalin A, Staphylococcus aureus, tetanus toxoid, Candida). Parent or guardian available to give written informed consent. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: >= 24 percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. In presence of abnormal bilirubin (age adjusted). PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. Estimated. PATIENT INCLUSION CRIT. OTHER: White blood cells (WBC) >= 1500 cells/mm3. Neutrophil count >= 750 cells/mm3. PATIENT AGE AGE: 03 Months - 12 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Pubertal females should be screened for pregnancy. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed within 4 weeks of study entry: Immunoglobulin for thrombocytopenia. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Steroids for children with lymphocytic interstitial pneumonitis (LIP) who are steroid dependent. Maintenance amphotericin B and antituberculosis chemotherapy. Immunoglobulin therapy for children who develop at least three serious bacterial infections while receiving zidovudine (AZT) therapy. Prophylactic therapy for children who have had a previous episode of Pneumocystis carinii pneumonia (PCP) and who are receiving such therapy. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following are excluded: Serious bacterial, fungal, or parasitic infections requiring parental therapy, at the time of study entry. Lymphocytic interstitial pneumonitis (LIP) and no additional AIDS-defining indicator disease as specified in the CDC Surveillance Case Definition for AIDS. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 2 Months. 13 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Unspecified. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Excluded: Active alcohol or drug abuse. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within 4 weeks of study entry: Lymphocyte transfusion for immune reconstitution. Excluded within 3 months of study entry: Bone marrow transplant. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 4 weeks of study entry: Other antiretroviral agents including ribavirin, HPA-23, dideoxycytosine (ddC), soluble CD4, and dideoxyadenosine (ddA) / didanosine (ddI). Immunomodulating agents including steroids, interferon, isoprinosine, and IL-2 not specifically allowed. Immunoglobulin not specifically allowed. Excluded within 2 weeks of study entry: Any other experimental therapy. Drugs that cause prolonged neutropenia or significant nephrotoxicity. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Clofazimine, ansamycin (or other experimental agents or agents that may modify zidovudine (AZT) toxicity or safety) for active chronic opportunistic infection at time of study entry. Chronic use of drugs that are metabolized by hepatic glucuronidation (and may alter the metabolism of AZT) (e.g., aetaminophen). Prophylaxis for Pneumocystis carinii pneumonia (PCP) for children who have not had a previous episode of PCP, oral candidiasis, or otitis media. Immunoglobulin therapy not specifically allowed. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following are excluded: Serious bacterial, fungal, or parasitic infections requiring parental therapy, at the time of study entry. PATIENT EXCLUSION CRIT. AVAILABILITY: Excluded: Unable to be followed for the duration of the study (24 weeks). SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0016 Didanosine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir TRADE NAME OF SUBSTANCE Drug 2‰ Videx MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Lisa Behrens (800) 722-9292 X 3633. MANUFACTURERS Drug 2: Bristol-Myers Squibb Company 2400 West Lloyd Expressway Evansville, IN 47721-0001 Contact: DDI Information (800) 662-7999. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Arm 1: 480 mg/m2/day or 20 mg/m2/hour. Arm 2: 180 mg/m2. Arm 3: Pending additional data. (AMENDED: ddI substitute). Drug 2: 90 mg/m2 q8h SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: Arm 1: 480 mg/m2. Arm 2: 720 mg/m2. Arm 3: Pending additional data. (AMENDED: ddI substitute). Drug 2: 180 mg/m2 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Arm 1: Intravenous, via portable, programmable infusionpump. Drug 2: Oral OTHER TREATMENT INFO. TREATMENT DURATION: Drug 1: 24 weeks, minimum. Drug 2: 24 weeks. OTHER TREATMENT INFO. END POINT: Evaluation of neurodevelopmental system; comparative changes in other measures of efficacy and toxicity. OTHER TREATMENT INFO. DISCONTINUE: Discontinue treatment for the following: Severe allergic reaction such as exfoliative erythroderma, anaphylaxis, or vascular collapse. Noncompliance: Not adhering to the dosing plan or failing to keep three scheduled consecutive clinical appointments. Requiring a cumulative total of 25 red blood cell transfusions or neutropenia (< 500 pmns) after two dose reductions (i.e., 50 percent of the original dosage). Requiring treatment with an experimental agent or another drug with known antiretroviral activity. OTHER TREATMENT INFO. MODIFICATION: For grade 3 or 4 hematologic toxicity: Reduce dose by approximately 25 percent following temporary discontinuation of zidovudine (AZT). For progressive bone marrow suppression and grade 3 or 4 toxicity as defined below: Temporarily withhold drug until hematologic parameters stabilize. For hemoglobin levels that fall to < 8 g/dl: transfuse. Withhold AZT: For transfusion dependence > 4 weeks. For a decrease in neutrophil count to < 500 cells/mm3 on two consecutive determinations 24 hours apart. For decrease in platelet count to = or < 25000 platelets/mm3. Resume therapy at 25 percent dose reduction once hematologic abnormalities return to baseline. Increase to original level if these baseline levels are stable for 1 month after dose reduction. SUPPORTING AGENCY National Cancer Institute Pediatric Intramural Studies, National Institute of Allergy & Infectious Diseases (ACTG). MESH HEADING Acquired Immunodeficiency Syndrome/ COMPLICATIONS/*DRUG THERAPY MESH HEADING Central Nervous System Diseases/*DRUG THERAPY/ ETIOLOGY MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Female MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Randomized Controlled Trials MESH HEADING Zidovudine/*ADMINISTRATION & DOSAGE/ PHARMACOKINETICS/THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 940425 ENTRY MONTH 8909 DISTRICT OF COLUMBIA Children's Hospital National Medical Center 111 Michigan Avenue NW Washington, DC 20010 Contact: Sherri Plumley (202) 939-3558 CLOSED 931027 ACTU: 5016. FLORIDA University Hospital of Jacksonville Florida 655 West 8th Street Jacksonville, FL 32209 Contact: Dr Sharon Paryani (904) 350-6872 CLOSED 931027. MARYLAND Walter Reed / USUHS / Pediatrics 4301 Jones Bridge Road Bethesda, MD 20889-4799 Contact: Nicki Nau (301) 829-0223 Contact: . CLOSED 931027. MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Susan Sandelli (301) 402-1391 Contact: (301) 402-1387 OPEN 940425. MARYLAND University of Maryland School of Medicine / Pediatrics 120 Penn Street Baltimore, MD 21201 Contact: Sue Lovelace (410) 706-8220 CLOSED 931027 ACTU: 3702. NORTH CAROLINA Duke University Medical Center / Pediatrics Box 3499 Durham, NC 27710 Contact: John Swetnam (919) 684-6335 CLOSED 931027 ACTU: 4701. NEW YORK The Children's Hospital at Albany Medical Center Department of Pediatrics New Scotland Avenue Albany, NY 12208 Contact: Dr Martha Lepow (518) 432-1501 CLOSED 931027. 63 UNIQUE IDENTIFIER NIH/00682 PROTOCOL ID NUMBERS NIAID 94 I-206 PROTOCOL TITLE A Phase I/II Pilot Study of the Safety of the Adoptive Transfer of Syngeneic Gene-Modified Cytotoxic T Lymphocytes in HIV-Infected Identical Twins. VERSION NUMBER & DATE (940808) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Walker RE GENERAL DESCRIPTION PURPOSE: To compare the safety, tolerance, and efficacy of infusions of activated, culture-expanded CD8+ (cytotoxic) lymphocytes with or without gene modification when obtained from HIV-seronegative identical twins and administered to their HIV-infected siblings. GENERAL DESCRIPTION RATIONALE: Transplantation of hematopoietic elements has been shown to correct the immune defects in certain primary immune deficiency diseases but has resulted in only temporary immunologic improvement in AIDS patients. This study assesses the potential value of genetically modifying T-lymphocytes in an attempt to prevent or control HIV infection. It will also permit the effects of gene modification of the cells to be distinguished from those effects of activated T-cell infusions alone. GENERAL DESCRIPTION METHODOLOGY: Peripheral blood lymphocytes are obtained by periodic apheresis from the HIV-seronegative identical twin of each HIV-positive patient. Cells are activated with OKT3 antibody and interleukin-2 and expanded. For 33 of 43 donors, cells are genetically modified prior to ex-vivo expansion. Prior to the randomization stage of the study, a separate group of three HIV-seropositive patients receive gene-modified lymphocytes at a dose of 10 million cells. If no dose-limiting toxicity (DLT) occurs, subsequent 6-patient cohorts are randomized to receive single infusions of unmodified lymphocytes (10 billion cells) or modified lymphocytes (100 million, 1 billion, or 10 billion cells). The expanded lymphocytes are infused over 60 minutes into the HIV-seropositive patient via a peripheral or central vein. Patients without DLT after their initial infusion may receive up to six additional infusions at 8-week intervals; patients who initially received unmodified cells receive the same dose and those who received modified cells receive the assessed maximum safe dose. Additionally, up to four new patients may receive unmodified lymphocytes and up to 12 new patients may receive modified lymphocytes. Patients are followed daily for 4 days after each infusion, then weekly for the duration of treatment. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941101) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: HIV seropositive, with an HIV-seronegative identical twin, as confirmed by ELISA, PCR, or Western blot. NOTE: If CD4 count is < 500 cells/mm3 at study entry, patient must have been on an FDA-approved or expanded-access antiretroviral therapy for at least 2 months. NOTE: Patients with Kaposi's sarcoma are eligible, provided they have received no systemic therapy for KS within 4 weeks prior to study entry. Diagnosis of KS must be confirmed by biopsy. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS BB-IND 5610. T-9401 STUDY DESIGN Open Label; Comparative; Randomized; Controlled; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Immunotherapy, Drug safety, Drug tolerance, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 43 patients. (33 patients receive modified T-lymphocytes; 10 patients receive unmodified T-lymphocytes) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Approximately 15 months. PROTOCOL DETAILS STUDY DURATION: Approximately 2 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity with an HIV-seronegative identical twin. 2. Life expectancy greater than 6 months. NOTE: If CD4 count is < 500 cells/mm3 at study entry, patient must have been on an FDA-approved or expanded-access antiretroviral therapy for at least 2 months. NOTE: Patients with Kaposi's sarcoma are eligible, provided they have received no systemic therapy for KS within 4 weeks prior to study entry. Diagnosis of KS must be confirmed by biopsy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: At least 2 months of prior antiretroviral therapy in patients with CD4 count < 500 cells/mm3 at study entry. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Recent history of substance abuse unless evidence is provided of ongoing therapeutic intervention (i.e., medical therapy or counseling) to control such abuse. Unwilling to appropriately notifiy all current sexual partners of individual's HIV-seropositive status and the risk of infection. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Systemic therapy for Kaposi's sarcoma within 4 weeks prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients (recipients) with the following symptoms or conditions are excluded: 1. Lymphoma. 2. Serious psychological or emotional illness. Donors with the following symptoms or conditions are excluded: 1. Untreated or inadequately treated medical condition (e.g., cardiopulmonary disease, acute infection) that precludes apheresis. 2. Serologic positivity for Epstein Barr virus, Cytomegalovirus, Hepatitis B, or Hepatitis C, if and only if the recipient twin is seronegative for the corresponding virus. SUBSTANCE IDENTIFICATION Drug 1 DRG-0146 Lymphocytes, Activated MANUFACTURERS Drug 1: National Institute of Allergy and Infectious Diseases 9000 Rockville Pike Building 10 Room 7D43 Bethesda, MD 20892 Contact: Candace Kurtz (301) 496-9320 Contact: (301) 402-0586. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 10 million to 10 billion cells q 8 weeks for six infusions SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV) OTHER TREATMENT INFO. END POINT: Primary: Safety of administering syngeneic genetically modified CD8+ cytotoxic T-lymphocytes. Secondary: Effects on primary disease status (CD4 count, HIV burden, p24 antigen), longevity of genetically modified transplanted T-lymphocytes. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Dose-limiting toxicity. 2. Development of another unexpected, life-threatening complication. 3. Profound disease progression or other medical complication that precludes further therapy. 4. Refusal of patient to continue study or patient noncompliance. SUPPORTING AGENCY National Institute of Allergy and Infectious Diseases. MESH HEADING AIDS-Related Complex/IMMUNOLOGY/*THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/IMMUNOLOGY/ *THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/IMMUNOLOGY/*THERAPY MESH HEADING Human MESH HEADING Immunotherapy, Adoptive MESH HEADING Male MESH HEADING Middle Age MESH HEADING T-Lymphocytes/IMMUNOLOGY/*TRANSPLANTATION MESH HEADING Transplantation, Isogeneic LAST REVISION DATE 941101 ENTRY MONTH 9411 MARYLAND National Institute of Allergy & Infectious Diseases 9000 Rockville Pike / Clinical Center Bethesda, MD 20892 Contact: Betsey Herpin (800) 772-5464 X 304Contact: Chris Boenning (800) 772-5464 X 401OPEN / USA accrual 941101. 64 UNIQUE IDENTIFIER NIH/00592 PROTOCOL ID NUMBERS NIAID 92 I-125 PROTOCOL TITLE A Study of Viral Burden in Peripheral Blood Versus Lymphoid Tissue in Human Immunodeficiency Virus Infected Individuals. VERSION NUMBER & DATE (940308) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Stanley SK PROTOCOL CHAIRS CO-CHAIR Fauci AS, Pantaleo G, Gr GENERAL DESCRIPTION PURPOSE: AMENDED 02/94: Enrollment limited to long-term immunologic nonprogressors. ORIGINAL: To determine the relative burden of HIV and the relative degree of HIV expression in the peripheral blood mononuclear cells (PBMC) versus the lymph nodes in individual patients with HIV infection. To delineate the precise nature of the perturbations in V-beta subsets of T cells in the peripheral blood versus the lymph nodes of HIV-infected individuals in order to pursue the role of superantigens in the immunopathogenesis of HIV infection. To examine the effect of therapy on viral burden and HIV expression in lymph node versus PBMC. GENERAL DESCRIPTION RATIONALE: Recent studies have demonstrated that there is ten times more virus (per constant number of CD4 T cells) in the lymph nodes than in the PBMC of HIV-infected patients with generalized lymphadenopathy, indicating that the lymph node may be the major reservoir of HIV presence and expression in the body. It is important to establish whether this situation exists in a broad spectrum of HIV patients at various stages of infection from initial acute infection through advanced disease. If patients with early asymptomatic disease are shown to have substantial viral replication in lymph nodes at a time when their peripheral blood reflects a relative latency, this finding will provide a basis for treating patients earlier in the course of their HIV infection. GENERAL DESCRIPTION METHODOLOGY: Patients will have no more than 400 cc of blood drawn during their participation on the study and will undergo surgical removal under local anesthesia of a lymph node from the groin, armpit, or neck. PROTOCOL PHASE Immunopathogenesis OPEN/CLOSED INDICATOR Open: Actively accruing patients (940308) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions. AMENDED 02/94 TO LIMIT ENROLLMENT AS FOLLOWS: 1. Documented HIV infection for > 7 years. 2. Long-term immunologic nonprogression. 3. CD4 count > 500 cells/mm3. 4. No prior antiviral therapy. 5. No AIDS dementia or AIDS-related malignancy other than minimal Kaposi's sarcoma. ORIGINAL ENTRY CRITERIA: 1. Documented HIV infection. 2. CD4 count of any value. 3. Antiretroviral therapy permitted. 4. No AIDS dementia or AIDS-related malignancy other than minimal Kaposi's sarcoma. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Nonrandomized PROTOCOL DETAILS STUDY INTENT: Immunology. PROTOCOL DETAILS PROJECTED ACCRUAL: UNLIMITED patients. PROTOCOL DETAILS ACTUAL ACCRUAL: 20/UNLIMITED (941116). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have (per 02/94 amendment): 1. Documented HIV infection for > 7 years. 2. Long-term immunologic nonprogression. 3. CD4 > 500 cells/mm3. 4. No prior antiviral therapy. 5. No AIDS dementia or AIDS-related malignancy other than minimal Kaposi's sarcoma. 6. Palpable lymph node. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: Normal platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: > 500 cells/mm3. ( 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 1000 cells/mm3. PT and PTT normal. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Prophylaxis for opportunistic infections. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior antiviral therapy. 2. Aspirin within 1 week prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Bleeding diathesis. 2. Need for chronic aspirin therapy. OTHER TREATMENT INFO. END POINT: Measurements of viral burden. SUPPORTING AGENCY National Institute of Allergy and Infectious Diseases. MESH HEADING AIDS-Related Complex/*IMMUNOLOGY/PATHOLOGY MESH HEADING Acquired Immunodeficiency Syndrome/ *IMMUNOLOGY/PATHOLOGY MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/*IMMUNOLOGY/PATHOLOGY MESH HEADING Human MESH HEADING Lymph Nodes/IMMUNOLOGY/*PATHOLOGY MESH HEADING Lymphoid Tissue/IMMUNOLOGY/*PATHOLOGY MESH HEADING Male MESH HEADING Middle Age LAST REVISION DATE 940308 ENTRY MONTH 9403 MARYLAND National Institute of Allergy & Infectious Diseases 9000 Rockville Pike / Bldg 10 / Room 11B13 Bethesda, MD 20892 Contact: Barbara Baird (301) 402-0980 X 420OPEN / USA Accrual 940308. 65 UNIQUE IDENTIFIER NIH/00055 PROTOCOL ID NUMBERS NIAID 91 CC-143 PROTOCOL TITLE Open-Label Trial to Evaluate IL-2 in Patients With HIV and Kaposi's Sarcoma. (Formerly A Phase I-II Study of the Combination of Azidothymidine and Interleukin-2 in the Treatment of AIDS Patients.) VERSION NUMBER & DATE (940616) TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Kovacs JA GENERAL DESCRIPTION PURPOSE: AMENDED 8/93: To evaluate the effect of interleukin-2 (IL-2) in patients with HIV and cutaneous Kaposi's sarcoma (KS). PER 6/21/91 AMENDMENT: To determine whether the changes that occur following a single course of IL-2 will recur or be enhanced with repeat courses and to evaluate the safety of repeat courses. ORIGINAL: To evaluate the toxicity and obtain preliminary information on the effectiveness of the combination of zidovudine (AZT) and IL-2 in patients with AIDS. GENERAL DESCRIPTION RATIONALE: AZT extends the survival of some patients with AIDS but is not 100 percent effective, and there is a need for the development of more effective treatments for AIDS and related disorders. IL-2 is a protein that is naturally produced by lymphocytes, but lymphocytes from patients with AIDS are not able to produce this protein normally. In preliminary studies, IL-2 improved some of the immunological functions that are abnormal in AIDS patients. (Immunological functions aid the body in fighting infections, such as AIDS). The combination of an antiviral agent such as AZT with an immunomodulatory agent such as IL-2 may provide beneficial effects that are not provided by either agent alone. Since the drugs have not been used in combination in AIDS patients, a study is needed to evaluate the toxicity of the combination. GENERAL DESCRIPTION METHODOLOGY: AMENDMENT 8/93: Newly enrolled patients with HIV and Kaposi's sarcoma receive IL-2 therapy. AMENDMENT: Per 6/21/91 amendment, up to six patients previously enrolled in the protocol who developed no grade 3/4 toxicity receive repeat doses of IL-2 (3 MU/day for 5 days) approximately every 2 months. The patients receive AZT (100 mg 5 times daily). ORIGINAL: At the beginning of the study, patients take AZT, either continuing their previous AZT therapy or starting oral AZT. After at least 6 weeks AZT treatment and 2 weeks after the last dosage change, patients are hospitalized for IL-2 treatment. IL-2 is given by continuous infusion for 3-weeks through a vein in the neck. The dose of IL-2 depends on the experience of previous patients. After the 3 weeks, patients are discharged, but continue to receive AZT for an additional 2 months. During the study, blood samples are taken periodically and skin biopsies of KS lesions are taken before and after the 9 week treatment period for those patients with KS. If the patient appears to have benefited from the treatment, AZT may be continued for up to 1 year and IL-2 may be given at the same dose for 3-week periods, but not more than once every 6 weeks. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940502) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: AMENDED 8/93: AIDS with histological evidence of cutaneous Kaposi's sarcoma. REQUIRED PER 6/21/91 AMENDMENT: 1. Laboratory values of grade 1 or 2. 2. Prior participation on NIAID 87 I-74 (Requirement not applicable to patients currently being enrolled). ELIGIBILITY AIDS / KS. OTHER PROTOCOL NUMBERS IRP 001. Project number 88174. IND/IDE number BB2683 STUDY DESIGN Open Label; 5-Arm; Dose Comparison PROTOCOL DETAILS STUDY INTENT: Drug toxicity, Combination drug therapy, Immunotherapy, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 30 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 1 year. PROTOCOL DETAILS ACTUAL ACCRUAL: 18/30 (901105). PROTOCOL DETAILS DATE OF FIRST ENROLLMENT: 880401 PROTOCOL DETAILS STUDY DURATION: 2 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 4 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: Serologic or culture evidence of infection with HIV and histological evidence of cutaneous Kaposi's sarcoma. Performance status: 0 - 1, where grade 0 is fully active and grade 1 is restricted in physically strenuous activity but fully active. Ability and willingness to take AZT (original design). [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 10 g/dl. prior to drug therapy. PATIENT INCLUSION CRIT. PLATELET COUNT: > 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: > 200 cells/mm3. (200 - 300 - 400 - 500 - 600 - 700 - 800 plus). PATIENT INCLUSION CRIT. BILIRUBIN: < 2 mg/dl. PATIENT INCLUSION CRIT. CREATININE: < 1.6 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. OTHER: Neutrophils > 1500 cells/mm3. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Negative pregnancy test within 7 days of study entry. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study and for 30 days after. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed if stopped 4 weeks prior to study entry: Chemotherapy. Corticosteroid therapy. Experimental therapy other than zidovudine (AZT). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Positive pregnancy test within 7 days of study entry. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control during study and for 30 days after. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 4 weeks of study entry: Chemotherapy. Corticosteroid therapy. Experimental therapy other than zidovudine (AZT). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Dideoxyinosine (ddI) and dideoxycytidine (ddC). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Malignancy other than Kaposi's sarcoma. 2. Concurrent opportunistic infection other than oropharyngeal candidiasis or herpes simplex. 3. Significant cardiac, pulmonary, or central nervous system disease. PATIENT EXCLUSION CRIT. AVAILABILITY: Unable to provide informed consent. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0021 Interleukin-2 TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: Cetus Corporation 1400 Fifty-Third Street Emeryville, CA 94608 Contact: Dr Gwen Fyfe (510) 601-3169. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg q4h, adjusted to 100 mg q4h for toxicity if needed. Drug 2: After 6 weeks of zidovudine (AZT) and at least 2 weeks after last AZT dose adjustment: 0.25 million units/day (MU/d) or 1.0 MU/d or 2.0 MU/d or 3.0 MU/d or 4.0 MU/d SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 400 mg or 800 mg. Drug 2: 0.25 million units (MU) or 1.0 MU or 2.0 MU or 3.0 MU or 4.0 MU SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: PO. Drug 2: IV infusion (continuous) OTHER TREATMENT INFO. TREATMENT DURATION: Drug 1: 9 weeks - 1 year, depending on individual response. Drug 2: 3 weeks, with additional 3-week courses every 6 weeks, up to 1 year after entry, depending on individual response. PER AMENDMENT: repeat courses administered at 2-month intervals. OTHER TREATMENT INFO. DISCONTINUE: Patients will be removed from the study for the following reasons: o Grade 3 or 4 toxicity of greater than 4 weeks duration while off both drugs. NOTE: Per 06/16/94 amendment, patients with Gilbert's disease who have elevated bilirubin may continue IL-2. o Development of a life-threatening infection or malignancy. o Progressive Kaposi's sarcoma that requires alternative therapy. o Patient non-compliance. OTHER TREATMENT INFO. MODIFICATION: Dosages will be modified at the designated toxicity grades (toxicity grades are defined by the of protocol) while patients are on zidovudine (AZT) alone: o Grade 2 - no change or decrease AZT by 50 percent. o Grade 3 - decrease AZT by 50 percent. o Grade 4 - discontinue AZT. The drug may be restarted at a lower dose if there is evidence of clinical or laboratory improvement. Dosages will be modified at the designated toxicity grades (as defined by the protocol) while patients are on AZT plus interleukin 2 (IL-2): o Grade 2 - no change or decrease IL-2 to next lowest dose. o Grade 3 anemia - no change. o Grade 3 other than anemia - decrease IL-2 to next lowest dose or stop both drugs. If toxicity continues after dose reduction, stop IL-2. Drugs may be restarted at a lower dose if there is evidence of clinical or laboratory improvement. o Grade 4 - discontinue both drugs. Drugs may be restarted at a lower dose if there is evidence of clinical or laboratory improvement. NOTE: Per 06/16/94 amendment, in patients with Gilbert's disease who have bilirubin > 5 mg/dl, hold IL-2 until level decreases to < 3.0 mg/dl. SUPPORTING AGENCY National Institute of Allergy and Infectious Diseases. MESH HEADING Acquired Immunodeficiency Syndrome/ COMPLICATIONS/*DRUG THERAPY MESH HEADING Adult MESH HEADING Drug Evaluation MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Interleukin-2/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/DRUG THERAPY MESH HEADING Zidovudine/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS CAS REGISTRY NUMBER 0 (Interleukin-2) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 940502 ENTRY MONTH 8904 MARYLAND National Institute of Allergy & Infectious Diseases 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Susan Vogel (800) 772-5464 X 403Contact: Donna O'Neill (301) 402-0566 OPEN / USA accrual 930802. 66 UNIQUE IDENTIFIER NIH/00571 PROTOCOL ID NUMBERS NCI 94 C-35 PROTOCOL TITLE A Phase I/II Study to Evaluate the Safety, Toxicity, and Preliminary Efficacy of Combinations of Lamivudine (3TC), Zidovudine (AZT), and Didanosine (ddI) in Children With HIV Infection. VERSION NUMBER & DATE (931026) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the pharmacokinetic interactions, toxicity, and tolerability of combinations of zidovudine (AZT) and lamivudine (3TC), didanosine (ddI) and 3TC, and all three agents in children with HIV infection. Methodology: Patients with no previous or less than 6 weeks of prior antiretroviral therapy are randomized to Arm A; those with prior therapy are randomized to Arm B. Patients on Arm A receive AZT/ddI/3TC but will be assigned alternately to two different AZT dose levels (90 or 180 mg/m2/dose). Patients on Arm B are assigned to a treatment regimen and dose level based on their past medical and treatment history, as follows: those with prior toxicity to ddI receive AZT/3TC; those with prior toxicity to AZT receive ddI/3TC; and those with prior toxicity to both AZT and ddI or with progressive HIV infection receive AZT/ddI/3TC (with AZT dose of 90 mg/m2). GENERAL DESCRIPTION METHODOLOGY: Patients with no previous or less than 6 weeks of prior antiretroviral therapy are randomized to Arm A; those with prior therapy are randomized to Arm B. Patients on Arm A receive AZT/ddI/3TC but will be assigned alternately to two different AZT dose levels (90 or 180 mg/m2/dose). Patients on Arm B are assigned to a treatment regimen and dose level based on their past medical and treatment history, as follows: those with prior toxicity to ddI receive AZT/3TC; those with prior toxicity to AZT receive ddI/3TC; and those with prior toxicity to both AZT and ddI or with progressive HIV infection receive AZT/ddI/3TC (with AZT dose of 90 mg/m2). PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940419) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions. 1. Class P-1b (asymptomatic) HIV infection with the following age-corrected CD4 count: < 1 year of age - 1750 cells/mm3; 1-2 years - 1000 cells/mm3; 2-6 years - 750 cells/mm3; 6-17 years - 500 cells/mm3. OR 2. Previously treated patients with class P-1b HIV infection with a 33 percent decline in CD4 count or percentage or a decrease to below 20 percent, confirmed by at least two measurements 4 weeks apart. OR 3. Class P-2 (symptomatic) infection with toxicity to antiretroviral therapy. OR 4. Class P-2 infection with progressive HIV disease while on antiretroviral therapy. Progressive disease is defined as: o Deterioration in neuropsychological function o Weight loss or failure to thrive o Organomegaly or lymphadenopathy not associated with opportunistic infection o Two or more serious HIV-related opportunistic infections o Decline in CD4 counts as described for P-1b patients. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS FDA 225A. NUCA 2005 STUDY DESIGN Randomized; 2-Arm; Drug Combination; Dose Comparison; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Pharmacokinetics, Drug safety, Combination drug therapy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: Class P-1b (asymptomatic) or P-2 (symptomatic) HIV infection with specific disease markers as described in the Disease Status field. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. (Transfusion permitted). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. (IVIG allowed). PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 10 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.0 x ULN. PATIENT INCLUSION CRIT. OTHER: WBC >= 100 cells/mm3 OR absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 03 Months - 17 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior antiretroviral therapy (except within the 2 weeks immediately preceding study entry). OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Maintenance therapy for stable mycobacterial or CMV infection. 2. Long-term suppression for mucosal candidiasis or mucocutaneous herpes virus infections. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 02 Months. 18 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Antiretroviral therapy within 2 weeks prior to study entry. 2. Chemotherapeutic or immunomodulating agents within 1 month prior to study entry (except for G-CSF as part of antiretroviral regimen, corticosteroids for LIP or reactive airway disease, or IVIG for prevention of bacterial infections or treatment for thrombocytopenia). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Induction therapy or ongoing treatment for active opportunistic infections, except as specifically allowed. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0126 Lamivudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0016 Didanosine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir TRADE NAME OF SUBSTANCE Drug 2‰ 3TC TRADE NAME OF SUBSTANCE Drug 3‰ Videx MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Glaxo Incorporated 5 Moore Drive Research Triangle Park, NC 27709 Contact: Patti Gage (800) 334-0089. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 90 or 180 mg/m2 q 6 hr. Drug 2: 4 mg/kg q 12 hr. Drug 3: 135 mg/m2 q 12 hr SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 360 or 720 mg/m2. Drug 2: 8 mg/kg. Drug 3: 270 mg/m2 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Oral. Drug 3: Oral SUPPORTING AGENCY National Cancer Institute Pediatric Intramural Studies. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Antiviral Agents/*ADVERSE EFFECTS/ PHARMACOKINETICS MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Didanosine/*ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Reverse Transcriptase/*ANTAGONISTS & INHIB MESH HEADING Zidovudine/*ADVERSE EFFECTS/PHARMACOKINETICS CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) CAS REGISTRY NUMBER EC 2 LAST REVISION DATE 940419 ENTRY MONTH 9402 CALIFORNIA Children's Hospital of Los Angeles 4650 Sunset Boulevard Los Angeles, CA 90027 Contact: Lin Woods (213) 669-4537 OPEN 940330. MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Susan Sandelli (301) 402-1391 Contact: (301) 402-1387 OPEN / USA Accrual 940203. 67 UNIQUE IDENTIFIER NIH/00569 PROTOCOL ID NUMBERS NCI 93 C-70 PROTOCOL TITLE A Phase I/II Assessment of Dose-Range/Escalation, Kinetics, Safety, and Preliminary Efficacy of Oral Rifabutin Suspension for the Prophylaxis of Mycobacterium avium Complex (MAC) Bacteremia in Pediatric Patients Infected With Human Immunodeficiency Virus and Low CD4+ Cell Counts. VERSION NUMBER & DATE (931026) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To assess single and multiple dose pharmacokinetics, microbiologic and clinical effects, and the safety and relative efficacy of three dose levels of rifabutin administered as prophylaxis against Mycobacterium avium Complex (MAC) in children with HIV infection and low CD4 counts. Methodology: Patients continue their current antiretroviral therapy with zidovudine (AZT), didanosine (ddI), dideoxycytidine (ddC), or some combination thereof. They receive either 5, 10, or 15 mg/kg rifabutin daily. GENERAL DESCRIPTION METHODOLOGY: Patients continue their current antiretroviral therapy with zidovudine (AZT), didanosine (ddI), dideoxycytidine (ddC), or some combination thereof. They receive either 5, 10, or 15 mg/kg rifabutin daily. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940419) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Class P-1B (asymptomatic) or class P-2 (symptomatic) HIV infection. 2. CD4 count < 100 cells/mm3 if >= 2 years of age OR < 200 cells/mm3 if < 2 years of age. 3. Negative for MAI on two blood cultures on two consecutive visits. 4. No previous or current disseminated infection due to MAC or other mycobacterial infections. 5. No active opportunistic infection OTHER THAN oral candidiasis. ELIGIBILITY ASYM. ARC. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Dose Escalating; Drug Tolerance; Pharmacokinetic; Drug Combination; Dose Ranging PROTOCOL DETAILS STUDY INTENT: Drug prophylaxis, Drug safety, Drug efficacy, Pharmacokinetics, Combination drug therapy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Class P-1B (asymptomatic) or class P-2 (symptomatic) HIV infection. 2. CD4 count < 100 cells/mm3 if >= 2 years of age OR < 200 cells/mm3 if < 2 years of age. 3. Negative blood cultures for MAI and no previous or current disseminated infection due to MAC or other mycobacterial infections. 5. No active opportunistic infection OTHER THAN oral candidiasis. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: < 100 cells/mm3. (if >= two years old). OR < 200 cells/mm3 (if < two years old). ( 0 - 100 ). PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2 x ULN. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase < 5 x ULN. Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 01 Days - 18 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Stable dose of AZT, ddC, ddI, or some combination for at least 4 weeks prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: Concomitant antiretroviral therapy. Allowed: Amikacin or ciprofloxacin if given for <= 14 days. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 4 weeks prior to study entry: 1. Any Phase I antiretroviral agents. 2. Antimycobacterial therapy, including rifampin, isoniazid, clofazimine, ethambutol, cycloserine, and ethionamide. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Antimycobacterial therapy, including rifampin, isoniazid, clofazimine, ethambutol, cycloserine, and ethionamide. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Positive tuberculin skin test (PPD > 5 mm). 2. Known hypersensitivity to rifabutin, rifampin, or other rifamycins. SUBSTANCE IDENTIFICATION Drug 1 DRG-0085 Rifabutin SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 4 DRG-0015 Dideoxycytidine TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir TRADE NAME OF SUBSTANCE Drug 3‰ Videx TRADE NAME OF SUBSTANCE Drug 4‰ HIVID MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. MANUFACTURERS Drug 4: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 5, 10, or 15 mg/kg daily. Drug 2: Current stable dose at study entry. Drug 3: Current stable dose at study entry. Drug 4: Current stable dose at study entry SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 5, 10, or 15 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, suspension SUPPORTING AGENCY National Cancer Institute. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Didanosine/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*PREVENTION & CONTROL MESH HEADING Rifabutin/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Zalcitabine/*THERAPEUTIC USE MESH HEADING Zidovudine/*THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) CAS REGISTRY NUMBER 72559-06-9 (Rifabutin) CAS REGISTRY NUMBER 7481-89-2 (Zalcitabine) LAST REVISION DATE 940419 ENTRY MONTH 9311 MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Susan Sandelli (301) 402-1391 Contact: (301) 402-1387 OPEN / USA accrual 931026. 68 UNIQUE IDENTIFIER NIH/00568 PROTOCOL ID NUMBERS NCI 93 C-21 PROTOCOL TITLE A Pilot Study of the Safety, Growth, and Immunologic Effects of Recombinant Human Insulin-Like Growth Factor (rhIGF-1) and Recombinant Human Growth Hormone (Nutropin; rhGH) in Children With HIV-1 Infection and Growth Retardation. VERSION NUMBER & DATE (931026) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To establish the tolerance and safety of recombinant human insulin-like growth factor (rhIGF-1) and recombinant human growth hormone (rhGH) in conjunction with combination antiretroviral therapy with zidovudine (AZT) and didanosine (ddI) in HIV-infected children who have received prior antiretroviral therapy and experienced growth failure. To provide preliminary data on the effects of rhIGF-1 and rhGH on growth, immune function, and viral burden, in order to define the clinical and laboratory parameters necessary for future efficacy studies. Methodology: Patients are initially placed on antiretroviral therapy with AZT/ddI and observed for 12 weeks. They are then randomized to receive either rhIGF-1 or rhGH for 12 weeks; those patients who experience no adverse effects and who demonstrate benefit may continue on study for an additional 12 weeks. GENERAL DESCRIPTION METHODOLOGY: Patients are initially placed on antiretroviral therapy with AZT/ddI and observed for 12 weeks. They are then randomized to receive either rhIGF-1 or rhGH for 12 weeks; those patients who experience no adverse effects and who demonstrate benefit may continue on study for an additional 12 weeks. PROTOCOL PHASE Pilot Study OPEN/CLOSED INDICATOR Open: Actively accruing patients (940419) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. P-2 class symptomatic HIV infection or a CD4 count that qualifies for antiretroviral therapy. 2. Failure to grow or a decrease in growth velocity. 3. Adequate nutrition, i.e., nutrition that provides at least 50 percent of the caloric RDA for weight. 4. No significant active opportunistic infections requiring specific therapy. 5. Euthyroid status (i.e., normally functioning thyroid). NOTE: Hypothyroid status corrected by adequate treatment as documented by normal TSH, T3, and T4 for 3 months is acceptable.) ELIGIBILITY ASYM. ARC. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Comparative; Drug Tolerance; Pilot Study PROTOCOL DETAILS STUDY INTENT: Drug safety, Immunotherapy, Comparative drug therapy, Combination drug therapy. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 24-36 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. P-2 class symptomatic HIV infection or a CD4 count that qualifies for antiretroviral therapy. 2. Failure to grow or a decrease in growth velocity. 3. Adequate nutrition, i.e., nutrition that provides at least 50 percent of the caloric RDA for weight. 4. No significant active opportunistic infections requiring specific therapy. 5. Euthyroid status (i.e., normally function thyroid). NOTE: Hypothyroid status corrected by adequate treatment as documented by normal TSH, T3, and T4 for 3 months is acceptable.) [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. Asymptomatic patients must have a CD4 count that qualifies for antiretroviral therapy. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 06 Months - 18 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 05 Months. 19 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Corticosteroids within 30 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Interferons or other cytokines. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Diabetes mellitus. 2. Critically ill or clinically unstable. SUBSTANCE IDENTIFICATION Drug 1 DRG-0131 Insulin-Like Growth Factor I SUBSTANCE IDENTIFICATION Drug 2 DRG-0132 Somatrem SUBSTANCE IDENTIFICATION Drug 3 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 4 DRG-0016 Didanosine TRADE NAME OF SUBSTANCE Drug 2‰ Nutropin TRADE NAME OF SUBSTANCE Drug 3‰ Retrovir TRADE NAME OF SUBSTANCE Drug 4‰ Videx MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. MANUFACTURERS Drug 4: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 120 mcg/kg daily at 8am and 6pm for 12-24 weeks. Drug 2: 40 mcg/kg daily for 12-24 weeks. Drug 3: 120 mg/m2 q 6 h for 24-36 weeks. Drug 4: 135 mg/m2 q 12 h for 24-36 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 120 mcg/kg. Drug 2: 40 mcg/kg. Drug 3: 480 mg/m2. Drug 4: 270 mg/m2 OTHER TREATMENT INFO. TREATMENT DURATION: At least 24 weeks. SUPPORTING AGENCY National Cancer Institute. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Didanosine/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Hormones, Synthetic/ADVERSE EFFECTS/ THERAPEUTIC USE MESH HEADING Human MESH HEADING Insulin-Like Growth Factor I/*ADVERSE EFFECTS/ THERAPEUTIC USE MESH HEADING Male MESH HEADING Somatomedins/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Zidovudine/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Somatomedins) CAS REGISTRY NUMBER 0 (Hormones, Synthetic) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 67763-96-6 (Insulin-Like Growth Factor I) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 940419 ENTRY MONTH 9311 MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Susan Sandelli (301) 402-1391 Contact: (301) 402-1387 OPEN / USA accrual 931026. 69 UNIQUE IDENTIFIER NIH/00621 PROTOCOL ID NUMBERS NCI 93 C-207 PROTOCOL TITLE Pilot Study for the Treatment of Non-Hodgkin's Lymphoma in Patients With Inherited and Acquired Immunodeficiency Syndromes. VERSION NUMBER & DATE (940426) TRIAL CATEGORY AIDS-Related Malignancies TRIAL CATEGORY Child GENERAL DESCRIPTION PURPOSE: To obtain preliminary response, survival, and toxicity data in patients with congenital and acquired immunodeficiency syndromes and non-Hodgkin's lymphoma who are treated with three cycles of chemotherapy (systemic cyclophosphamide/methotrexate and intrathecal cytarabine/methotrexate) plus cytokines (granulocyte-colony stimulating factor), plus antiretroviral therapy (zidovudine and didanosine) if HIV-infected. Methodology: Patients are treated with three cycles of chemotherapy (systemic cyclophosphamide/methotrexate and intrathecal cytarabine/methotrexate) plus cytokines (granulocyte-colony stimulating factor), plus antiretroviral therapy (zidovudine and didanosine) if HIV-infected. Patients with intracerebral lymphoma receive a combination of systemic and radiation therapy. Two additional agents (ifosfamide and cytarabine) will be used in patients who relapse or who have persistent disease at completion of therapy. Patients who fail the initial drug combination will be permitted to receive a second drug combination (three cycles of ifosfamide and cytarabine with intrathecal methotrexate). GENERAL DESCRIPTION METHODOLOGY: Patients are treated with three cycles of chemotherapy (systemic cyclophosphamide/methotrexate and intrathecal cytarabine/methotrexate) plus cytokines (granulocyte-colony stimulating factor), plus antiretroviral therapy (zidovudine and didanosine) if HIV-infected. Patients with intracerebral lymphoma receive a combination of systemic and radiation therapy. Two additional agents (ifosfamide and cytarabine) will be used in patients who relapse or who have persistent disease at completion of therapy. Patients who fail the initial drug combination will be permitted to receive a second drug combination (three cycles of ifosfamide and cytarabine with intrathecal methotrexate). PROTOCOL PHASE Pilot Study OPEN/CLOSED INDICATOR Open: Actively accruing patients (940426) DISEASE STUDIED Lymphoma, non-Hodgkin's. DISEASES STATUS Patients have the following symptoms and conditions: 1. Congenital or acquired immunodeficiency syndrome, including HIV infection. 2. Proven B-cell non-Hodgkin's lymphoma of small non-cleaved cell or diffuse large cell type and no overt, serious concurrent infection OR a polyclonal lymphoproliferative process with failure on a trial of alpha interferon/IVIG. ELIGIBILITY AIDS. OTHER - immunocompromised. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Drug Combination; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Combination drug therapy, Combination modality therapy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Congenital or acquired immunodeficiency syndrome, including HIV infection. 2. Proven B-cell non-Hodgkin's lymphoma of small non-cleaved cell or diffuse large cell type and no overt, serious concurrent infection OR a polyclonal lymphoproliferative process with failure on a trial of alpha interferon/IVIG. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 03 Months - 18 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed in patients with intracerebral lymphoma: Radiation therapy. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required in patients with a polyclonal lymphoproliferative process superimposed on an immunodeficiency syndrome: Prior non-cytotoxic therapy (i.e., alpha interferon/IVIG). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 02 Months. 19 Years - 99 Years. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Therapy for a new opportunistic infection (may be eligible after infection has resolved or is controlled). SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 3 DRG-0048 Cyclophosphamide SUBSTANCE IDENTIFICATION Drug 4 DRG-0024 Methotrexate SUBSTANCE IDENTIFICATION Drug 5 DRG-0038 Cytarabine SUBSTANCE IDENTIFICATION Drug 6 DRG-0086 Granulocyte colony-stimulating factor SUBSTANCE IDENTIFICATION Drug 7 DRG-0207 Ifosfamide TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. MANUFACTURERS Drug 4: Drugs are provided by each participating unit site. MANUFACTURERS Drug 5: Drugs are provided by each participating unit site. MANUFACTURERS Drug 6: Drugs are provided by each participating unit site. MANUFACTURERS Drug 7: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 4: Intrathecal and systemic. Drug 5: Intrathecal SUPPORTING AGENCY National Cancer Institute. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Combined Modality Therapy MESH HEADING Cyclophosphamide/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Cytarabine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Didanosine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Granulocyte Colony-Stimulating Factor/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Ifosfamide/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Immunocompromised Host MESH HEADING Infant MESH HEADING Lymphoma, Non-Hodgkin's/COMPLICATIONS/*DRUG THERAPY MESH HEADING Male MESH HEADING Methotrexate/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Zidovudine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 147-94-4 (Cytarabine) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 3778-73-2 (Ifosfamide) CAS REGISTRY NUMBER 50-18-0 (Cyclophosphamide) CAS REGISTRY NUMBER 59-05-2 (Methotrexate) CAS REGISTRY NUMBER 62683-29-8 (Granulocyte Colony-Stimulating Factor) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 940426 ENTRY MONTH 9404 MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Susan Sandelli (301) 402-1391 Contact: (301) 402-1387 OPEN / USA accrual 940426. 70 UNIQUE IDENTIFIER NIH/00566 PROTOCOL ID NUMBERS NCI 93 C-193 PROTOCOL TITLE A Phase II Study of Paclitaxel (Taxol) Administered as a Three-Hour Infusion for Patients With HIV Infection and Kaposi's Sarcoma. VERSION NUMBER & DATE (931013) TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Saville W GENERAL DESCRIPTION PURPOSE: To study paclitaxel (Taxol) as a 3-hour infusion administered every 21 days in patients with HIV infection and Kaposi's sarcoma. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (931013) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection. 2. Kaposi's sarcoma. NOTE: Patients with pulmonary Kaposi's sarcoma that causes more than mild symptoms or with other acutely life-threatening lesions are not eligible. 3. Receiving a stable dose of antiretroviral therapy consisting of AZT, ddI, ddC, or stavudine (d4T), either alone or in combination, for at least 1 month prior to study entry. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS MB 324 STUDY DESIGN Dose Escalating PROTOCOL DETAILS STUDY INTENT: Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 10 - 34 patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Kaposi's sarcoma. 3. Been receiving a stable dose of antiretroviral therapy for at least 1 month prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. (Transfusion permitted within 1 month prior to study entry). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 125 units/L. PATIENT INCLUSION CRIT. SGPT(ALT): <= 125 units/L. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. /1.73 m2. (if creatinine value not available.) PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. PTT or PT no more than 120 percent of control. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. PRIOR TREATMENT: Allowed: Transfusion within 1 month prior to study entry. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Stable dose of antiretroviral therapy (AZT, ddI, ddC, d4T) for at least 1 month prior to study entry. Allowed: One prior cytotoxic chemotherapy regimen, excluding interferon and retinoic acid. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of hepatic cirrhosis or dysfunction. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within 4 weeks prior to study entry: 1. Radiation therapy. 2. Intralesional therapy. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: 1. Radiation therapy. 2. Intralesional therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 4 weeks prior to study entry: 1. Cytotoxic chemotherapy. 2. Interferon. 3. Other systemic anti-KS agents. 4. Systemic steroids. Excluded within 24 hours prior to Taxol infusion: 1. ddI. 2. Ketoconazole. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Cytotoxic chemotherapy. 2. Interferon. 3. Other systemic anti-KS agents. 4. Systemic steroids. 5. ddI (within 24 hours prior to Taxol infusion). 6. Ketoconazole (within 24 hours prior to Taxol infusion). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Grade 2 peripheral neuropathy. 2. H/O cardiac disease including myocardial infarction, congestive heart failure, angina, and coronary artery disease. SUBSTANCE IDENTIFICATION Drug 1 DRG-0190 Taxol MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 135 mg/m2 over 3 hr on day 0, 155 mg/m2 on day 21, and then 175 mg/m2 on day 42 and q 21 days thereafter SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous SUPPORTING AGENCY National Cancer Institute Adult Intramural Studies. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY MESH HEADING Taxol/*THERAPEUTIC USE CAS REGISTRY NUMBER 33069-62-4 (Taxol) LAST REVISION DATE 931013 ENTRY MONTH 9310 MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Jill Lietzau (301) 496-5489 Contact: Kathy Wyvill (301) 496-8959 OPEN / USA accrual 931013. 71 UNIQUE IDENTIFIER NIH/00567 PROTOCOL ID NUMBERS NCI 93 C-192 PROTOCOL TITLE A Pilot Study to Evaluate the Safety and Efficacy of the Combination of AZT, ddI, and BI-RG-587 (Nevirapine) in Children With Progressive HIV Disease. VERSION NUMBER & DATE (931026) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the safety and efficacy of combination therapy with zidovudine (AZT), didanosine (ddI), and nevirapine in children aged 6 months to 18 years, who have either a persistently elevated or rising p24 antigen level while receiving AZT/ddI. To study the impact of this triple regimen on viral burden in plasma and tissue sites (i.e., lymph nodes), the effect on viral resistance, and the pharmacokinetics of single-dose nevirapine. Methodology: Patients receive nevirapine/AZT/ddI in combination for at least 24 weeks. They remain on their previously established AZT/ddI regimen throughout the study. A lymph node biopsy is required prior to beginning combination therapy and at week 24. Patients are followed monthly during the first 24 weeks and every other month thereafter. GENERAL DESCRIPTION METHODOLOGY: Patients receive nevirapine/AZT/ddI in combination for at least 24 weeks. They remain on their previously established AZT/ddI regimen throughout the study. A lymph node biopsy is required prior to beginning combination therapy and at week 24. Patients are followed monthly during the first 24 weeks and every other month thereafter. PROTOCOL PHASE Pilot Study OPEN/CLOSED INDICATOR Open: Actively accruing patients (940419) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. P-2 class symptomatic HIV infection OR asymptomatic HIV infection with an age-corrected absolute CD4 count recommended for initiation of antiretroviral therapy (i.e., 1-11 months - 1750 cells/mm3; 12-23 months - 1000 cells/mm3; 24 months to 5 years - 750 cells/mm3; >= 6 years - 500 cells/mm3). 2. Prior treatment with AZT/ddI for at least 12 weeks according to protocol NCI 91 C-09 (ACTG 176), at one of the following dose levels: AZT 90 mg/m2 every 6 hours plus ddI 135 mg/m2 every 12 hours; AZT 120 mg/m2 every 6 hours plus ddI 135 or 180 mg/m2 every 12 hours; or AZT 180 mg/m2 every 6 hours plus ddI 135 mg/m2 every 12 hours. 3. No active opportunistic infection requiring acute intervention. 4. Persistently positive serum p24 antigen > 100 pg/ml after 24 weeks of combination AZT/ddI therapy OR an increase in serum p24 antigen by 50 percent or more after at least 12 weeks of combination AZT/ddI therapy. ELIGIBILITY ASYM. ARC. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Drug Combination; Pilot Study PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Pharmacokinetics, Combination drug therapy. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: At least 24 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. P-2 class symptomatic HIV infection OR asymptomatic HIV infection with an age-corrected absolute CD4 count recommended for initiation of antiretroviral therapy. 2. Prior treatment with AZT/ddI for at least 12 weeks according to protocol NCI 91 C-09 (ACTG 176), at one of the specified dose levels. 3. No active opportunistic infection requiring acute intervention. 4. Persistently positive serum p24 antigen > 100 pg/ml after 24 weeks of combination AZT/ddI therapy OR an increase in serum p24 antigen by 50 percent or more after at least 12 weeks of combination AZT/ddI therapy. 5. Availability of parent or guardian to given informed consent and to be sufficiently reliable to return for the child's follow-up visits. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. (Recent transfusion acceptable). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. (If P-2 class symptomatic). OR If asymptomatic, then age-corrected CD4 count: one to eleven months - 1750 cells/mm3; twelve to twenty-three months - 1000 cells/mm3; twenty-four months to five years - 750 ce PATIENT INCLUSION CRIT. BILIRUBIN: <= 10 x ULN mg/dl. (ULN = upper limit of normal). Children with chronic elevations of known etiology will be enrolled but not evaluated for hepatotoxicity. PATIENT INCLUSION CRIT. SGOT(AST): <= 10 x ULN. (If bilirubin value unavailable). Children with chronic elevations of k PATIENT INCLUSION CRIT. SGPT(ALT): <= 10 x ULN. (If bilirubin value unavailable). Children with chronic elevations of known etiology will be enrolled but not evaluated for hepatotoxicity. PATIENT INCLUSION CRIT. CREATININE: <= 2 x ULN. PATIENT INCLUSION CRIT. OTHER: White blood cells >= 1000 cells/mm3. Neutrophils plus bands >= 750 cells/mm3. PATIENT AGE AGE: 06 Months - 18 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Corticosteroids for LIP or an autoimmune process. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 05 Months. 19 Years - 99 Years. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within 30 days prior to study entry: Radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 30 days prior to study entry: 1. Immunomodulating agents. 2. Cytolytic agents. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following condition are excluded: Critically ill or unstable. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 3 DRG-0116 Nevirapine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir TRADE NAME OF SUBSTANCE Drug 2‰ Videx TRADE NAME OF SUBSTANCE Drug 3‰ BI-RG-587 MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 90, 120, or 180 mg/m2 q 6 h, according to previously established regimen. Drug 2: 135 mg/m2 q 12 h, according to previously established regimen. Drug 3: 120 mg/m2 daily during weeks 1 through 4, then 240 mg/mdaily during weeks 5 through 24 SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 360, 480, or 720 mg/m2. Drug 2: 270 mg/m2. Drug 3: 120 mg/m2 (weeks 1 through 4); 240 mg/m2 (weeks 5 throu24) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Oral. Drug 3: Oral OTHER TREATMENT INFO. TREATMENT DURATION: At least 24 weeks. SUPPORTING AGENCY National Cancer Institute. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Antiviral Agents/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Didanosine/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Pyridines/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Zidovudine/*ADVERSE EFFECTS/THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 129618-40-2 (BI-RG 587) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 940419 ENTRY MONTH 9311 MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Susan Sandelli (301) 402-1391 Contact: (301) 402-1387 OPEN / USA accrual 931026. 72 UNIQUE IDENTIFIER NIH/00570 PROTOCOL ID NUMBERS NCI 93 C-155 PROTOCOL TITLE Treatment of Thrombocytopenia With Dideoxynucleosides and Anti-Rh Antibodies (Anti-D) in Children With HIV Infection: A Phase II Study. VERSION NUMBER & DATE (931118) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To establish the role of combination antiretroviral therapy with zidovudine (AZT) and didanosine (ddI) in the treatment of HIV-associated thrombocytopenia in children and to establish the utility of intravenous anti-Rh antibodies (anti-D) in HIV-infected children with thrombocytopenia unresponsive to antiretroviral therapy. Methodology: In Arm A of the study, patients receive AZT and ddI in combination for at least 6 weeks. In Arm B, anti-D is given plus AZT/ddI (or any other stable antiretroviral therapy), following at least 6 prior weeks of AZT/ddI (or any other stable antiretroviral therapy) during which thrombocytopenia worsened or did not improve. Bone marrow biopsies are performed at study entry and repeated after 6 and 12 weeks of treatment. GENERAL DESCRIPTION METHODOLOGY: In Arm A of the study, patients receive AZT and ddI in combination for at least 6 weeks. In Arm B, anti-D is given plus AZT/ddI (or any other stable antiretroviral therapy), following at least 6 prior weeks of AZT/ddI (or any other stable antiretroviral therapy) during which thrombocytopenia worsened or did not improve. Bone marrow biopsies are performed at study entry and repeated after 6 and 12 weeks of treatment. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940419) DISEASE STUDIED Primary HIV infection / thrombocytopenia. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection. 2. Rhesus positive (Rh+). 3. No obvious cause for thrombocytopenia other than HIV infection. 4. Absence of life-threatening bleeding. 5. No significant active opportunistic infection requiring drug therapy at study entry. Part A - o Platelets < 50000 on two separate days within a 2-week period. o Received no prior antiretroviral therapy OR received prior single-agent therapy (any drug) OR combination therapy with agents other than AZT and ddI. Part B - o Have received prior combination AZT/ddI (or any other stable antiretroviral therapy) for at least 6 weeks and either developed thrombocytopenia or have not had improvement in platelet count to >= 30000. o Platelets < 30000 on two separate days within a 1-week period after 6 weeks of treatment with AZT/ddI. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Drug Combination; 2-Arm PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Immunotherapy, Combination drug therapy. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: At least 12 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Rhesus positive (Rh+). 3. No obvious cause for thrombocytopenia other than HIV infection. 4. Absence of life-threatening bleeding. 5. Platelet count < 50000 for Part A and < 30000 for Part B. 6. No significant active opportunistic infection at study entry. 7. PART A - Must have received no prior antiretroviral therapy OR received prior single-agent therapy (any drug) OR prior combination therapy with agents other than AZT and ddI. PART B - Have received prior combination AZT/ddI (or any other stable antiretroviral therapy) for at least 6 weeks with developing on continuing thrombocytopenia. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: < 50000 platelets/mm3. (on Part A). < 30000 (on Part B). PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 3 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 10 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): < 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 50 ml/min. /1.73 m2. (If creatinine value not available). PATIENT AGE AGE: 03 Months - 18 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of acute or chronic pancreatitis. 2. History of withdrawal grade toxicity during treatment with AZT and ddI, thrombocytopenia excluded. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 02 Months. 19 Years - 99 Years. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: 1. Radiation therapy within 30 days prior to study entry. 2. Bone marrow transplantation within 6 months prior to study entry. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 30 days prior to study entry: 1. Immunomodulating agents (interleukin-2, interferons, or other biologic response modifiers). 2. Cytolytic chemotherapeutic agents. Excluded within 14 days prior to study entry: 1. G-CSF. 2. Corticosteroids (unless needed for treatment of a condition other than thrombocytopenia). 3. Immunoglobulins. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Significant active other infection requiring drug therapy at study entry. 2. Known hemolytic anemia (Part B). 3. Known severe allergic reactions to plasma products (Part B). SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0191 Anti-Rh antibodies SUBSTANCE IDENTIFICATION Drug 3 DRG-0016 Didanosine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir TRADE NAME OF SUBSTANCE Drug 2‰ Anti-D TRADE NAME OF SUBSTANCE Drug 3‰ Videx MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 120 mg/m2 q 6 h for at least 12 weeks. Drug 2: 40 mcg/kg not more often than weekly, for at least 6 we(following 6 weeks of combination antiretroviral therapy). Drug 3: 135 mg/m2 q 12 h for at least 12 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 480 mg/m2. Drug 3: 270 mg/m2 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 2: Intravenous SUPPORTING AGENCY National Cancer Institute. MESH HEADING AIDS-Related Complex/COMPLICATIONS/*DRUG THERAPY/IMMUNOLOGY MESH HEADING Acquired Immunodeficiency Syndrome/ COMPLICATIONS/*DRUG THERAPY/IMMUNOLOGY MESH HEADING Adolescence MESH HEADING Antibodies/*IMMUNOLOGY MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Didanosine/*THERAPEUTIC USE MESH HEADING Female MESH HEADING HIV Infections/COMPLICATIONS/*DRUG THERAPY/ IMMUNOLOGY MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Thrombocytopenia/COMPLICATIONS/IMMUNOLOGY/ *THERAPY MESH HEADING Zidovudine/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antibodies) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 940419 ENTRY MONTH 9311 MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Susan Sandelli (301) 402-1391 Contact: (301) 402-1387 OPEN / USA accrual 931026. 73 UNIQUE IDENTIFIER NIH/00541 PROTOCOL ID NUMBERS NCI 92 C-47 PROTOCOL TITLE A Phase I/II Trial of Amphotericin B Lipid Complex (ABLC) in the Treatment of Hepatosplenic Candidiasis in Children With Neoplastic Diseases. VERSION NUMBER & DATE (920421) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Child PROTOCOL CHAIRS CHAIR Pizzo PA PROTOCOL CHAIRS CO-CHAIR Walsh TJ GENERAL DESCRIPTION PURPOSE: To investigate the safety, pharmacokinetics, and antifungal response of three dosing regimens of amphotericin B lipid complex (ABLC) for the treatment of hepatosplenic candidiasis in pediatric patients with neoplastic diseases. GENERAL DESCRIPTION RATIONALE: Hepatosplenic candidiasis commonly presents in children receiving aggressive cytotoxic chemotherapy. To improve treatment of this infection, amphotericin B has been formulated into a lipid complex, which permits administration of larger doses with less toxicity. GENERAL DESCRIPTION METHODOLOGY: Patients are enrolled in three cohorts of 10 patients each. When eight of ten patients in a given cohort have completed therapy with ABLC, treatment begins for the next cohort at a higher dose for a shorter duration. Patients are evaluated at months 1, 2, 3, and 6 following completion of therapy. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940419) DISEASE STUDIED Candidiasis, Hepatosplenic. DISEASES STATUS Patients have the following symptoms and conditions: 1. Underlying neoplastic disease. 2. Candida in liver or spleen, proven histopathologically or by culture. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS T92-0001 STUDY DESIGN Dose Escalating; Open Label; Pharmacokinetic; Pilot Study PROTOCOL DETAILS STUDY INTENT: Drug safety, Pharmacokinetics, Drug efficacy, Drug dosing schedule. PROTOCOL DETAILS PROJECTED ACCRUAL: 30 patients. PROTOCOL DETAILS STUDY DURATION: Approximately 18 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Underlying neoplastic disease. 2. Candida in liver or spleen. 3. Central venous catheterization. 4. Consent of parent or guardian. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 3 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 7 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 7 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 30 ml/min. /1.73 m2. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 02 Years - 18 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Blood, blood products, or intravenous lipids (if administered at least 3 hours before or 1 hour after ABLC infusions). OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Corticosteroids. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of anaphylaxis attributed to amphotericin B. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 01 Years. 19 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Investigational drugs (other than cytotoxic chemotherapeutic or immunomodulatory agents) within 2 weeks prior to study entry. 2. Amphotericin B within 2 months prior to study entry. (NOTE: Patients who have received < 3 mg/kg amphotericin B within the past 2 months are eligible if drug is discontinued at least 7 days prior to study entry). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Cytotoxic chemotherapeutic or immunomodulatory agents. 2. Other systemic antifungal agents, including non-liposomal amphotericin B, 5-FC, or fluconazole. 3. Interferon, IL-2, GM-CSF, or isoprinosine. 4. Salicylates, nonsteroidal anti-inflammatory agents, or other compounds known to interfere with prostaglandin synthesis (except if indicated for adverse events). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Any other concomitant condition that would preclude participation. PATIENT EXCLUSION CRIT. AVAILABILITY: Unavailable for follow-up. SUBSTANCE IDENTIFICATION Drug 1 DRG-0096 Amphotericin B Lipid Complex MANUFACTURERS Drug 1: Bristol-Myers Squibb Company PO Box 4000 Princeton, NJ 08534-4000 Contact: Dr Joe Sonk (609) 252-5710. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Cohort 1: 2.5 mg/kg daily for 42 days. Cohort 2: 5.0 mg/kg daily for 21 days. Cohort 3: 7.5 mg/kg daily for 14 days. Total cumulative dose for each cohort: 105 mg/kg SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 2.5, 5.0, or 7.5 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous, 20 ml vials OTHER TREATMENT INFO. TREATMENT DURATION: 14, 21, or 42 days. OTHER TREATMENT INFO. END POINT: Toxicity, pharmacokinetics, antifungal response. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Deterioration of clinical status. 2. Pregnancy. 3. Development of profound hepatotoxicity or hyperbilirubinemia. 4. Unable to correct prothrombin time to < 3 sec above normal control after two doses of vitamin K. 5. Development of acute severe hemolytic anemia attributable to study drug. 6. Requirement for concomitant treatment with investigational drugs that are not part of neoplastic therapy or supportive care protocol. 7. Serious or intolerable adverse events that preclude further treatment with ABLC. OTHER TREATMENT INFO. MODIFICATION: For serum creatinine > 3.0 mg/dl: hold study drug until value decreases to 2.5 mg/dl or less, then resume study drug. If serum creatinine does not decrease to acceptable level within 7 days, discontinue study drug permanently. SUPPORTING AGENCY National Cancer Institute / Pediatric Branch. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Amphotericin B/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Candidiasis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Opportunistic Infections/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 1397-89-3 (Amphotericin B) LAST REVISION DATE 940419 ENTRY MONTH 9307 MARYLAND National Cancer Institute / Pediatric Branch 9000 Rockville Pike / Bldg 10 Rm 13N240 Bethesda, MD 20892 Contact: Dr Thomas Walsh (301) 402-3371 OPEN / USA accrual 920421. 74 UNIQUE IDENTIFIER NIH/00466 PROTOCOL ID NUMBERS NCI 92 C-228 PROTOCOL TITLE A Pilot/Phase I Study of the Toxicity, Pharmacokinetics, and Activity of TNP-470 Administered to Patients With HIV Infection and Kaposi's Sarcoma. TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Yarchoan R GENERAL DESCRIPTION PURPOSE: To determine the toxicity and pharmacokinetic profiles of TNP-470 (formerly AGM 1470) when administered to patients with HIV-associated Kaposi's sarcoma. To obtain preliminary information on the activity of TNP-470 on HIV-associated Kaposi's sarcoma. Methodology: Three to six patients receive TNP-470 at the starting dose IV every other day for 18 weeks. Subsequent cohorts of three to six patients receive TNP-470 at escalating doses until the MTD is determined. GENERAL DESCRIPTION METHODOLOGY: Three to six patients receive TNP-470 at the starting dose IV every other day for 18 weeks. Subsequent cohorts of three to six patients receive TNP-470 at escalating doses until the MTD is determined. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (930511) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. Antibodies to HIV. 2. Kaposi's sarcoma evaluable by noninvasive methods. NOTE: Patients with pulmonary KS, acute life-threatening KS that is responsive to other therapy, or actively bleeding or critically located KS are NOT eligible. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS T92-0041 STUDY DESIGN Pharmacokinetic; Dose Escalating; Pilot Study PROTOCOL DETAILS STUDY INTENT: Drug safety, Pharmacokinetics, Drug efficacy, Maximum tolerated dose (MTD). PROTOCOL DETAILS PROJECTED ACCRUAL: 48 patients. (3-6 patients per dose level) PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Antibodies to HIV. 2. Kaposi's sarcoma evaluable by noninvasive methods. 3. Ambulatory status. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.0 mg/dl. or <= 2 x ULN (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 125 units/L. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. per 1.73 m2 (if creatinine value not available). PATIENT INCLUSION CRIT. KARNOFSKY: > 70. PATIENT INCLUSION CRIT. OTHER: ANC >= 1000 cells/mm3. APTT or PT <= 120 percent of control. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Stable dose of antiretroviral therapy for 1 month prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: Stable dose of antiretroviral therapy. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of substantial noniatrogenic bleeding diasthesis. 2. History of hepatic cirrhosis. 3. History of seizures within the past 10 years. 4. Body temperature of 39 degrees C or greater within the past 10 days, unless not caused by severe underlying infection. 5. Past history of tumor or malignancy other than KS, with the exception of completely resected basal cell carcinoma of the skin. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Unwilling to refrain from activities that may result in reinfection with HIV. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: 1. Radiation therapy within the past 3 weeks. 2. Blood transfusion within the past month. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Suramin within the past 6 months. 2. Any chemotherapy, interferon, other systemic anti-Kaposi's sarcoma agents or regimens, steroids, or any local treatment (e.g., intralesional injections) within the past 3 weeks. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Anticonvulsants. 2. Steroids. 3. NSAIDS. 4. Anticoagulants. 5. Any other agent that may exacerbate bleeding. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Grade 2 or worse peripheral neuropathy of any cause. 2. Present hepatic dysfunction. 3. Present history of tumor or malignancy other than KS, with the exception of completely resected basal cell carcinoma of the skin. 4. Evidence of active severe or life-threatening infection. 5. Hypersensitivity to TNP-470, fumagillin, cyclodextrin, or other related compounds. PATIENT EXCLUSION CRIT. AVAILABILITY: Unwilling to be an inpatient. SUBSTANCE IDENTIFICATION Drug 1 DRG-0148 TNP-470 MANUFACTURERS Drug 1: National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Kathy Wyvill (301) 496-8959 Contact: Jill Lietzau (301) 496-8959 Contact: Dr James Pluda (301) 496-1196. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 4.6, 9.3, 15.4, 23.2, 32.4, 43.1, 57.4, or 76.3 mg/m2 over 1 hour every other day for 18 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 4.6 - 76.3 mg/m2 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous SUPPORTING AGENCY National Cancer Institute Adult Intramural Studies. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Antibiotics, Antineoplastic/*ADVERSE EFFECTS/ PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY MESH HEADING Sesquiterpenes/*ADVERSE EFFECTS/ PHARMACOKINETICS/THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antibiotics, Antineoplastic) CAS REGISTRY NUMBER 129298-91-5 (AGM 1470) LAST REVISION DATE 930511 ENTRY MONTH 9210 MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Kathy Wyvill (301) 496-8959 Contact: Jill Lietzau (301) 496-8959 Contact: Dr James Pluda (301) 496-1196 OPEN / USA Accrual 921015. 75 UNIQUE IDENTIFIER NIH/00465 PROTOCOL ID NUMBERS NCI 92 C-146 PROTOCOL TITLE A Pilot Phase I/II Study of the Activity of all-trans-Retinoic Acid (Tretinoin) Administered to Patients With HIV Infections and Kaposi's Sarcoma. TRIAL CATEGORY AIDS-Related Malignancies PROTOCOL CHAIRS CHAIR Yarchoan R GENERAL DESCRIPTION PURPOSE: To evaluate the activity and tolerance of tretinoin (all-trans-retinoic acid) when administered to patients with HIV-associated Kaposi's sarcoma, both alone and, if necessary, in combination with interferon-alfa. GENERAL DESCRIPTION RATIONALE: Current therapies for Kaposi's sarcoma are associated with considerable toxicity, particularly myelosuppression. Recent reports suggest that tretinoin may have activity against HIV-associated Kaposi's sarcoma. GENERAL DESCRIPTION METHODOLOGY: Tretinoin is administered PO at 40 mg/m2/day in three divided doses every 8 hours for 7 days, followed by no tretinoin for the next 7 days. Courses are repeated every 2 weeks for as long as the patient remains on study. If no toxicity develops during the first week of tretinoin administration, doses are escalated by 20 mg/m2/day with each course to a maximum dose of 100 mg/m2/day or until the MTD for that patient is reached, whichever is the lower dose. Patients who fail tretinoin therapy after 3 months will be offered additional treatment with tretinoin plus interferon-alfa. All patients must be receiving a stable dose of antiretroviral therapy (either AZT or ddI) for one month prior to study entry, although the doses of these drugs may be reduced or discontinued during the study. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (930511) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. Serum antibodies to HIV. 2. Kaposi's sarcoma that is evaluable by noninvasive methods, is not acutely life-threatening, and is without pulmonary involvement. Patients with active bleeding or critically located KS lesions may be ineligible for the study, at the discretion of the principal investigator or if such conditions pose an immediate risk to the patient. 3. At least 50 percent of patients should have a CD4 count > 100 cells/mm3. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS Not given STUDY DESIGN Dose Escalating; Drug Tolerance; Pilot Study PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug tolerance. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Serum antibodies to HIV. 2. Kaposi's sarcoma that is non-life-threatening and without pulmonary involvement. 3. Life expectancy > 6 months. 4. Ambulatory status. 5. At least half of patients should have a CD4 count > 100 cells/mm3. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. (At least 50 percent of patients should have CD4 count > 100 cells/mm3). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.0 mg/dl. or <= 2 x ULN (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 125 units/L. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. per 1.73 m2. (If creatinine value not available). PATIENT INCLUSION CRIT. KARNOFSKY: >= 70. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. PT or PTT <= 120 percent of control. Fasting triglyceride <= 750 mg/dl or nonfasting triglyceride <= 1000 mg/dl. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: AZT or ddI for 1 month prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: AZT or ddI. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of substantial bleeding diathesis (unless completely self-limited). 2. History of hepatic cirrhosis. 3. Past history of tumors or malignancies other than Kaposi's sarcoma, with the exception of completely resected basal cell carcinoma of the skin. 4. Evidence of an underlying severe or life-threatening infection with bacterial, viral, fungal, or protozoal pathogens within 14 days prior to study entry. 5. Body temperature of 39 degrees C or greater within 10 days prior to study entry, unless apparently not caused by severe underlying infection. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: 1. Radiation therapy within 3 weeks prior to study entry. 2. Blood transfusion within the past month. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Suramin within 6 months prior to study entry. 2. Cytotoxic chemotherapy, interferon, other systemic anti-Kaposi's sarcoma agents or regimens, or steroids within 3 weeks prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Present hepatic dysfunction. 2. Present history of tumors or malignancies other than Kaposi's sarcoma, with the exception of completely resected basal cell carcinoma of the skin. 3. Hypersensitivity to tretinoin or other related compounds. SUBSTANCE IDENTIFICATION Drug 1 DRG-0147 Tretinoin MANUFACTURERS Drug 1: National Cancer Institute 9000 Rockville Pike Bethesda, MD 20892 Contact: Dr H C Stevenson (301) 496-8798. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 40 mg/m2/day (with subsequent escalation to a maximum o100 mg/m2/day or until the MTD for the patient is reached), in divided doses q 8 hr for 7 days, administered q other week SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 40 mg/m2 SUPPORTING AGENCY National Cancer Institute Adult Intramural Studies. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY MESH HEADING Tretinoin/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 302-79-4 (Tretinoin) LAST REVISION DATE 930511 ENTRY MONTH 9210 MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Kathy Wyvill (301) 496-8959 Contact: Jill Lietzau (301) 496-8959 Contact: Dr James Pluda (301) 496-1196 OPEN / USA Accrual 921015. 76 UNIQUE IDENTIFIER FDA/00686 PROTOCOL ID NUMBERS FDA 240A PROTOCOL TITLE The Pilot Study of Foscarnet Cream in the Treatment of Mucocutaneous Herpes Simplex Virus Infections in Immunocompromised Patients Unresponsive to Acyclovir Treatment. VERSION NUMBER & DATE (941206) TRIAL CATEGORY Opportunistic Infections PROTOCOL CHAIRS CHAIR Hardy WD GENERAL DESCRIPTION PURPOSE: PRIMARY: To evaluate the clinical activity of foscarnet cream on the index lesion of mucocutaneous herpes simplex virus (HSV) infections in immunocompromised patients previously unresponsive to acyclovir treatment. SECONDARY: To evaluate the clinical activity and virologic activity of foscarnet cream on all treated lesions in this patient population. To evaluate the local tolerance and side effects of treatment with foscarnet cream in this patient population. Methodology: Patients receive topical applications of one percent foscarnet cream five times daily for up to 6 weeks; those who show no evidence of epithelialization of the index lesion after 3 or more weeks are removed from study and offered intravenous foscarnet. Patients who show a good response to topical foscarnet cream at the end of 6 weeks may continue receiving treatment at the discretion of the investigator. GENERAL DESCRIPTION METHODOLOGY: Patients receive topical applications of one percent foscarnet cream five times daily for up to 6 weeks; those who show no evidence of epithelialization of the index lesion after 3 or more weeks are removed from study and offered intravenous foscarnet. Patients who show a good response to topical foscarnet cream at the end of 6 weeks may continue receiving treatment at the discretion of the investigator. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941206) DISEASE STUDIED Herpes simplex, mucocutaneous. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection or AIDS by CDC criteria. 2. Virologically confirmed mucocutaneous HSV infection with at least one clinically evaluable HSV lesion of < 25 cm2 that can serve as an index lesion. 3. Prior oral (1000 mg/day) or intravenous (5 mg/kg/day) acyclovir of 7 or more days duration, with no acceptable clinical effect (i.e., with < 25 percent decrease in HSV lesion size and continued viral shedding). ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 92-FT-57 STUDY DESIGN Multicenter; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 12 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 6 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 6 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection or AIDS. 2. Mucocutaneous HSV infection with at least one clinically evaluable lesion. 3. Prior acyclovir without clinical benefit. 4. Life expectancy of at least 3 months. 5. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CREATININE: < 2.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 50. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Ganciclovir (provided drug was administered for at least 14 days prior to study entry, and the HSV isolate exhibits resistance against acyclovir). 2. Other medication considered necessary for patient's welfare, at the discretion of the investigator. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: Previous participation in the study. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Intravenous foscarnet within 2 months prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Intravenous foscarnet for current episode of HSV. 2. Acyclovir, interferon, or any investigational drug that might have anti-HSV activity (e.g., 256U87, HPMPC, VBD-araU, trifluridine). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known hypersensitivity to the study drug. 2. Any medical, psychiatric, or other condition that would preclude study compliance. 3. Incapable of self administration of medication or presence of a care provider administering medication. SUBSTANCE IDENTIFICATION Drug 1 DRG-0017 Foscarnet sodium MANUFACTURERS Drug 1: Astra Pharmaceutical Products Incorporated 50 Otis Street Westborough, MA 01581-4500 Contact: Sandra Gulezian (800) 388-4148 Contact: (508) 366-1100 X 2309. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1 percent cream applied 5 times daily for up to 6 week SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Topical OTHER TREATMENT INFO. TREATMENT DURATION: Up to 6 weeks. SUPPORTING AGENCY Astra Pharmaceutical Products Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Foscarnet/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Herpes Simplex/COMPLICATIONS/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 4428-95-9 (Foscarnet) LAST REVISION DATE 941206 ENTRY MONTH 9412 FLORIDA South Miami Hospital 7000 Southwest 62nd Avenue / Suite 650 South Miami, FL 33143 Contact: Dr Michael Wohlfeiler (305) 661-1150 OPEN 941206. ILLINOIS Dr Thomas Klein 711 West North Avenue / Suite 209 Chicago, IL 60610 Contact: Dr Thomas Klein (312) 280-0996 OPEN 941206. NEW YORK Bellevue Hospital Center AIDS Program First Avenue and 27th Street / Room 12 East 12 New York, NY 10016 Contact: Dr Kedernath Javaly (212) 561-3906 OPEN 941206. RHODE ISLAND Roger Williams Hospital 825 Chalkstone Avenue Providence, RI 02908 Contact: Dr Gail Skowron (401) 456-2437 Contact: Dr David Friedman OPEN 941206. 77 UNIQUE IDENTIFIER FDA/00685 PROTOCOL ID NUMBERS FDA 239A PROTOCOL TITLE Treatment of Psoriasis Using Acitretin in HIV-Positive Patients. VERSION NUMBER & DATE (941006) TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To determine the efficacy of acitretin in the treatment of psoriasis in HIV/AIDS patients. GENERAL DESCRIPTION RATIONALE: Etretinate, a retinoid, has proven successful in the treatment of HIV-infected patients with psoriasis, but it has an elimination half-life of 100 days. Acitretin, a metabolite of etretinate, has a much shorter half-life of 2 to 3 days. Acitretin has proven effective in treating psoriasis in patients without HIV infection by reducing skin involvement and clearing of the condition, but it has not been thoroughly evaluated in HIV-infected patients. GENERAL DESCRIPTION METHODOLOGY: Patients receive acitretin (0.35 mg/kg) daily, with dose increases every 4 weeks based on quantitative assessment of the skin using the Psoriasis Area and Severity Index (PASI). Treatment continues for a total of 20 weeks. Patients are followed every 2 weeks. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (930909) DISEASE STUDIED Psoriasis. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV positive. 2. Psoriasis involving at least 10 percent of body surface. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS 65-93(2) STUDY DESIGN Randomized; Controlled PROTOCOL DETAILS STUDY INTENT: Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 30 patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Psoriasis involving at least 10 percent of body surface. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 18 Years - 55 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Postmenopausal or permanent sterility including hysterectomy or bilateral tubal ligation. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Any nondermatologic medication. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 56 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Reproductive potential. SUBSTANCE IDENTIFICATION Drug 1 DRG-0218 Acitretin TRADE NAME OF SUBSTANCE Drug 1‰ Soriatane MANUFACTURERS Drug 1: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Beginning dose of 0.35 mg/kg/day (maximum 25 mg/day), with possible dose increases q 4 weeks up to 1.4 mg/kg/day (max100 mg/day) SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 0.35 mg/kg (maximum 25 mg), with possible increases q 4weeks up to 1.4 mg/kg (maximum 100 mg) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral OTHER TREATMENT INFO. TREATMENT DURATION: 20 weeks. SUPPORTING AGENCY Hoffmann-La Roche, Incorporated. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acitretin/ADMINISTRATION & DOSAGE/ *THERAPEUTIC USE MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Psoriasis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 55079-83-9 (Acitretin) LAST REVISION DATE 930909 ENTRY MONTH 9411 NEW YORK Beth Israel Medical Center 1st Avenue at 16th Street New York, NY 10003 Contact: Dr Laura Buccheri (212) 420-2184 OPEN 941121. 78 UNIQUE IDENTIFIER FDA/00642 PROTOCOL ID NUMBERS FDA 237A PROTOCOL TITLE A Phase I Trial to Evaluate the Safety, Tolerance, and Pharmacokinetics of 935U83 After Multiple Dosing in Patients With HIV Infection. VERSION NUMBER & DATE (940722) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To assess the safety, tolerance, and steady-state pharmacokinetics of multiple oral doses of 935U83 administered to patients with HIV infection. To obtain preliminary evidence of antiretroviral activity of 935U83. To prospectively evaluate the emergence of in vitro drug resistance. To determine the effects of 935U83 dosing on CD4+ cell counts. Methodology: Patients (10 per dose level) are randomized to receive 100, 200, 300, or 500 mg 935U83 every 8 hours for 12 weeks. Five patients at each dose level must complete 4 weeks of treatment without serious toxicity before subsequent patients are entered at the next higher dose. If lack of antiretroviral effect or unacceptable toxicity is demonstrated at a particular dose level, the dose regimens may be adjusted. GENERAL DESCRIPTION METHODOLOGY: Patients (10 per dose level) are randomized to receive 100, 200, 300, or 500 mg 935U83 every 8 hours for 12 weeks. Five patients at each dose level must complete 4 weeks of treatment without serious toxicity before subsequent patients are entered at the next higher dose. If lack of antiretroviral effect or unacceptable toxicity is demonstrated at a particular dose level, the dose regimens may be adjusted. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (931001) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA (confirmed by Western blot), positive HIV blood culture, or positive HIV serum antigen. 2. CD4 count 200 - 500 cells/mm3 twice within 30 days prior to study entry and at least 7 days apart. 3. No history of or current AIDS-defining indicator disease by CDC criteria. 4. No antiretroviral therapy within the past 6 months. ELIGIBILITY ASYM. ARC. OTHER PROTOCOL NUMBERS 02 STUDY DESIGN Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Pharmacokinetics, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 40 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Minimum of 12 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 7 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CD4 count 200 - 500 cells/mm3. 3. No history of or current AIDS-defining indicator disease by CDC criteria. 4. No antiretroviral therapy within the past 6 months. 5. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 12.0 g/dl. (men); >= 10.5 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 500 cells/mm3. ( 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 2 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 2 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 50 ml/min. PATIENT INCLUSION CRIT. OTHER: Neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 7 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Recommended: PCP prophylaxis for patients whose CD4 counts fall below 200 cells/mm3 or who develop PCP during study participation. Allowed: Acute treatment and secondary prophylaxis for tuberculosis, Mycobacterium avium intracellulare, toxoplasmosis, histoplasmosis, cryptococcosis, disseminated candidiasis, or cytomegalovirus infection. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of chemical, viral, or alcohol-induced clinical hepatitis within the past 3 years. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 7 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Current alcohol or illicit drug use that may interfere with study compliance. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within the past 4 weeks: Radiation therapy. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within the past 6 months: 1. Any antiretroviral therapy. 2. HIV immunotherapeutic vaccine. Excluded within the past 4 weeks: 1. Cytotoxic chemotherapy. 2. Immunomodulating agents such as systemic corticosteroids, IL-2, alpha interferon, beta interferon, or gamma interferon. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Cytotoxic chemotherapy. 2. Other antiretroviral drugs. 3. Immunomodulators. 4. Foscarnet. 5. GM-CSF or G-CSF. 6. Erythropoietin. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patient with the following symptoms or conditions are excluded: 1. Current evidence of chronic hepatitis of any etiology. 2. Seropositivity for HBsAg or hepatitis C virus by second generation ELISA. SUBSTANCE IDENTIFICATION Drug 1 DRG-0215 935U83 MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Lisa Behrens (800) 722-9292 X 3633. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 100, 200, 300, or 500 mg q 8 h for 12 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 300, 600, 900, or 1500 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral OTHER TREATMENT INFO. TREATMENT DURATION: 12 weeks. SUPPORTING AGENCY Burroughs Wellcome. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/*ADVERSE EFFECTS/ PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antiviral Agents) LAST REVISION DATE 931001 ENTRY MONTH 9408 CALIFORNIA ViRx Medical Group 1375 Sutter Street Suite 407 San Francisco, CA 94102 Contact: Joyce Amann (415) 474-4440 OPEN 940722. DISTRICT OF COLUMBIA Georgetown University Medical Center 3800 Reservoir Rd NW / Suite 110 Kober-Cogan Bldg Washington, DC 20007 Contact: Keith Dawson (202) 687-7387 OPEN 940722. FLORIDA Dr Goodgame and Hopkins 340 N Maitland Avenue Maitland, FL 32751 Contact: Chuck DeMarzo (407) 647-6000 OPEN 940722. INDIANA Indiana University Hospital 550 North University Boulevard / Room 5550 Indianapolis, IN 46202 Contact: Kristin Todd (317) 274-8456 Contact: Dr Kenneth FIfe (317) 274-8114 OPEN 940722. NORTH CAROLINA Duke University Medical Center Hosp South Room 0207 / Box 3284 Durham, NC 27710 Contact: Ken Ship (919) 684-5260 OPEN 940722 ACTU: 1601. OHIO University of Cincinnati Medical Center / Holmes Division Eden and Bethesda Avenues Cincinnati, OH 45267 Contact: Jill Leonard (513) 558-8373 OPEN 940722. PENNSYLVANIA University of Pittsburgh / School of Medicine 3515 Fifth Avenue Pittsburgh, PA 15261 Contact: Rosella Rosener (412) 647-8125 OPEN 940722. 79 UNIQUE IDENTIFIER FDA/00649 PROTOCOL ID NUMBERS FDA 236C PROTOCOL TITLE An Open-Label Extension Study of Maintenance Therapy in HIV-Positive Subjects With Fluconazole-Refractory Oropharyngeal Candidiasis Who Have Responded to Itraconazole Oral Solution. VERSION NUMBER & DATE (940819) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To provide maintenance treatment with itraconazole solution for patients who were clinical responders in the ITR-USA-94 protocol, even if they subsequently relapsed. Methodology: Patients who responded to therapy on protocol FDA 236B receive maintenance with itraconazole oral solution for up to 6 months. GENERAL DESCRIPTION METHODOLOGY: Patients who responded to therapy on protocol FDA 236B receive maintenance with itraconazole oral solution for up to 6 months. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940816) DISEASE STUDIED Candidiasis, oropharyngeal. DISEASES STATUS Patients have the following symptoms and conditions: 1. Met criteria for clinical response on protocol FDA 236B with no residual visible lesion of oropharygeal candidiasis upon completion of that study. OR 2. Initial response on protocol FDA 236B with subsequent relapse and retreatment with itraconazole solution or other therapies. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS ITR-USA-107 STUDY DESIGN Open Label; Nonrandomized PROTOCOL DETAILS STUDY INTENT: Drug efficacy. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 6 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Met criteria for clinical response on protocol FDA 236B with no residual visible lesion of oropharygeal candidiasis upon completion of that study OR had initial response on protocol FDA 236B with subsequent relapse and retreatment with itraconazole solution or other therapies. 2. Life expectancy of at least 3 months. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 7.5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 7.5 x ULN. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 7.5 x ULN. PATIENT AGE AGE: 18 Years - 65 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Previously documented disseminated candidiasis. 2. Previous clinically significant adverse event during treatment with itraconazole oral solution, unless clearly attributable to an intercurrent illness or condition. 3. History of significant hepatic abnormalities or clinical evidence of significant hepatic disease within 2 months prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 66 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Any investigational drug (other than itraconazole solution) within 1 month prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Rifampin. 2. Rifabutin. 3. Phenobarbital. 4. Phenytoin. 5. Carbamazepine. 6. Terfenadine. 7. Astemizole. 8. Systemic antifungals. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Underlying clinical condition that would preclude completion of study or place subject at significant risk. 2. Judged unreliable with respect to physician's directives. SUBSTANCE IDENTIFICATION Drug 1 DRG-0044 Itraconazole TRADE NAME OF SUBSTANCE Drug 1‰ Sporanox MANUFACTURERS Drug 1: Janssen Research Foundation 1125 Trenton-Harbourton Road Titusville, NJ 08560-0200 Contact: Unspecified (908) 730-3183. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Administered for up to 6 months SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, solution OTHER TREATMENT INFO. TREATMENT DURATION: Up to 6 months. SUPPORTING AGENCY Janssen Research Foundation. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Candidiasis, Oral/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Itraconazole/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 84625-61-6 (Itraconazole) LAST REVISION DATE 940816 ENTRY MONTH 9408 PENNSYLVANIA Buckley Braffman Stern Medical Associates PC 822 Pine Street / Suite 3A Philadelphia, PA 19107 Contact: Nancy Pietroski (215) 925-8010 OPEN 940819. 80 UNIQUE IDENTIFIER FDA/00638 PROTOCOL ID NUMBERS FDA 236B PROTOCOL TITLE An Open Study of the Effect of Itraconazole Oral Solution for the Treatment of Fluconazole Refractory Oropharyngeal Candidiasis in HIV-Positive Subjects. VERSION NUMBER & DATE (940815) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To assess the efficacy and safety of itraconazole oral solution (100 mg twice daily) in HIV-seropositive patients with oropharyngeal candidiasis that is refractory to fluconazole. Methodology: Patients receive itraconazole oral solution twice daily. Per 08/15/94 amendment, patients with complete resolution of oropharyngeal candidiasis lesions upon completion of treatment are eligible for maintenance treatment on protocol FDA 236C. Patients who decline maintenance are followed for 6 weeks. Patients who relapse during follow-up are re-treated for 14-28 days; if lesions clear, patients may enter the maintenance protocol. GENERAL DESCRIPTION METHODOLOGY: Patients receive itraconazole oral solution twice daily. Per 08/15/94 amendment, patients with complete resolution of oropharyngeal candidiasis lesions upon completion of treatment are eligible for maintenance treatment on protocol FDA 236C. Patients who decline maintenance are followed for 6 weeks. Patients who relapse during follow-up are re-treated for 14-28 days; if lesions clear, patients may enter the maintenance protocol. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940621) DISEASE STUDIED Candidiasis, oropharyngeal. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV antibody seropositive or diagnosis of AIDS. 2. Oropharyngeal candidiasis characterized by white patches on oral mucosal surfaces or typcial erythematous lesions on oral mucosal surfaces, and confirmed by histologic exam and culture. 3. Failed fluconazole treatment within the past 14 days (minimum 200 mg daily for 2 weeks or more). 4. NO symptoms of esophageal candidiasis (e.g., dysphagia) unless endoscopic exam of esophagus was performed and fungal esophagitis was not present. 5. NO prior disseminated candidiasis. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS ITR-USA-94 STUDY DESIGN Open Label PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 18 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV antibody seropositivity or diagnosis of AIDS. 2. Confirmed oropharyngeal candidiasis. 3. Failed fluconazole treatment within the past 14 days. 4. Life expectancy of at least 3 months. 5. NO symptoms of esophageal candidiasis (e.g., dysphagia) unless endoscopic exam of esophagus was performed and fungal esophagitis was not present. 5. NO prior disseminated candidiasis. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 7.5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 7.5 x ULN. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 7.5 x ULN. PATIENT AGE AGE: 18 Years - 65 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of hypersensitivity to imidazole or azole compounds. 2. Clinical evidence of significant hepatic disease within the past 2 months. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 66 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Investigational drugs within 1 month prior to study entry (approved expanded access drugs are permitted). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Investigational drugs (approved expanded access drugs are permitted). 2. Rifampin. 3. Rifabutin. 4. Phenobarbital. 5. Phenytoin. 6. Carbamazepine. 7. Terfenadine. 8. Astemizole. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Underlying clinical condition that precludes study completion or places the patient at significant risk. 2. Considered unreliable about following physician's directives. SUBSTANCE IDENTIFICATION Drug 1 DRG-0044 Itraconazole MANUFACTURERS Drug 1: Janssen Research Foundation 1125 Trenton-Harbourton Road Titusville, NJ 08560-0200 Contact: Unspecified (908) 730-3183. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 100 mg twice daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 200 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, solution SUPPORTING AGENCY Janssen Research Foundation. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Candidiasis, Oral/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Itraconazole/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 84625-61-6 (Itraconazole) LAST REVISION DATE 940621 ENTRY MONTH 9407 ALABAMA University of Alabama at Birmingham 980 20th St South Room 245B Birmingham, AL 35294 Contact: Michael S Saag (205) 854-3583 OPEN 940607. ARKANSAS University of AR for Medical Sciences 4301 West Markham Street Mail Slot 639 Little Rock, AR 72205 Contact: Robert W Bradsher Jr (501) 686-5585 OPEN 940607. CALIFORNIA Dr W Jeffrey Fessel 2200 OFarrel San Francisco, CA 94115 Contact: Dr W Jeffrey Fessel (415) 202-3485 OPEN 940607. CALIFORNIA East Bay AIDS Center 3031 Telegraph Avenue Suite 235 Berkeley, CA 94705 Contact: Nancy Orcutt (510) 204-1291 OPEN 940607. DISTRICT OF COLUMBIA Dr Douglas Ward 1737 20th Street NW Washington, DC 20009 Contact: Dr Douglas Ward (202) 745-0201 OPEN 940607. DISTRICT OF COLUMBIA The George Washington Univ Med Ctr / Div of Infect Diseases 2150 Pennsylvania Avenue NW / Suite 5-403 Washington, DC 20037 Contact: Dr Carmelita Tuazon (202) 994-4716 Contact: (202) 994-4179 OPEN 940607. DISTRICT OF COLUMBIA Veterans Administration Medical Center Infect Disease Sect 50 Irving Street NW Washington, DC 20422 Contact: Dr Virginia Kan (202) 745-8301 OPEN 940607. INDIANA Infectious Disease Research Clinic / Indiana Univ Hospital 550 North University Blvd Room 5550 Indianapolis, IN 46202 Contact: Dr Mitchell Goldman (317) 630-6262 OPEN 940607. MARYLAND National Institute of Allergy & Infectious Diseases Bldg 10 Rm 11C304 Bethesda, MD 20892 Contact: Dr Antonia Geber (301) 496-1238 OPEN 940607. MICHIGAN Veterans Administration Medical Center Inf Diseases Sect 2215 Fuller Road Ann Arbor, MI 48105 Contact: Dr Carol Ann Kauffman (313) 761-7984 OPEN 940607. MICHIGAN Wayne State University / Harper Hospital 4160 John R Suite 202 Harper Hospital Detroit, MI 48201 Contact: Dr Jose Vazquez (313) 745-0457 OPEN 940607. MISSOURI Washington University Clinical Trials Unit 4511 Forest Park Suite 304 St Louis, MO 63108 Contact: William G Powderly (314) 454-0058 OPEN 940607. OHIO Ohio State University Division of Infectious Disease 410 W 10th Avenue N-1135 Doan Hall Columbus, OH 43210 Contact: Dr Susan L Koletar (614) 293-8745 OPEN 940607. OKLAHOMA Veterans Administration Medical Center 921 Northeast 13th Street 111C Oklahoma City, OK 73104 Contact: Dr Ronald Greenfield (405) 270-0501 OPEN 940607. PENNSYLVANIA Pennsylvania Hospital 822 Pine Street Suite 3a Philadelphia, PA 19107 Contact: John J Stern (215) 925-8010 OPEN 940607. 81 UNIQUE IDENTIFIER FDA/00637 PROTOCOL ID NUMBERS FDA 236A PROTOCOL TITLE Randomized, Controlled, Double-Blind Study of Itraconazole Oral Solution Versus Fluconazole Tablets for the Treatment of Esophageal Candidiasis. VERSION NUMBER & DATE (940621) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the safety and efficacy of itraconazole oral solution (100-200 mg daily) versus fluconazole tablets (100-200 mg daily) for the treatment of esophageal candidiasis in immunocompromised patients. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940607) DISEASE STUDIED Candidiasis, esophageal. DISEASES STATUS Patients have the following symptoms and conditions: 1. Esophageal candidiasis characterized by dysphagia, odynophagia, retrosternal/oropharyngeal discomfort, confirmed by endoscopy. 2. Histological evidence of Candida spp. at baseline with confirmation by positive mycological culture. 3. HIV infection or other predisposing risk factor, such as antibiotic, corticosteroid, or radiation therapy, or myelosuppression. ELIGIBILITY AIDS. OTHER - immunocompromised. OTHER PROTOCOL NUMBERS ITR-USA-12 STUDY DESIGN Controlled; Randomized; Double-Blind PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Comparative drug therapy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 18 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Esophageal candidiasis. 2. Histological evidence of Candida spp. at baseline with confirmation by positive mycological culture. 3. HIV infection or other predisposing risk factor. 4. Life expectancy of at least 2 months. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of significant hepatic abnormalities or clinical evidence of hepatic disease within 2 months prior to study entry. 2. History of hypersensitivity to imidazole or azole compounds. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Other orally administered antifungal therapy within 3 days prior to study entry. 2. Any investigational drug within 1 month prior to study entry (expanded access drugs are allowed). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Rifampin. 2. Rifabutin. 3. Phenobarbital. 4. Phenytoin. 5. Carbamazepine. 6. Terfenadine. 7. Astemizole. 8. H2 blockers. 9. Continual antacids. 10. Any investigational drug (expanded access drugs are allowed). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Malignancies of the head or neck, if the treatment or disease will interfere with response assessment. 2. Evidence of systemic fungal infection. 3. Underlying clinical condition that would preclude study completion. 4. Judged to be unreliable in regard to following physician's directives. SUBSTANCE IDENTIFICATION Drug 1 DRG-0044 Itraconazole SUBSTANCE IDENTIFICATION Drug 2 DRG-0005 Fluconazole TRADE NAME OF SUBSTANCE Drug 1‰ Sporanox MANUFACTURERS Drug 1: Janssen Research Foundation 1125 Trenton-Harbourton Road / PO Box 200 Titusville, NJ 08560-0200 Contact: Unspecified (908) 730-3139. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 100-200 mg once daily for 3-8 weeks. Drug 2: 100-200 mg once daily for 3-8 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 100-200 mg. Drug 2: 100-200 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, solution. Drug 2: Oral, tablets OTHER TREATMENT INFO. TREATMENT DURATION: 3 - 8 weeks. SUPPORTING AGENCY Janssen Research Foundation. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Candidiasis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Fluconazole/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Immunocompromised Host MESH HEADING Itraconazole/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 84625-61-6 (Itraconazole) CAS REGISTRY NUMBER 86386-73-4 (Fluconazole) LAST REVISION DATE 940607 ENTRY MONTH 9406 ARIZONA Dr Eskild A Petersen 1501 N Campbell Avenue / Section of Infectious Diseases Tucson, AZ 85724 Contact: Dr Eskild A Petersen (602) 626-5184 OPEN 940607. CALIFORNIA Los Angeles - USC Medical Center / GI and Liver Disease 1200 North State Street / Room 12-137 Los Angeles, CA 90033 Contact: Francisco Garcia (213) 226-6939 Contact: Dr Loren Laine (213) 226-7994 Contact: (213) 226-7995 OPEN 940607. CALIFORNIA UCSD Medical Center 200 W Arbor San Diego, CA 92103 Contact: Dr Robert H Goldklang (619) 543-3252 OPEN 940607. DISTRICT OF COLUMBIA The George Washington Univ Med Ctr / Div of Infect Diseases 2150 Pennsylvania Avenue NW / Suite 5-403 Washington, DC 20037 Contact: Dr Carmelita Tuazon (202) 994-4716 Contact: (202) 994-4179 OPEN 940607. GEORGIA Emory University School of Medicine / GI Division 69 Butler Street SE Atlanta, GA 30303 Contact: Lorraine Alexander (404) 616-4436 Contact: Dr C Mel Wilcox (404) 616-4435 Contact: Fax (404) 522-0404 OPEN 940607. ILLINOIS Rush Medical Center 600 South Paulina / Suite 143 AcFac Chicago, IL 60612 Contact: Dr John C Pottage Jr (312) 942-5865 OPEN 940607. MARYLAND Johns Hopkins University School of Medicine 1830 E Monument Street Suite 7401 Baltimore, MD 21205 Contact: Dr Joel Gallant (410) 955-1754 OPEN 940607. MICHIGAN Wayne State University c/o Harper Hospital / 3990 John R Detroit, MI 48201 Contact: Dr Ravi Dhar (313) 745-7521 OPEN 940607. MISSOURI University of Missouri - Kansas City 2411 Holmes Kansas City, MO 64108 Contact: Dr Stuart Chen (816) 556-3768 OPEN 940607. MISSOURI Dr David S McKinsey 2316 East Meyer Blvd Kansas City, MO 64132 Contact: Dr David S McKinsey (816) 276-4038 OPEN 940607. NORTH CAROLINA Bowman Gray School of Medicine Medical Center Boulevard Winston Salem, NC 27157 Contact: Dr P Samuel Pegram (910) 716-4246 OPEN 940607. NORTH CAROLINA University of No Carolina / Department of Medicine CB #7080 Burnett Womack Chapel Hill, NC 27514 Contact: Dr Eugene Bozymski (919) 966-2511 OPEN 940607. NEW YORK Dr Douglas Dieterich 345 East 37th Street Suite 204 New York, NY 10016 Contact: Kathleen Farrell (212) 263-6485 Contact: Dr Douglas Dieterich (212) 986-3330 OPEN 940607. NEW YORK Montefiore Medical Center 111 E 210th Street Bronx, NY 10467 Contact: Dr Larry Brandt (718) 920-4476 Contact: Dr Aaron Tokayer (718) 920-4476 OPEN 940607. NEW YORK Erie County Medical Center 462 Grider Street Buffalo, NY 14215 Contact: Dr Ross G Hewitt (716) 898-4119 OPEN 090607. OHIO Division of Infectious Disease / ACTU 2061 Cornell Road Room 120 Foley Building Cleveland, OH 44106 Contact: Dr John Carey (216) 844-8786 OPEN 940607. 82 UNIQUE IDENTIFIER FDA/00636 PROTOCOL ID NUMBERS FDA 235B PROTOCOL TITLE Randomized Study Comparing Itraconazole to Placebo in the Prevention of Histoplasmosis in Patients With Human Immunodeficiency Virus Infection. VERSION NUMBER & DATE (940621) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To assess the safety and efficacy of itraconazole (200 mg daily) versus placebo for prevention of histoplasmosis in HIV-infected patients with CD4 counts < 150 cells/mm3 who reside where histoplasmosis is endemic. To assess the safety and efficacy of itraconazole for preventing other debilitating fungal infections, such as cryptococcosis, aspergillosis, recalcitrant oropharyngeal or vaginal candidiasis, and recurrent esophageal candidiasis. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940607) DISEASE STUDIED Histoplasmosis. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA or Western blot. 2. Residing in an area endemic for H. capsulatum. 3. Absolute CD4 count < 150 cells/mm3. 4. No current or past active histoplasmosis. 5. No other active fungal infection. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS MSG 28. ITR-USA-73 STUDY DESIGN Randomized; Comparative PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Drug prophylaxis. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 7 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Residence in an area endemic for H. capsulatum. 3. Absolute CD4 count < 150 cells/mm3. 4. No current or past active histoplasmosis. 5. No other active fungal infection. 6. Life expectancy of at least 1 year. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: < 150 cells/mm3. ( 0 - 100 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 5 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of intolerance to imidazole or azole compounds. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 1 month prior to study entry: Investigational drugs (expanded access drugs are acceptable). Excluded within 15 days prior to study entry: 1. Rifampin. 2. Rifabutin. 3. Terfenadine. 4. Astemizole. 5. Phenobarbital. 6. Phenytoin. 7. Carbamazepine. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Systemically-active antifungals. 2. Investigational drugs (expanded access drugs are acceptable). 3. Rifampin. 4. Rifabutin. 5. Terfenadine. 6. Astemizole. 7. Phenobarbital. 8. Phenytoin. 9. Carbamazepine. 10. H2 blockers. 11. Omeprazole. 12. Continual antacids. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Life-threatening infection or malignancy other than cutaneous Kaposi's sarcoma. 2. Inability to take oral medication. SUBSTANCE IDENTIFICATION Drug 1 DRG-0044 Itraconazole TRADE NAME OF SUBSTANCE Drug 1‰ Sporanox MANUFACTURERS Drug 1: Janssen Research Foundation 1125 Trenton-Harbourton Road / PO Box 200 Titusville, NJ 08560-0200 Contact: Unspecified (908) 730-3139. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg (or placebo) daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 200 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral SUPPORTING AGENCY Janssen Research Foundation. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Histoplasmosis/COMPLICATIONS/*PREVENTION & CONTROL MESH HEADING Human MESH HEADING Itraconazole/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 84625-61-6 (Itraconazole) LAST REVISION DATE 940607 ENTRY MONTH 9406 INDIANA Infectious Disease Research Clinic 550 North University Blvd Room 5550 Indianapolis, IN 46202 Contact: Dr L Joseph Wheat (317) 630-6262 OPEN 940607. INDIANA Infectious Diseases of Indianapolis 10610 N Pennsylvania / Suite A Indianapolis, IN 46280 Contact: Dr Joseph Fraiz (317) 587-2300 Contact: Dr Thomas Slama (317) 587-2300 OPEN 940607. MISSOURI University of Missouri School of Medicine - Kansas City 2411 Holmes / Red 4 Unit Kansas City, MO 64108 Contact: Dr David Bamberger (816) 276-1940 OPEN 940607. MISSOURI Infectious Disease Association of Kansas City 2316 E Meyer Street Kansas City, MO 64132 Contact: Dr David McKinsey (816) 276-4038 OPEN 940607. 83 UNIQUE IDENTIFIER FDA/00631 PROTOCOL ID NUMBERS FDA 234D PROTOCOL TITLE A Pilot Study of OPC-8212 (Vesnarinone) in Persons With AIDS-Related Kaposi's Sarcoma. VERSION NUMBER & DATE (940517) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: To examine the safety and efficacy of 60 or 90 mg vesnarinone in patients with AIDS-related Kaposi's sarcoma. Methodology: Twenty-eight patients (14 per cohort) receive daily vesnarinone at one of two doses. At least seven patients at the lower dose must have completed 2 weeks of therapy before subsequent patients are entered at the higher dose. Patients who successfully complete 16 weeks of treatment may receive maintenance therapy for the duration of the study (approximately 12-18 months). GENERAL DESCRIPTION METHODOLOGY: Twenty-eight patients (14 per cohort) receive daily vesnarinone at one of two doses. At least seven patients at the lower dose must have completed 2 weeks of therapy before subsequent patients are entered at the higher dose. Patients who successfully complete 16 weeks of treatment may receive maintenance therapy for the duration of the study (approximately 12-18 months). PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940401) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA confirmed by a secondary test. 2. Biopsy-proven Kaposi's sarcoma. 3. No current constitutional signs of HIV disease. 4. No active AIDS-defining opportunistic infection, malignancy (other than Kaposi's sarcoma), or other medical condition by CDC criteria. NOTE: For each cohort, seven patients must have CD4 count < 200 cells/mm3 and seven patients must have CD4 count > 200 cells/mm3. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 22-93-254 STUDY DESIGN Open Label; Dose Escalating PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 28 patients. (14 patients in each of 2 cohorts) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 12 - 18 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. Kaposi's sarcoma. 3. No current constitutional signs of HIV disease or AIDS-defining conditions other than Kaposi's sarcoma. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 1.5 mg/dl. (except for patients with Gilbert's disease. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 70. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. TSH < 1.5 x ULN. Electrolytes within normal limits. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Limited electron-beam radiation therapy to non-marker lesions for treatment of Kaposi's sarcoma. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Chemoprophylaxis for Pneumocystis carinii, candida, and mycobacteria. 2. Acyclovir as acute treatment for herpes outbreaks. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Prior history of significant cardiac disease or anomaly. 2. History of agranulocytosis or severe grade 3 drug-induced neutropenia or documented abnormalities in granulocyte function. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active illicit drug abuse (specifically cocaine, amyl nitrate, heroin, or other cardioactive agents). PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within 30 days prior to study entry: Blood or cellular blood product. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy including electron beam irradiation (other than limited electron-beam radiation to non-marker lesions for treatment of Kaposi's sarcoma). PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. AZT within 14 days prior to study entry. 2. Acyclovir as prophylaxis for herpes within 48 hours prior to study entry. Excluded within 30 days prior to study entry: 1. Interferon. 2. Biologic response modifiers. 3. Cytotoxic chemotherapy. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antiretroviral agents, including ddI, ddC, AZT, and d4T. 2. Immunosuppressive agents. 3. Investigational HIV drugs/therapies including vaccines (except those on treatment IND for approved indications). 4. Other anti-Kaposi's sarcoma/HIV drugs. 5. Corticosteroids (other than topical). 6. Biologic response modifiers. 7. Megestrol acetate. 8. Agents known to cause neutropenia. 9. Trimethoprim/sulfamethoxazole in excess of 160 mg trimethoprim and 800 mg sulfamethoxazole thrice weekly. 10. Cytotoxic chemotherapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active malignancy other than Kaposi's sarcoma, cutaneous basal cell carcinoma, or in situ carcinoma of the cervix. 2. Current significant cardiac disease or anomaly (including prolonged QTC on EKG). 3. Abnormal cardio-thoracic ratio on chest x-ray. SUBSTANCE IDENTIFICATION Drug 1 DRG-0210 Vesnarinone TRADE NAME OF SUBSTANCE Drug 1‰ OPC-8212 MANUFACTURERS Drug 1: Otsuka America Pharmaceutical Inc 2440 Research Blvd Rockville, MD 20874 Contact: Dr Robert G Petit (301) 990-0030. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 60 or 90 mg/day for up to 18 months SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 60 or 90 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, tablets OTHER TREATMENT INFO. TREATMENT DURATION: 12 - 18 months. SUPPORTING AGENCY Otsuka America Pharmaceutical Inc. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Quinolines/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 81840-15-5 (OPC 8212) LAST REVISION DATE 940401 ENTRY MONTH 9405 CALIFORNIA UCLA School of Medicine / Division of Hematology / Oncology Room 60 051 CHS Los Angeles, CA 90012-1973 Contact: Dr Ronald Mitsuyasu (310) 206-6414 OPEN 940401. ILLINOIS Northwestern University Medical School 233 East Erie Street / Suite 700 Chicago, IL 60611 Contact: Dr J Hayden von Roenn (312) 908-9412 OPEN 940401. 84 UNIQUE IDENTIFIER FDA/00630 PROTOCOL ID NUMBERS FDA 234C PROTOCOL TITLE A Long-Term, Follow-On Safety Study of Four Doses of OPC-8212 (Vesnarinone) in HIV-Infected Persons. VERSION NUMBER & DATE (940517) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To examine the continued safety and tolerability of four doses of vesnarinone in HIV-infected patients who have completed a short-term study (less than 12 months on continuous treatment) of the drug. Methodology: Patients who have completed a limited duration study (less than 12 months of continuous treatment) of vesnarinone on protocols FDA 234A or FDA 234B and who have no current signs or symptoms of AIDS-defining illnesses may roll over to this study and continue receiving their regimen of vesnarinone for 12 months beyond their original participation. GENERAL DESCRIPTION METHODOLOGY: Patients who have completed a limited duration study (less than 12 months of continuous treatment) of vesnarinone on protocols FDA 234A or FDA 234B and who have no current signs or symptoms of AIDS-defining illnesses may roll over to this study and continue receiving their regimen of vesnarinone for 12 months beyond their original participation. PROTOCOL PHASE OTHER OPEN/CLOSED INDICATOR Open: Actively accruing patients (940517) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients meet the following criteria: Successful completion of short-term therapy with vesnarinone on FDA 234A or FDA 234B. ELIGIBILITY ASYM. AIDS. OTHER PROTOCOL NUMBERS 22-93-253 STUDY DESIGN Open Label; Dose Comparison; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: OPEN patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 12 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients meet the following criteria: Successful completion of short-term therapy with vesnarinone on FDA 234A or FDA 234B. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. (men); >= 8.0 (women). PATIENT INCLUSION CRIT. PLATELET COUNT: Criteria met for protocol FDA 234A or FDA 234B. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. Criteria met for protocol FDA 234A or FDA 234B. PATIENT INCLUSION CRIT. BILIRUBIN: < 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: Criteria met for protocol FDA 234A or FDA 234B. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils: Criteria met for protocol FDA 234A or FDA 234B. Alkaline phosphatase < 5 x ULN. TSH < 1.5 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Chemoprophylaxis for Pneumocystis carinii, candida, and mycobacteria. 2. Acyclovir for acute treatment of herpes. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Poor compliance (less than 80 percent of drug taken) on the Phase I protocol (FDA 234A or FDA 234B). 2. Missed more than one clinic visit on the Phase I protocol. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active illicit drug abuse. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Acyclovir as prophylaxis for herpes within 48 hours prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antiretroviral agents, including ddI, ddC, AZT, and d4T. 2. Immunosuppressive agents. 3. Investigational HIV drugs/therapies including vaccines. 4. Interferon or other immunomodulating agents. 5. Corticosteroids (other than topical). 6. Megestrol acetate. 7. Agents known to cause neutropenia. 8. Ganciclovir. 9. Cytotoxic chemotherapy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0210 Vesnarinone TRADE NAME OF SUBSTANCE Drug 1‰ OPC-8212 MANUFACTURERS Drug 1: Otsuka America Pharmaceutical Inc 2440 Research Blvd Rockville, MD 20874 Contact: Dr Robert G Petit (301) 990-0030. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 30, 60, 90, or 120 mg/day for 12 months SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 30, 60, 90, or 120 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, Tablets OTHER TREATMENT INFO. TREATMENT DURATION: 12 months. SUPPORTING AGENCY Otsuka America Pharmaceutical Inc. MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Quinolines/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 81840-15-5 (OPC 8212) LAST REVISION DATE 940517 ENTRY MONTH 9405 CALIFORNIA UCLA School of Medicine / Division of Hematology / Oncology Room 60 051 CHS Los Angeles, CA 90012-1973 Contact: Dr Ronald Mitsuyasu (310) 206-6414 OPEN 940517. GEORGIA AIDS Research Consortium of Atlanta 131 Ponce de Leon / Suite 130 Atlanta, GA 30308 Contact: Dr Melanie Thompson (404) 876-2317 OPEN 940517. 85 UNIQUE IDENTIFIER FDA/00629 PROTOCOL ID NUMBERS FDA 234B PROTOCOL TITLE A Phase I Safety and Tolerability Study of Four Doses of OPC-8212 (Vesnarinone) in Advanced HIV Disease. VERSION NUMBER & DATE (940517) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the safety and tolerability of four doses of oral vesnarinone in patients with advanced HIV disease. Methodology: Fourteen patients per dose level receive vesnarinone at 30, 60, 90, and 120 mg/day for 12 weeks. At least seven patients at a given dose level must have completed 4 weeks of treatment before dose is escalated in subsequent patients. GENERAL DESCRIPTION METHODOLOGY: Fourteen patients per dose level receive vesnarinone at 30, 60, 90, and 120 mg/day for 12 weeks. At least seven patients at a given dose level must have completed 4 weeks of treatment before dose is escalated in subsequent patients. PROTOCOL PHASE Phase I B OPEN/CLOSED INDICATOR Open: Actively accruing patients (940401) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA confirmed by Western blot. 2. CD4 count 50 - 300 cells/mm3 obtained 24 hours to 21 days apart, with the second count obtained within 21 days prior to study entry. 3. No active opportunistic infections. 4. No fever, diarrhea, or Herpes zoster. ELIGIBILITY ASYM. AIDS. OTHER PROTOCOL NUMBERS 22-93-252 STUDY DESIGN Open Label; Dose Escalating; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 56 patients. (14 patients at each of four dose levels) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 12 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. CD4 count 50 - 300 cells/mm3. 3. No active opportunistic infections. 4. No fever, diarrhea, or Herpes zoster. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. (men); >= 8.0 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 50 - 300 cells/mm3. ( 100 - 200 - 300 ). PATIENT INCLUSION CRIT. BILIRUBIN: < 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 70. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1200 cells/mm3. Alkaline phosphatase < 5 x ULN. TSH < 1.5 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Chemoprophylaxis for Pneumocystis carinii, candida, mycobacteria, and other opportunistic infections. 2. Acyclovir for up to 14 days for acute herpes outbreaks. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Prior history of cardiac disease. 2. History of agranulocytosis or severe (grade 3 or worse) drug-induced neutropenia or documented abnormalities in granulocyte function. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active use of illicit drugs (specifically cocaine, amyl nitrate, heroin, and other cardioactive agents). PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within 30 days prior to study entry: 1. Erythropoietin, transfusion, or blood product use. 2. Radiation therapy (including electron beam irradiation). PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. AZT, ddI, ddC, d4T, or other nucleoside analog antiretroviral therapy within 14 days prior to study entry. 2. Prior cytotoxic chemotherapy. 3. Acyclovir for herpes prophylaxis within 48 hours prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antiretroviral agents, including ddI, ddC, AZT, and d4T. 2. Immunosuppressive agents. 3. Investigational HIV drugs/therapies including vaccines. 4. Interferon or other immunomodulating agents. 5. Corticosteroids (other than topical). 6. Hematopoietins. 7. Megestrol acetate. 8. Agents known to cause neutropenia. 9. Trimethoprim/sulfamethoxazole in excess of 160 mg trimethoprim and 800 mg sulfamethoxazole thrice weekly. 10. Cytotoxic chemotherapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Clinically significant current cardiac disease, including patients who exhibit long QTC syndrome on EKG screening and who have an abnormal cardiothoracic ratio on chest x-ray at baseline. 2. Active malignancy (other than cutaneous Kaposi's sarcoma or cutaneous basal cell carcinoma or in situ carcinoma of the cervix). SUBSTANCE IDENTIFICATION Drug 1 DRG-0210 Vesnarinone TRADE NAME OF SUBSTANCE Drug 1‰ OPC-8212 MANUFACTURERS Drug 1: Otsuka America Pharmaceutical Inc 2440 Research Blvd Rockville, MD 20874 Contact: Dr Robert G Petit (301) 990-0030. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 30, 60, 90, or 120 mg/day for 12 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 30, 60, 90, or 120 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, tablets SUPPORTING AGENCY Otsuka America Pharmaceutical Inc. MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Quinolines/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 81840-15-5 (OPC 8212) LAST REVISION DATE 940401 ENTRY MONTH 9405 GEORGIA AIDS Research Consortium of Atlanta 131 Ponce de Leon / Suite 130 Atlanta, GA 30308 Contact: Dr Melanie Thompson (404) 876-2317 OPEN 940401. 86 UNIQUE IDENTIFIER FDA/00628 PROTOCOL ID NUMBERS FDA 234A PROTOCOL TITLE A Phase I Study of Three Doses of OPC-8212 (Vesnarinone) in HIV-Infected Persons With CD4+ Cell Number > 300 Cells/mm3. VERSION NUMBER & DATE (940622) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To examine the safety and tolerance of three doses of oral vesnarinone in HIV-infected patients with CD4 count > 300 cells/mm3. Methodology: Twelve patients per dose level receive vesnarinone at 30, 60, and 90 mg/day for 12 weeks. At least six patients at a given dose level must have completed 2 weeks of treatment before dose is escalated in subsequent patients. GENERAL DESCRIPTION METHODOLOGY: Twelve patients per dose level receive vesnarinone at 30, 60, and 90 mg/day for 12 weeks. At least six patients at a given dose level must have completed 2 weeks of treatment before dose is escalated in subsequent patients. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (930801) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Asymptomatic HIV infections by ELISA confirmed by a secondary test. 2. CD4 count > 300 cells/mm3 on two consecutive occasions 48 hours to 21 days apart, with the second count obtained within 14 days prior to study entry. 3. No prior history of AIDS-defining illness or current constitutional symptoms of HIV disease. ELIGIBILITY ASYM. OTHER PROTOCOL NUMBERS 22-93-251 STUDY DESIGN Open Label; Dose Escalating; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 36 patients. (12 patients at each of three dose levels) PROTOCOL DETAILS STUDY DURATION: 28 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Asymptomatic HIV infection. 2. CD4 count > 300 cells/mm3. 3. No prior AIDS-defining illness or current constitutional symptoms of HIV disease. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. (men); >= 8.0 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: > 300 cells/mm3. ( 300 - 400 - 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. BILIRUBIN: < 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 90. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 2000 cells/mm3. Alkaline phosphatase < 5 x ULN. TSH < 1.5 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Chemoprophylaxis for Pneumocystis carinii, candida, mycobacteria, and herpes simplex. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Prior history of cardiac disease. 2. History of agranulocytosis or severe (grade 3) drug-induced neutropenia or documented abnormalities in granulocyte number or function. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active illicit drug abuse. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Radiation therapy (including electron beam irradiation) within 30 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. AZT, ddI, and ddC within 14 days prior to study entry. 2. Prior cytotoxic chemotherapy. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antiretroviral agents, including ddI, ddC, and AZT. 2. Immunosuppressive agents. 3. Investigational HIV drugs/therapies including vaccines. 4. Interferon. 5. Steroids (other than topical). 6. Hematopoietins. 7. Megestrol acetate. 8. Trimethoprim/sulfamethoxazole in excess of 160 mg trimethoprim and 800 mg sulfamethoxazole thrice weekly. 9. Cytotoxic chemotherapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Current history of cardiac disease, including patients who exhibit long QT syndrome on EKG screening. 2. Active malignancy other than cutaneous basal cell carcinoma or in situ carcinoma of the cervix. SUBSTANCE IDENTIFICATION Drug 1 DRG-0210 Vesnarinone TRADE NAME OF SUBSTANCE Drug 1‰ OPC-8212 MANUFACTURERS Drug 1: Otsuka America Pharmaceutical Inc 2440 Research Blvd Rockville, MD 20874 Contact: Dr Robert G Petit (301) 990-0030. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 30, 60, or 90 mg/day for 12 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 30, 60, or 90 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, tablets SUPPORTING AGENCY Otsuka America Pharmaceutical Inc. MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Quinolines/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS CAS REGISTRY NUMBER 81840-15-5 (OPC 8212) LAST REVISION DATE 930801 ENTRY MONTH 9405 CALIFORNIA UCLA School of Medicine / Division of Hematology / Oncology Room 60 051 CHS Los Angeles, CA 90012-1973 Contact: Dr Ronald Mitsuyasu (310) 206-6414 OPEN 930801. 87 UNIQUE IDENTIFIER FDA/00624 PROTOCOL ID NUMBERS FDA 233A PROTOCOL TITLE A Phase I, Randomized, Single-Dose, Placebo-Controlled Trial to Evaluate the Safety and Pharmacokinetics of 524W91. VERSION NUMBER & DATE (940510) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To assess the safety and pharmacokinetics of single oral doses of 524W91 administered in HIV-infected patients. To determine the effects of food on bioavailability of 524W91. Methodology: Patients are randomized to receive six single escalating doses of 524W91 or placebo, with each dose separated by at least a 6-day washout interval. Doses of 524W91 are 100, 200, 400, 400, 800, and 1200 mg. During the two 400 mg doses, the effect of food on pharmacokinetics will be investigated, with one dose administered in conjunction with a high-fat meal and one dose administered in a fasted state. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive six single escalating doses of 524W91 or placebo, with each dose separated by at least a 6-day washout interval. Doses of 524W91 are 100, 200, 400, 400, 800, and 1200 mg. During the two 400 mg doses, the effect of food on pharmacokinetics will be investigated, with one dose administered in conjunction with a high-fat meal and one dose administered in a fasted state. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940401) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA confirmed by another test. 2. CD4 count >= 200 cells/mm3 within 14 days prior to study entry. 3. No active opportunistic infection. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Single-Blind; Dose Escalating; Pharmacokinetic; Randomized; Placebo-Controlled PROTOCOL DETAILS STUDY INTENT: Drug safety, Pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 18 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Minimum of 11 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. CD4 count >= 200 cells/mm3. 3. No active opportunistic infection. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 11.0 g/dl. (men); >= 10.0 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 200 cells/mm3. ( 200 - 300 - 400 - 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. SGOT(AST): < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 50 ml/min. PATIENT INCLUSION CRIT. OTHER: Neutrophils >= 1500 cells/mm3. PATIENT AGE AGE: 18 Years - 55 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 7 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. WEIGHT: 50 - 85 kg. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of hepatitis, pancreatitis, or cardiomyopathy within the past 5 years. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 56 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 7 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Current alcohol or illicit drug use that may affect patient compliance. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Antiretrovirals within 24 hours prior to each dose. 2. Any prescription or over-the-counter medications within 48 hours prior to each dose. 3. Alcoholic beverages within 48 hours prior to each dose. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded on the day of each dose: 1. Antiretrovirals. 2. Any prescription or over-the-counter medication. 3. Alcoholic beverages. 4. Coffee, tea, and other xanthine-containing beverages and foods. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Malignancy or other condition that would confound study assessment or interfere with ability to complete the study. 2. Malabsorption syndrome or other gastrointestinal dysfunction that might interfere with gastrointestinal absorption. SUBSTANCE IDENTIFICATION Drug 1 DRG-0208 524W91 MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Lisa Behrens (800) 722-9292 X 3633. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Single doses of 100, 200, 400, 400, 800, and 1200 mg (oplacebo), with each dose separated by at least a 6-day washout interval SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, capsules SUPPORTING AGENCY Burroughs Wellcome. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Antiviral Agents/*ADVERSE EFFECTS/ PHARMACOKINETICS MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antiviral Agents) LAST REVISION DATE 940401 ENTRY MONTH 9405 CALIFORNIA ViRx Medical Group 1375 Sutter Street Suite 407 San Francisco, CA 94102 Contact: Joyce Amann (415) 474-4440 OPEN 940401. 88 UNIQUE IDENTIFIER FDA/00683 PROTOCOL ID NUMBERS FDA 232B PROTOCOL TITLE A Phase I/II Study of Safety, Tolerance, Pharmacokinetics, and Anti-HIV Activity of 9-[2-(Bispivaloyloxymethyl)phosphonylmethoxye- thyl]adenine (bis-POM PMEA) and Placebo in HIV-Infected Patients. VERSION NUMBER & DATE (941028) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To study the safety, tolerance, single and multiple dose pharmacokinetics, and anti-HIV activity of bis-POM PMEA versus placebo when administered orally on a daily basis for 2 weeks to HIV-infected patients. Methodology: Patients are randomized to receive bis-POM PMEA at one of three fixed dose levels or placebo daily for 2 weeks. At each dose level, nine patients receive bis-POM PMEA and three patients receive placebo. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive bis-POM PMEA at one of three fixed dose levels or placebo daily for 2 weeks. At each dose level, nine patients receive bis-POM PMEA and three patients receive placebo. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (941028) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA and Western blot OR diagnosis of AIDS by CDC criteria. 2. CD4 count >= 100 cells/mm3 within 35 days prior to study entry. 3. p24 antigen (immune-complex dissociated) >= 50 pg/ml. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS GS-93-402 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Drug Tolerance; Dose Escalating PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Pharmacokinetics, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 36 patients. (12 patients at each of three dose levels) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 2 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. CD4 count >= 100 cells/mm3. 3. p24 antigen (immune-complex dissociated) >= 50 pg/ml. 4. Life expectancy of at least 6 months. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. (women); >= 10.0 g/dl (men). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 100 cells/mm3. ( 100 - 200 - 300 - 400 - 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.8 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 100 IU/l. PATIENT INCLUSION CRIT. SGPT(ALT): <= 100 IU/l. PATIENT INCLUSION CRIT. CREATININE: <= 1.6 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 70. PATIENT INCLUSION CRIT. OTHER: Proteinuria < 2+. Lipase <= 260 IU/l. Neutrophils >= 1000 cells/mm3. Prothrombin time < 14 sec. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior prophylaxis with aerosolized pentamidine, fluconazole, ketoconazole, trimethoprim/sulfamethoxazole, or dapsone. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Prophylaxis with aerosolized pentamidine, fluconazole, ketoconazole, trimethoprim/sulfamethoxazole, or dapsone, provided a stable regimen has been maintained for at least 4 weeks prior to study entry. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of lactose intolerance. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse (including alcohol) as determined by questionnaire or positive drug screen. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 2 weeks prior to study entry: 1. Any parenteral antibiotic therapy. 2. Diuretics. 3. Amphotericin B. 4. Didanosine (ddI). 5. Fluconazole. 6. Foscarnet. 7. Ganciclovir. 8. Interferon-alpha. 9. Interferon-beta. 10. Isoniazid. 11. Aminoglycoside antibiotics. 12. Ketoconazole (topical allowed). 13. Itraconazole. 14. Rifabutin. 15. Rifampin. 16. Stavudine (d4T). 17. Zalcitabine (ddC). 18. Zidovudine (AZT). 19. Lamivudine (3TC). 20. Any investigational agents (except with sponsor approval). Excluded within 4 weeks prior to study entry: Systemic therapy for Kaposi's sarcoma. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Any parenteral antibiotic therapy. 2. Diuretics. 3. Amphotericin B. 4. Didanosine (ddI). 5. Fluconazole. 6. Foscarnet. 7. Ganciclovir. 8. Interferon-alpha. 9. Interferon-beta. 10. Isoniazid. 11. Aminoglycoside antibiotics. 12. Ketoconazole (topical allowed). 13. Itraconazole. 14. Rifabutin. 15. Rifampin. 16. Stavudine (d4T). 17. Zalcitabine (ddC). 18. Zidovudine (AZT). 19. Lamivudine (3TC). 20. Any investigational agents (except with sponsor approval). 21. Systemic therapy for Kaposi's sarcoma. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active, serious infection (other than HIV infection) requiring parenteral antibiotic therapy. 2. Malignancy other than cutaneous Kaposi's sarcoma. 3. Clinically significant cardiac disease, including symptoms of ischemia, congestive heart failure, or arrhythmia. 4. Gastrointestinal malabsorption syndrome. 5. Inability to take oral medication. SUBSTANCE IDENTIFICATION Drug 1 DRG-0209 bis-POM PMEA MANUFACTURERS Drug 1: Gilead Sciences Inc 353 Lakeside Drive Foster City, CA 94404 Contact: Dr Jay Toole (415) 573-4751. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 125, 250, or 500 mg (or placebo) daily for 2 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 125, 250, or 500 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, tablets OTHER TREATMENT INFO. TREATMENT DURATION: 2 weeks. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Requirement for parenteral therapy of a serious illness. SUPPORTING AGENCY Gilead Sciences Inc. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adenine/ANALOGS & DERIVATIVES/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Adult MESH HEADING Antiviral Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 106941-25-7 (9-(2-phosphonylmethoxyethyl)adenine) LAST REVISION DATE 941028 ENTRY MONTH 9411 MARYLAND Johns Hopkins University 600 North Wolfe Street Baltimore, MD 21205 Contact: Dr Paul Lietman (410) 955-9707 OPEN 941028. 89 UNIQUE IDENTIFIER FDA/00625 PROTOCOL ID NUMBERS FDA 232A PROTOCOL TITLE Phase I Study of the Safety, Tolerance, and Pharmacokinetics of 9-[2-(Bispivaloyloxymethyl)phosphonylmethoxye- thyl]adenine (bis-POM PMEA) in HIV-Infected Patients. VERSION NUMBER & DATE (940506) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To study the safety, tolerance, and pharmacokinetics of a single dose of bis-POM PMEA when administered by the oral route in patients with HIV infection. Methodology: Five patients are entered at each of three dose levels of bis-POM PMEA: 200, 350, and 500 mg administered orally in a single dose. GENERAL DESCRIPTION METHODOLOGY: Five patients are entered at each of three dose levels of bis-POM PMEA: 200, 350, and 500 mg administered orally in a single dose. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940506) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: HIV seropositive by ELISA and Western blot OR a clinical syndrome indicative of AIDS by CDC criteria. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS GS-93-401 STUDY DESIGN Single Dose; Dose Escalating; Drug Tolerance; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 15 patients. (5 patients at each of three dose levels) PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection or diagnosis of AIDS. 2. Life expectancy of at least 3 months. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. (women); >= 10.0 g/dl (men). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 70 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 70. PATIENT INCLUSION CRIT. OTHER: < 1+ proteinuria. Lipase within normal limits. Neutrophils >= 1000 cells/mm3. PT < 14 seconds. PTT < 40 seconds. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: 1. Prior AZT, ddI, or ddC. 2. Prophylactic aerosolized pentamidine, fluconazole, ketoconazole, trimethoprim/sulfamethoxazole, or dapsone. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. AZT, ddI, or ddC (provided patient has been on a stable regimen for at least 4 weeks prior to study entry). 2. Prophylactic aerosolized pentamidine, fluconazole, ketoconazole, trimethoprim/sulfamethoxazole, or dapsone (provided patient has been on a stable regimen for at least 4 weeks prior to study entry). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse (including alcohol or drug abuse). PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 2 weeks prior to study entry: 1. Diuretics. 2. Amphotericin B. 3. Aminoglycoside antibiotics. 4. Parenteral antibiotics. 5. Other nephrotoxic agents. 6. Other investigational agents. Excluded within 3 days prior to study entry: 1. Non-steroidal anti-inflammatory drugs 2. Aspirin. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Diuretics. 2. Amphotericin B. 3. Aminoglycoside antibiotics. 4. Parenteral antibiotics. 5. Other nephrotoxic agents. 6. Other investigational agents. 7. Non-steroidal anti-inflammatory drugs. 8. Aspirin. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active, serious infections (other than HIV infections) that require parenteral antibiotic therapy. 2. Clinically significant cardiac disease, including symptoms of ischemia, congestive heart failure, or arrhythmia. 3. Gastrointestinal malabsorption syndrome or inability to receive oral medication. SUBSTANCE IDENTIFICATION Drug 1 DRG-0209 bis-POM PMEA TRADE NAME OF SUBSTANCE Drug 1‰ GS-0840 MANUFACTURERS Drug 1: Gilead Sciences Inc 353 Lakeside Drive Foster City, CA 94404 Contact: Dr Jay Toole (415) 573-4751. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200, 350, or 500 mg as a single dose SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, granules SUPPORTING AGENCY Gilead Sciences Inc. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adenine/ANALOGS & DERIVATIVES/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Adult MESH HEADING Antiviral Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 106941-25-7 (9-(2-phosphonylmethoxyethyl)adenine) LAST REVISION DATE 940506 ENTRY MONTH 9405 MARYLAND Johns Hopkins University 600 North Wolfe Street Baltimore, MD 21205 Contact: Dr Paul Lietman (410) 955-9707 OPEN 940506. 90 UNIQUE IDENTIFIER FDA/00622 PROTOCOL ID NUMBERS FDA 230A PROTOCOL TITLE A Phase II, Parallel Group, Randomized, Placebo-Controlled Study of the Safety and Efficacy of Thalidomide in Reducing Weight Loss in Adults With HIV Wasting Syndrome. VERSION NUMBER & DATE (940428) GENERAL DESCRIPTION PURPOSE: To evaluate the safety, antiviral and anti-TNF-alpha activity, and preliminary efficacy of thalidomide in reducing weight loss in patients with HIV wasting syndrome. Methodology: Patients are randomized to receive either thalidomide at 100 or 200 mg/day or placebo for 8 weeks. Patients who respond may continue in double-blinded treatment for an additional 4 weeks; nonresponding patients may receive thalidomide at 200 mg/day for up to 4 weeks. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either thalidomide at 100 or 200 mg/day or placebo for 8 weeks. Patients who respond may continue in double-blinded treatment for an additional 4 weeks; nonresponding patients may receive thalidomide at 200 mg/day for up to 4 weeks. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940428) DISEASE STUDIED Wasting syndrome. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV-1 seropositive by ELISA and Western blot. 2. Wasting as defined by profound involuntary weight loss (> 10 percent of pre-morbid body weight) plus weakness with or without documented fever for 30 days, in the absence of a concurrent illness or condition other than HIV infection that could explain the findings. 3. Negative blood PCR for acid-fast bacteria (AFB) or a negative AFB blood culture within 48 days prior to study entry. 4. No active opportunistic infection requiring systemic therapy within 6 weeks prior to study entry. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS W-001 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; 3-Arm; Parallel-Group; Multicenter PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 75 patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 4 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. Wasting syndrome. 3. Negative blood PCR for acid-fast bacteria (AFB) or a negative AFB blood culture within 48 days prior to study entry. 4. No active opportunistic infection requiring systemic therapy within 6 weeks prior to study entry. 5. Life expectancy of at least 6 weeks. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 5.0 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 5.0 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. Sodium 130 - 150 mEq/liter. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. No future reproduction. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required ONLY IF patient is on antiretroviral therapy: Stable regimen of AZT or ddI for at least 1 month prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Primary prophylaxis for opportunistic infections (if AFB blood culture negative). 2. Chronic suppressive therapy (maintenance) for opportunistic infections OTHER THAN Mycobacterium avium Complex (MAC). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Any neoplasms other than non-medicated (i.e., not receiving systemic or intralesional chemotherapy) Kaposi's sarcoma within 1 month prior to study entry. 2. Prior intolerance to thalidomide. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. Future reproduction. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active drug abuse within 3 months prior to study entry. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Radiotherapy within 6 weeks prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiotherapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. ddC within 1 month prior to study entry. 2. Acute systemic therapy for opportunistic infections within 6 weeks prior to study entry. 3. Agents that are anabolic, catabolic, or immunomodulatory (including interferons, megestrol, dronabinol, oxandrolone, growth hormone, systemic corticosteroids, and pentoxifylline) within 30 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Chronic suppressive therapy (maintenance) or secondary prophylaxis for Mycobacterium avium Complex (MAC) (suppressive therapy for other opportunistic infections is allowed). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Chronic diarrhea (five or more unformed stools per day). 2. Peripheral neuropathy of grade 2 or worse. 3. Requirement for tube feeding or intravenous feeding. 4. Any disorder associated with moderate to severe edema (e.g., cirrhosis, nephrosis, congestive heart failure). 5. Inability to ingest at least a maintenance diet based on present weight. 6. Any condition that precludes study participation. 7. Not under the care of a primary physician. SUBSTANCE IDENTIFICATION Drug 1 DRG-0184 Thalidomide MANUFACTURERS Drug 1: Celgene Corporation 7 Powder Horn Drive Warren, NJ 07059 Contact: Steve Thomas (908) 805-3914 Contact: Victor Wright (908) 271-4119. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 100 or 200 mg (or placebo) daily for at least 8 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 100 or 200 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral OTHER TREATMENT INFO. TREATMENT DURATION: 8 weeks. SUPPORTING AGENCY Celgene Corporation. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Cachexia/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Thalidomide/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 50-35-1 (Thalidomide) LAST REVISION DATE 940428 ENTRY MONTH 9405 CALIFORNIA San Francisco General Hospital / Division of Endocrinology 1001 Portrero Avenue Building 100 Room 286 San Francisco, CA 94110 Contact: Kathleen Mulligan PhD (415) 206-5882 OPEN 940913. CALIFORNIA Marin County Specialty Clinic 250 Bon Air Road Greenbrae, CA 94904 Contact: Clair Ginesi (415) 499-7377 OPEN 940913. NEW YORK Rockefeller University 1230 York Avenue New York, NY 10021 Contact: Unspecified (212) 327-8375 OPEN 940428. PENNSYLVANIA Thomas Jefferson University 1015 Walnut Street Philadelphia, PA 19107 Contact: Unspecified (215) 955-8575 OPEN 940428. 91 UNIQUE IDENTIFIER FDA/00619 PROTOCOL ID NUMBERS FDA 229B PROTOCOL TITLE A Randomized, Multicenter, Double-Blind, Phase III, Parallel Study of Zidovudine (AZT) Alone Versus AZT Plus Zalcitabine (Dideoxycytidine; ddC) Versus AZT Plus Ro 31-8959 (Saquinavir; HIV Proteinase Inhibitor) Versus AZT Plus ddC Plus Ro 31-8959 in Previously Untreated or Minimally Pretreated HIV-Infected Patients With CD4 Lymphocyte Counts From 50 VERSION NUMBER & DATE (940926) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To compare, in zidovudine (AZT)-naive patients, the safety, tolerance, and efficacy of Ro 31-8959 alone versus AZT alone versus AZT in combination with Ro 31-8959, dideoxycytidine (ddC), or both. To compare various disease markers among the different regimens. Methodology: Patients are randomized to receive a minimum of 80 weeks of AZT alone, AZT plus ddC, AZT plus Ro 31-8959, or all three drugs. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive a minimum of 80 weeks of AZT alone, AZT plus ddC, AZT plus Ro 31-8959, or all three drugs. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940926) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV-1 seropositive by ELISA confirmed by an alternative method. 2. CD4 count 50 - 350 cells/mm3. 3. No prior antiretroviral therapy. 4. No acute serious opportunistic infections requiring immediate treatment. 5. No unexplained fever persisting for 14 days within 90 days prior to study entry. 6. No significant unexplained diarrhea persisting for 14 days within 30 days prior to study entry. 7. No visceral Kaposi's sarcoma or lymphoma currently requiring chemotherapy and/or radiotherapy. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS SV 14604A. SV 14604C STUDY DESIGN Randomized; Double-Blind; Dose Comparison; Drug Combination PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance, Comparative drug therapy, Combination and single drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 3000 patients. (1000 patients from U.S.) PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CD4 count 50 - 350 cells/mm3. 3. No prior antiretroviral therapy. 4. No acute serious opportunistic infections requiring immediate treatment. 5. No unexplained fever persisting for 14 days within 90 days prior to study entry. 6. No significant unexplained diarrhea persisting for 14 days within 30 days prior to study entry. 7. No visceral Kaposi's sarcoma or lymphoma currently requiring chemotherapy and/or radiotherapy. 8. Life expectancy of at least 80 weeks. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 50 - 350 cells/mm3. ( 100 - 200 - 300 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Neutrophils >= 1000 cells/mm3. Alkaline phosphatase <= 5 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Local skin radiotherapy. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Erythropoietin and G-CSF. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of non-Hodgkin's lymphoma. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiotherapy (other than local skin radiotherapy). PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Acute therapy for opportunistic infection within 14 days prior to study entry. 2. Prior HIV proteinase inhibitor. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other investigational agents. 2. Antineoplastic agents. 3. Biologic response modifiers (including interferons). 4. Foscarnet. 5. Anti-HIV drugs other than the study drugs. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Malabsorption. 2. Severe chronic diarrhea. 3. Inadequate oral intake (unable to eat one or more meals daily because of chronic nausea, emesis, or abdominal/oral-esophageal discomfort). 4. Any grade 3 or worse toxicity. 5. Inability to comply with study requirements. PATIENT EXCLUSION CRIT. AVAILABILITY: Not geographically accessible throughout study. SUBSTANCE IDENTIFICATION Drug 1 DRG-0164 Ro 31-8959 SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0015 Dideoxycytidine TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir MANUFACTURERS Drug 1: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 600 mg (or placebo) TID for at least 80 weeks. Drug 2: 200 mg (or placebo) TID for at least 80 weeks. Drug 3: 0.75 mg (or placebo) TID for at least 80 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 1800 mg. Drug 2: 600 mg. Drug 3: 2.25 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 200 mg capsules. Drug 2: Oral, 100 mg capsules. Drug 3: Oral, 0.375 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 80 weeks. OTHER TREATMENT INFO. END POINT: Time to first AIDS-defining clinical event or death, adverse effects. SUPPORTING AGENCY Hoffmann-La Roche, Incorporated. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING HIV Protease Inhibitors/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Isoquinolines/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Quinolines/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Zidovudine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (HIV Protease Inhibitors) CAS REGISTRY NUMBER 127779-20-8 (Ro 31-8959) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 940926 ENTRY MONTH 9409 NEW JERSEY Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367 OPEN / USA accrual 940926 ACTU: 0007. 92 UNIQUE IDENTIFIER FDA/00618 PROTOCOL ID NUMBERS FDA 229A PROTOCOL TITLE A Randomized, Double-Blind, Multicenter, Parallel Study of Ro 31-8959 (Saquinavir; HIV Proteinase Inhibitor) Alone, HIVID (Dideoxycytidine; Zalcitabine, ddC) Alone, and Both in Combination, as Treatment for Advanced HIV Infection (CD4 50-300 Cells/mm3) in Patients Discontinuing or Unable to Take Retrovir (Zidovudine; AZT) Therapy. VERSION NUMBER & DATE (940926) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: PRIMARY: To compare the safety, tolerance, and efficacy of Ro 31-8959 alone, dideoxycytidine (ddC) alone, and both in combination, in patients discontinuing or unable to take zidovudine (AZT). SECONDARY: To compare survival, changes in clinical status and laboratory markers, decreases in viral susceptibility, and quality of life among the treatment groups. Methodology: Patients are randomized to one of three treatment regimens: ddC alone, Ro 31-8959 alone, and ddC plus Ro 31-8959. Treatment continues for at least 48 weeks. Patients are stratified by baseline CD4 count. (Per 09/26/94 amendment, a fourth arm, lower dose Ro 31-8959 (200 mg q 8 hr) plus ddC, was discontinued.) GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to one of three treatment regimens: ddC alone, Ro 31-8959 alone, and ddC plus Ro 31-8959. Treatment continues for at least 48 weeks. Patients are stratified by baseline CD4 count. (Per 09/26/94 amendment, a fourth arm, lower dose Ro 31-8959 (200 mg q 8 hr) plus ddC, was discontinued.) PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Pending first patient enrolled (940404) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by ELISA confirmed by Western blot or p24 antigen. 2. CD4 count 50 - 300 cells/mm3. 3. Received prior AZT that has been discontinued at least 28 days prior to study entry. 4. No active opportunistic infection requiring immediate treatment. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS NV 14256A. NV 14256B STUDY DESIGN Randomized; Double-Blind; Drug Tolerance; 3-Arm; Comparative; Drug Combination PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Drug efficacy, Combination and single drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 900 patients. (300 patients on each of 3 treatment arms) PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 47 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. CD4 count 50 - 300 cells/mm3. 3. Received prior AZT that has been discontinued at least 28 days prior to study entry. 4. No active opportunistic infection requiring immediate treatment. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. (May not be transfusion dependent). PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1000 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 50 - 300 cells/mm3. ( 100 - 200 - 300 ). PATIENT INCLUSION CRIT. BILIRUBIN: < 1.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 5.0 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): < 5.0 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. Serum amylase <= 1.5 x ULN (unless elevated fraction is salivary amylase or patient has macroamylasemia or in the setting of a normal lipase value). PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Limited localized radiation therapy to the skin. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Prior AZT. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. G-CSF and erythropoietin. 2. Prophylaxis or chronic suppression/maintenance therapy with dapsone, aerosolized pentamidine, isoniazid, rifampin, fluoroquinolones, pyrazinamide, ethambutol, fluconazole, intraconazole, acyclovir, clotrimazole, nystatin, trimethoprim/sulfamethoxazole, pyrimethamine, folic acid, sulfadiazine, clindamycin, and fansidar. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of non-Hodgkin's lymphoma. 2. Unexplained fever >= 38.5 C (101.5 F) persisting for 14 days or longer within the 28 days prior to study entry. 3. Unexplained, chronic diarrhea (defined as 3 or more loose stools daily) persisting for 14 days or longer within the 28 days prior to study entry. 4. History of grade 2 or worse peripheral neuropathy. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: More than 3 units of blood in any 21-day period within 3 months prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy other than limited localized therapy to skin. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior HIV proteinase inhibitor. 2. Prior antiretroviral therapy other than AZT. 3. Acute therapy for opportunistic infection within 14 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other antiretroviral drugs. 2. Experimental drugs. 3. Nephrotoxic or hepatotoxic drugs. 4. Drugs likely to cause peripheral neuropathy. 5. Antineoplastic agents. 6. Biologic response modifiers. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Signs or symptoms of peripheral neuropathy. 2. Malabsorption or inadequate oral intake (defined as unable to eat one or more meals daily because of chronic nausea, emesis, or abdominal/oral-esophageal discomfort. 3. Malignancy, visceral Kaposi's sarcoma, or lymphoma requiring systemic chemotherapy and/or radiotherapy within the next 48 weeks. 4. Any grade 3 or worse laboratory or clinical abnormality. 5. Inability to comply with protocol requirements. SUBSTANCE IDENTIFICATION Drug 1 DRG-0164 Ro 31-8959 SUBSTANCE IDENTIFICATION Drug 2 DRG-0015 Dideoxycytidine TRADE NAME OF SUBSTANCE Drug 2‰ Hivid MANUFACTURERS Drug 1: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. MANUFACTURERS Drug 2: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 600 mg (or placebo) q 8 hr for at least 48 weeks. (Per 09/26/94 amendment, the 200 mg dose given q 8 hr was discontinuDrug 2: 0.75 mg (or placebo) q 8 hr for at least 48 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 1800 mg. Drug 2: 2.25 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 200 mg capsules. Drug 2: Oral, 0.375 mg tablets OTHER TREATMENT INFO. TREATMENT DURATION: 48 weeks. OTHER TREATMENT INFO. END POINT: Time to first clinical AIDS-defining event or death, time to death, change in weight and Karnofsky score, changes in surrogate markers, quality of life, adverse effects. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Requirement for foscarnet or ganciclovir as treatment for cytomegalovirus infections. SUPPORTING AGENCY Hoffmann-La Roche, Incorporated. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Isoquinolines/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Quinolines/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Zalcitabine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 127779-20-8 (Ro 31-8959) CAS REGISTRY NUMBER 7481-89-2 (Zalcitabine) LAST REVISION DATE 940404 ENTRY MONTH 9404 CALIFORNIA UCLA School of Medicine / Division of Hematology / Oncology Room 60 051 CHS Los Angeles, CA 90012-1973 Contact: Dr Ronald Mitsuyasu (310) 206-6414 OPEN 940412. CALIFORNIA UCLA / Care Center Room BH412 CHS / 10833 Le Conte Avenue Los Angeles, CA 90024 Contact: Dr David Hardy (310) 206-6414 OPEN 940412. CALIFORNIA UCLA / Harbor Medical Center 1000 West Carson Street Torrance, CA 90505 Contact: Dr Gildon Beall (310) 222-2365 OPEN 940412. CALIFORNIA Kaiser Foundation Hospital 25825 S. Vermont Avenue Harbor City, CA 90710 Contact: Dr Jared Spotkov (310) 325-5111 OPEN 940412. CALIFORNIA Pacific Oaks Medical Group / Research and Scientific Invest 4940 Van Nuys Boulevard Sherman Oaks, CA 91403 Contact: Dr Paul S Berry (818) 990-3396 OPEN 940412. CALIFORNIA UCSD / Departments of Pathology and Medicine 0679 9500 Gilman Drive La Jolla, CA 92093-0679 Contact: Dr Douglas Richman (619) 552-7439 OPEN 940412. CALIFORNIA Sunnyvale Medical Center 596 Carroll Street Sunnyvale, CA 94086 Contact: Dr Robert Frascino (408) 524-5075 OPEN 940412. CALIFORNIA San Francisco General Hospital 995 Potrero Avenue San Francisco, CA 94110 Contact: Dr Paul Volberding (415) 476-4082 OPEN 940412. CALIFORNIA Davies Medical Center / Institute - HIV Research & Treatment Castro and Duboce Streets San Francisco, CA 94114 Contact: Dr Stephen Follansbee (415) 565-6153 Contact: (415) 565-6524 OPEN 940412. CALIFORNIA Mt Zion Medical Center / University California San Francisco 1600 Divisadero Street San Francisco, CA 94115 Contact: Dr Jacob Lalezari (415) 476-6356 OPEN 940412. CALIFORNIA San Francisco Veterans' Administration Medical Center 4150 Clement Street #111W San Francisco, CA 94121 Contact: Manon Marovich (415) 221-4810 X 394Contact: Sandra Charles (415) 221-4810 X 394OPEN 940412 ACTU: 0807. CALIFORNIA University of California Davis / Department of Internal Med 4301 X Street Sacramento, CA 95817 Contact: Dr Stuart H Cohen (916) 453-3741 OPEN 940412. CALIFORNIA Sunnybrook Medical Center 2075 Bayview Avenue North / Room A226 Toronto Ontario, CA M4N 3M5 Contact: Dr Anita Rachlis 416-480-4689 OPEN 940620. CALIFORNIA Montreal General Hospital 1650 Cedar Avenue Room B7117 Montreal Quebec, CA H3G1A4 Contact: Christos Tsoukas (514)272-0707 OPEN 940620. CALIFORNIA McMaster University Medical Center 1200 Main Street West 2N29 Hamilton Ontario, CA L8N3Z5 Contact: Fiona M Smaill (905)521-2100 OPEN 940620. CALIFORNIA Clinique Medicale L Actuel 1001 boul de Maissonneuve Est Suite 1130 Montreal Quebec, CA H2L 4P9 Contact: Gervais Frechette (514)524-1001 OPEN 940620. CALIFORNIA Southern Alberta HIV Clinic 1403 29th Street NW Calgary Alberta, CA T2N 2T9 Contact: M John Gill (403)670-2481 OPEN 940620. DISTRICT OF COLUMBIA Veterans Administration Medical Center 50 Irving Street N W Washington, DC 20422 Contact: Dr Fred Gordon (202) 745-8695 Contact: Patricia Ackerson (202) 745-8695 OPEN 940412. FLORIDA Univ of Miami School of Med / Comprehensive AIDS Program Div of Gen Med R-60A / 1800 NW 10th Avenue Miami, FL 33101 Contact: Margaret A Fischl (305) 547-3847 OPEN 940412. FLORIDA Miami Veterans Administration Medical Center 1201 NW 16th Street / Special Immunology Unit (111-I) Miami, FL 33125 Contact: Dr Nancy Klimas (305) 324-4455 X 433Contact: Dr Gordon M Dickinson (305) 324-4455 OPEN 940412. FLORIDA Stratogen Hospital 300 Arthur Godfrey Road / 2nd Floor Miami Beach, FL 33140 Contact: Dr Lionel Resnick (305) 538-1400 OPEN 940503. GEORGIA AIDS Research Consortium of Atlanta 131 Ponce de Leon / Suite 130 Atlanta, GA 30308 Contact: Dr Melanie Thompson (404) 876-2317 OPEN 940412. GEORGIA West Paces Clinic Research 3193 Howell Mill Road / Suite 306 Atlanta, GA 30327 Contact: Dr Steven Marlowe (404) 350-5690 OPEN 940412. ILLINOIS Rush Presbyterian - St Luke's Med Ctr / Infectious Diseases 1753 West Congress Parkway Chicago, IL 60612 Contact: Dr John Pottage (312) 942-5862 OPEN 940412. KANSAS University of Kansas 1010 North Kansas Wichita, KS 67214 Contact: Dr Suzanne Gagnon (316) 261-2855 OPEN 940412. LOUISIANA Tulane University Medical Center / Infectious Disease Sectio 1430 Tulane Avenue New Orleans, LA 70112 Contact: Dr Newton E Hyslop (504) 587-7316 OPEN 940412. MASSACHUSETTS New England Medical Center Hospitals / Div of Geographic Med 750 Washington Street / NEMCH 67 Boston, MA 02111 Contact: Dr Paul Skolnik (617) 350-8186 OPEN 940412. MASSACHUSETTS Massachusetts General Hospital / Dept Med Harvard Med School Fruit Street Boston, MA 02114 Contact: Dr Martin S Hirach (617) 726-3815 OPEN 940412. MASSACHUSETTS New England Deaconess Medical Hospital / Infectious Disease AK6 / One Autumn Street Boston, MA 02215 Contact: Dr Davis Allan (617) 632-0769 OPEN 940412. MICHIGAN Harper Hospital Harper Professional Bldg / Suite 202 / 4160 John R Detroit, MI 48201 Contact: Dr Crane (313) 745-9131 OPEN 940412. MISSOURI Washington University School of Medicine Campus Box 8011 / 4511 Forest Park Parkway / Suite 304 St Louis, MO 63108 Contact: Dr William Powderly (314) 361-5231 Contact: Mark Myers (314) 454-0058 OPEN 940412. NEW JERSEY University of Medicine and Dentistry of NJ / Dep of Medicine 185 South Orange Avenue Newark, NJ 08103 Contact: Dr Dennis Cunniff (201) 982-7598 OPEN 940412. NEW JERSEY University of Medicine and Denistry NJ / Cooper Hospital Education and Research Building / 401 Haddon Ave / Rm 270 Camden, NJ 08103 Contact: Lynn Jeffries (609) 757-9783 OPEN 940412. NEW YORK Beth Israel Medical Center / Division of Infectious Diseases 10th Flr Pavilion / 1st Avenue at 16th Street New York, NY 10003 Contact: Wendy Lupin (212) 420-4432 Contact: Peter Berge (212) 420-4519 OPEN 940412. NEW YORK St. Vincent's Hospital Medical Center 412 Sixth Avenue 4th Floor New York, NY 10011 Contact: Dr Ramon Torres (212) 604-7000 Contact: Karen MacIntyre (212) 604-8319 OPEN 940412. NEW YORK Harkness Pavilion 5th Floor Room 516 / 180 Fort Washington Avenue New York, NY 10032 Contact: Dr Jay Dobkin (212) 305-8507 OPEN 940412. NEW YORK Albany Medical College / Division of Medical Oncology A-52 47 New Scotland Avenue Albany, NY 12208 Contact: Dr Scot Remick (518) 262-6713 OPEN 940412. OHIO Ohio State University Hospital Doan Hall / Room N 1148 / 410 West Tenth Avenue Columbus, OH 43210 Contact: Dr Maybeth Ramundo (614) 293-8112 OPEN 940412. OREGON Oregon Health Sciences University 3181 Southwest Sam Jackson Road Portland, OR 97201 Contact: Mark Loveless (503) 295-0950 OPEN 940412. OTHER San Juan Veterans Administration Medical Center One Veterans Plaza 111 San Juan, PR 00927-5800 Contact: Dr Carlos Ramirez-Ronda (809) 758-6900 OPEN 940412. PENNSYLVANIA Thomas Jefferson Medical College 1015 Walnut Street - 701 Curtis Building Philadelphia, PA 19107 Contact: Dr Stephen Hauptman (215) 955-7785 Contact: Roberta Benjamin OPEN 940412. PENNSYLVANIA Tuttleman Cancer Center / Graduate Hospital of Philadelphia 1840 South Street Philadelphia, PA 19146 Contact: Dr David Henry (215) 893-7520 OPEN 940412. 93 UNIQUE IDENTIFIER FDA/00614 PROTOCOL ID NUMBERS FDA 228B PROTOCOL TITLE A Double-Blind, Randomized, Dose-Response Study of Three Fixed Doses of Delavirdine Mesylate (U-90152S) in Combination With Zidovudine (AZT) Versus AZT Alone in HIV-1 Infected Individuals With CD4 Counts of 200-500/mm3. VERSION NUMBER & DATE (940331) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the safety, tolerance, efficacy, and pharmacokinetics of three fixed doses of delavirdine mesylate (U-90152S) in combination with zidovudine (AZT) versus AZT alone in HIV-positive patients. Methodology: Patients are randomized to receive U-90152S plus AZT or AZT alone. Didanosine may be added if the CD4 count falls below 50 percent of baseline at two consecutive visits 72 or more hours apart or if the patients develops a new or recurrent AIDS-defining illness. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive U-90152S plus AZT or AZT alone. Didanosine may be added if the CD4 count falls below 50 percent of baseline at two consecutive visits 72 or more hours apart or if the patients develops a new or recurrent AIDS-defining illness. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940315) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV-1 seropositive by EIA or ELISA and Western blot or HIV culture. 2. CD4 count 200 - 500 cells/mm3 within 35 days prior to study entry. 3. No active or acute (onset within the past month) opportunistic infections such as active cryptococcosis, pneumocystis carinii, herpes zoster, histoplasmosis, or cytomegalovirus (CMV). NOTE: Patients with cutaneous Kaposi's sarcoma requiring no systemic therapy are permitted. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS M/3331/0021 STUDY DESIGN Randomized; Multicenter; Double-Blind; Parallel-Group; Drug Combination; Comparative; Drug Tolerance; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance, Combination and single drug therapy, Combination and single pharmacokinetics. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 2 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 86 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV-1 seropositivity. 2. CD4 count 200 - 500 cells/mm3. 3. No active or acute (onset within the past month) opportunistic infections such as active cryptococcosis, pneumocystis carinii, herpes zoster, histoplasmosis, or cytomegalovirus (CMV). 4. Consent of parent or guardian if less than 18 years of age. 5. Understanding of potential risk to fetus related to study participation. 6. Acceptable medical history, physical exam, EKG, and chest x-ray during screening. NOTE: Patients with cutaneous Kaposi's sarcoma requiring no systemic therapy are permitted. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 500 cells/mm3. ( 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. KARNOFSKY: >= 80. PATIENT AGE AGE: 14 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 15 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior AZT (no more than 6 months total). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of pancreatitis within the past 2 years. 2. History of clinically significant nervous system or muscle disease, seizure disorder, AIDS dementia, or psychiatric disorder that would preclude study compliance. 3. History of grade 2 or worse peripheral neuropathy. 4. Intolerance to AZT in previous treated patients. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 13 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 15 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. More than 6 months total of prior AZT. 2. Any prior ddC, d4T, 3TC, or ddI. 3. Prior nonnucleoside reverse transcriptase inhibitors, including L-drugs, nevirapine, TIBO, HEPT, delavirdine, atevirdine, and alpha-APA. 4. Other investigational antiretroviral medications (including foscarnet) or immunomodulators (including all interferons) within 21 days prior to initial study drug dose. 5. Prior prophylactic or therapeutic HIV-1 gp120 or 160 vaccines. 6. Rifampin, rifabutn, astemizole, loratadine, or terfenadine within 21 days prior to initial study drug dose. 7. Any unapproved investigational medication for any indication within 21 days prior to initial study drug dose. 8. Any enzyme-inducing drugs known to affect cytochrome P450 3A, (e.g., ketoconazole, fluconazole, isoniazid, itraconazole, etc.) within 21 days prior to initial study drug dose. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active tuberculosis that is sensitive to rifampin. 2. Inability to swallow numerous tablets. 3. Clinically significant active or acute medical problems, including progressive multifocal leukoencephalopathy, lymphoma, or malignancy requiring systemic therapy. 4. Clinically significant hypersensitivity to piperazine-type drugs (e.g., Antepar and Stelazine). 5. Grade 2 or worse baseline organ function. NOTE: Hemophiliacs with grade 2 bilirubin, alkaline phosphatase, SGOT, or SGPT will be considered if these values have been stable over the past year. NOTE: Patients with suspected Gilbert's syndrome will be considered if bilirubin is grade 2 or better. SUBSTANCE IDENTIFICATION Drug 1 DRG-0166 U-90152 SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine MANUFACTURERS Drug 1: The Upjohn Company 7000 Portage Road Kalamazoo, MI 49001 Contact: James VanSweden (616) 323-4696. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, compressed film-coated tablets SUPPORTING AGENCY The Upjohn Company. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/ADVERSE EFFECTS/ PHARMACOKINETICS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zidovudine/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 940315 ENTRY MONTH 9404 ALABAMA University of Alabama at Birmingham 933 19th Street S/1917 Research Clinic Room 219 Birmingham, AL 35294-2041 Contact: Robin Noles (205) 934-7349 OPEN 940315. CALIFORNIA CARE / UCLA Medical Center / Department of Medicine 10833 Le Conte Avenue / Room BH 413 / CHS Los Angeles, CA 90024 Contact: Lori Bort (310) 206-6414 OPEN 940315. CALIFORNIA University of Southern California / LAC - USC Medical Cntr 1175 North Cummings Street / 5021 Clinic Los Angeles, CA 90033-1079 Contact: Novella Quesada (213) 343-8277 OPEN 940315. CALIFORNIA King / Drew Medical Center 12021 South Wilmington Avenue Los Angeles, CA 90059 Contact: Bessie Hughes (310) 603-4213 OPEN 940315. CALIFORNIA Harbor / UCLA Medical Center PO Box 449 / 1000 W Carson St Torrance, CA 90509 Contact: Jeannette Shelly (310) 222-3848 OPEN 940315. CALIFORNIA Shared Medical Research Foundation 5620 Wilbur / S 322 Tarzana, CA 91356 Contact: Eve Zisman (818) 345-2172 OPEN 940315. CALIFORNIA UCSD / Center for Special Immunology 2918 Fifth Ave / Suite 300 San Diego, CA 92103 Contact: Dr Scott Loss (619) 543-8080 OPEN 940315. CALIFORNIA UCI Medical Center Building 53 Route 81 / 101 City Drive South Orange, CA 92668 Contact: Josephine Mosquara (714) 456-7612 OPEN 940315. CALIFORNIA California Medical Research Group 8636 North First Street / Suite 120 Fresno, CA 93726 Contact: Margaret Northrop (209) 221-1327 OPEN 940315. CALIFORNIA ACRC AIDS Community Research Consortium 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harriss (415) 364-6564 OPEN 940315. CALIFORNIA ViRx Medical Group 1375 Sutter Street Suite 407 San Francisco, CA 94102 Contact: Joyce Amann (415) 474-4440 OPEN 940315. CALIFORNIA St Francis Hospital / Clinical Research 909 Hyde Street San Francisco, CA 94109 Contact: Max Huckabee (415) 353-6299 OPEN 940315. CALIFORNIA General Hospital / AIDS Clinical Trials Unit 995 Potrero Avenue / Bldg 80 / Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 846OPEN 940315 ACTU: 0808. CALIFORNIA Davies Medical Center / Institute for HIV Treatment and Rsch Castro and Duboce Streets San Francisco, CA 94114 Contact: Sue Kelly (415) 565-6153 OPEN 940315. CALIFORNIA East Bay AIDS Center 3031 Telegraph Avenue / Suite 235 Berkeley, CA 94705 Contact: Sherry Lyman (510) 204-1870 Contact: Dr Carol Brosgart (510) 204-1201 OPEN 940315. CALIFORNIA U of CA / Davis Med Ctr / AIDS and Related Disorders Clinic 2221 Stockton Blvd / PCC Rm 3107 Sacramento, CA 95817 Contact: Sheila Enders (916) 734-7004 OPEN 940315. COLORADO University Hospital / Univ of Colorado Health Sci Ctr Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: Graham Ray (303) 270-8551 OPEN 940315 ACTU: 0105. DISTRICT OF COLUMBIA Georgetown University / Medical Center 3800 Reservoir Road Washington, DC 20007 Contact: Sara Swartzendruber (202) 687-1079 OPEN 940315. DISTRICT OF COLUMBIA George Washington University / Medical Faculty Associates 2150 Pennsylvania Avenue / Suite 5-419 Washington, DC 20037 Contact: Barbara Lewis (202) 994-2417 OPEN 940315. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue 1st Floor Eliot Building Miami, FL 33136 Contact: Janie Reese (305) 547-3840 OPEN 940315. FLORIDA Caremark Incorporated 3345 Burns Road / Suite 302 Palm Beach Gardens, FL 33410 Contact: Unspecified (407) 775-7544 OPEN 940315. FLORIDA St Josephs Hospital / Infectious Disease Research Institute 4600 N Habana Ave / Suite 14 Tampa, FL 33614 Contact: Allis Emmett (813) 870-4760 OPEN 940315. GEORGIA Southeast Clinical Resources 1758 A Century Boulevard Atlanta, GA 30345 Contact: Kym Prieto (404) 325-4677 OPEN 940315. IOWA University of Iowa 200 Hawkins Drive / Southwest 54 GH Iowa City, IA 52242 Contact: Unspecified (319) 356-3168 OPEN 940315. ILLINOIS Rush Presbyterian / St Luke's Medical Center Room 140 - 143 Academic Facility / 600 South Paulina Chicago, IL 60612 Contact: Marilyn Ashmann (312) 942-5865 OPEN 940315. ILLINOIS University of Illinois 840 South Wood Street Chicago, IL 60612 Contact: Unspecified (312) 996-6732 OPEN 940315. INDIANA Indiana University Medical School / Department of Medicine 550 N University Blvd / Room 5550 Indianapolis, IN 46202 Contact: Jean Craft (317) 274-8456 OPEN 940315. KANSAS University of Kansas School of Med / University Hospital 39th at Rainbow Kansas City, KS 66160-7354 Contact: Jane Harms (913) 588-6035 Contact: (913) 588-3896 OPEN 940315. KANSAS Univ of Kansas School of Medicine - Wichita / Clinical Rsch 1010 North Kansas Wichita, KS 67214-3199 Contact: Dal Harrison (316) 261-2855 OPEN 940315. KENTUCKY University of Kentucky Medical Center 800 Rose Street / Room MN633A Lexington, KY 40536 Contact: Karen Bowen (606) 257-5473 OPEN 940315. LOUISIANA Tulane University Medical School / AIDS Clinical Trials Unit 1430 Tulane Avenue New Orleans, LA 70112-2699 Contact: Russell Strada (504) 584-3605 OPEN 940315. MASSACHUSETTS Baystate Medical Center / Infectious Disease Division 759 Chestnut Street Springfield, MA 01199 Contact: Deborah Prescod (413) 784-3046 OPEN 940315. MASSACHUSETTS University of Massachusetts Medical School 55 Lake Avenue North / Div Infectious Diseases Worcester, MA 01655 Contact: Joan L Avto (508) 856-2456 Contact: (508) 856-2666 OPEN 940315 ACTU: 3001. MASSACHUSETTS Massachusetts General Hospital Gray 5 / Infectious Disease Unit Boston, MA 02114 Contact: Ellen Godfrey (617) 726-5598 Contact: Teri Flynn (617) 726-3819 OPEN 940315. MASSACHUSETTS Brigham Women's Hospital / Infectious Disease Division 75 Francis Street Boston, MA 02115 Contact: Ann Elperin (617) 732-5885 OPEN 940315. MASSACHUSETTS Boston City Hospital / FGH-1 818 Harrison Avenue / Thorndike Room 209 Boston, MA 02118 Contact: Nancy Reinhalter (617) 534-5404 OPEN 940315. MASSACHUSETTS New England Deaconess Hospital 185 Pilgrim Road Boston, MA 02215 Contact: Helen Fitch (617) 735-0785 OPEN 940315 ACTU: 0103. MAINE AIDS Consultation Service / Maine Medical Center 22 Bramhall Street Portland, ME 04102 Contact: Sandy Putnam (207) 871-2995 OPEN 940315. MARYLAND University of Maryland / SOM / Department of Med / Adult HIV Box 165 / 22 S Green Street Baltimore, MD 21201 Contact: Andrea Fisch (410) 706-1806 OPEN 940315. MARYLAND Johns Hopkins University Hospital Richard Starr Ross Rsch Bldg / 720 Rutland Avenue Room 1159 Baltimore, MD 21205-2196 Contact: Becky Becker (410) 955-4370 OPEN 940315. MICHIGAN University of Michigan / Division of Infectious Diseases 3116 B Taubman Center Ann Arbor, MI 48109 Contact: unspecified (313) 936-5205 OPEN 940315. MICHIGAN Harper Hospital Harper Professional Bldg / Suite 202 / 4160 John R Detroit, MI 48201 Contact: Dr Crane (313) 745-9131 OPEN 940315. MICHIGAN Henry Ford Hospital / Infectious Diseases 2799 West Grand Blvd / CFP 111 Detroit, MI 48202 Contact: Ann Marie Krystoforsky (313) 876-2798 OPEN 940315. MINNESOTA St Paul Ramsey Medical Center / HIV Program Office 640 Jackson Street St Paul, MN 55101 Contact: Holly Melroe (612) 221-1280 OPEN 940315. MISSOURI Washington University Clinical Trials Unit 4511 Forest Park Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0058 OPEN 940315. MISSOURI University of Missouri Kansas City / School of Medicine 2411 Holmes Kansas City, MO 64108 Contact: Donna Simpson (816) 556-3478 OPEN 940315. NORTH CAROLINA University of NC / School of Medicine / Div Infec Diseases 547 Burnett Womack Building / CB7030 Chapel Hill, NC 27599-7030 Contact: Barbara Longmeyer (919) 966-7883 OPEN 940315. NORTH CAROLINA Duke University Medical Center / Infectious Diseases Clinic PO Box 3284 Durham, NC 27710 Contact: Ken Ship (919) 684-5260 OPEN 940315. NORTH CAROLINA Carolinas Medical Center / Department of Internal Medicine 1000 Blythe Blvd AHEC Room 507 Charlotte, NC 28203 Contact: Joan Connell (704) 355-5292 Contact: (704) 355-3165 OPEN 940315 ACTU: 3204. NEBRASKA University of Nebraska Medical Center / HIV Clinic 600 South 42nd Street Omaha, NE 68198-5130 Contact: Colleen R Kelly (402) 559-8163 OPEN 940315. NEW JERSEY Jersey Shore Medical Center 1945 Route #33 Neptune, NJ 07754 Contact: Susan Bataille (908) 776-4700 OPEN 940315. NEW YORK CRIA of New York 275 Seventh Avenue / 20th Floor New York, NY 10001 Contact: Bette Smith (212) 924-3934 OPEN 940315. NEW YORK Beth Israel Medical Center / Department of Medicine First Avenue and 16th Street New York, NY 10003 Contact: Alice Fox (212) 420-4519 OPEN 940315. NEW YORK St Vincents Hospital and Medical Center 412 Sixth Ave / 4th Floor New York, NY 10011 Contact: Noel George (212) 604-7625 OPEN 940315. NEW YORK St Luke / Roosevelt Hospital Center / Dir HIV / AIDS CTP 428 West 59th Street New York, NY 10019 Contact: Julie Rivera (212) 523-6723 OPEN 940315. NEW YORK New York Hospital / Cornell Medical Center 505 East 70th Street New York, NY 10021 Contact: Paul Douglas (212) 746-4177 OPEN 940315. NEW YORK Mount Sinai Hospital / Clinical Trials Unit 1 Gustave Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-0433 OPEN 940315. NEW YORK Westchester County Medical Center / Department of Infec Dis 209 South East / Macy Pavillion Valhalla, NY 10595 Contact: Gilda Forseter (914) 285-1561 Contact: Diane Holmgren (914) 285-7400 Contact: Dr Marissa Montecalvo (914) 285-8865 Contact: Dr Gary Wormser (914) 285-8865 OPEN 940315. NEW YORK SUNY at Stony Brook Health Sciences Center / Div Infect Dis HSC T 15 Room 080 Stony Brook, NY 11794-8153 Contact: Ruth Ann Burk (516) 444-1658 OPEN 940315. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 940315 ACTU: 7401. NEW YORK SUNY at Buffalo / Erie County Medical Center 462 Grider Street Buffalo, NY 14215 Contact: David Meger (716) 898-4482 OPEN 940315. NEW YORK Community Health Network 758 South Avenue Rochester, NY 14620 Contact: Lorraine Newcomb (716) 244-9000 OPEN 940315. NEW YORK University of Rochester Medical Center 601 Elmwood Avenue / Box 689 Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 940315. OHIO University Hospitals of Cleveland/Case Western Reserve Univ 206 Cornell Road Cleveland, OH 44106 Contact: Michael Chance (216) 844-8175 OPEN 940315. OHIO University of Cincinnati Medical Center / Holmes Division Eden and Bethesda Avenues Cincinnati, OH 45267 Contact: Jill Leonard (513) 558-8373 OPEN 940315. OREGON Research and Education Group 2701 NW Vaughn Streets / 770 Portland, OR 97210 Contact: Sallie Israelit (503) 229-8428 OPEN 940315. OTHER University of Puerto Rico / Department of Medicine Medical Science Center / Room A 838 San Juan, PR 00936 Contact: Unspecified (809) 754-3755 OPEN 940315. PENNSYLVANIA University of Pittsburgh / School of Medicine 3515 Fifth Avenue Pittsburgh, PA 15261 Contact: Rosella Rosener (412) 647-8125 OPEN 940315. PENNSYLVANIA Pennsylvania State University / Hershey Medical Center 500 Univ Drive / PO Box 850 / Biomedical Rsrch Bldg C-6833 Hershey, PA 17033 Contact: Francine Damianos (717) 531-7488 OPEN 940315. PENNSYLVANIA University of Pennsylvania / Dept of Infect Dis / HIV Clinic 536 Johnson Pavilion / 6073 Philadelphia, PA 19104 Contact: Heidi Lehman (215) 662-6932 OPEN 940315. PENNSYLVANIA Buckley Braffman Stern Medical Associates PC 822 Pine Street / Suite 3A Philadelphia, PA 19107 Contact: Nancy Pietroski (215) 925-8010 OPEN 940315. PENNSYLVANIA Oncology and Hematology Association 1840 South Street / 2nd Floor Philadelphia, PA 19146 Contact: Barbara Rensman (215) 893-7541 OPEN 940315. RHODE ISLAND Stratogen Health / Independent Research Nurses 769 Park Ave Cranston, RI 02910 Contact: Lynn Haughey (401) 781-2400 OPEN 940315. SOUTH CAROLINA Medical University of South Carolina 171 Ashley Avenue Charleston, SC 29425 Contact: Unspecified (803) 792-4541 OPEN 940315. 94 UNIQUE IDENTIFIER FDA/00613 PROTOCOL ID NUMBERS FDA 228A PROTOCOL TITLE A Double-Blind, Randomized, Comparative Study of Delavirdine Mesylate (U-90152S) in Combination With Didanosine (ddI) Versus ddI Alone in HIV-1 Infected Individuals With CD4 Counts of <= 300/mm3. VERSION NUMBER & DATE (940331) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the safety, tolerance, pharmacokinetics, and efficacy of delavirdine mesylate (U-90152S) in combination with didanosine (ddI) versus ddI alone in HIV-positive patients PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940315) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV-1 seropositive by EIA or ELISA and Western blot or HIV culture. 2. CD4 count <= 300 cells/mm3 within 35 days prior to study entry. 3. No active or acute (onset within the past month) opportunistic infections such as active cryptococcosis, pneumocystis carinii, herpes zoster, histoplasmosis, or cytomegalovirus (CMV). NOTE: Patients with cutaneous Kaposi's sarcoma requiring no systemic therapy are permitted. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS M/3331/0017 STUDY DESIGN Randomized; Multicenter; Double-Blind; Parallel-Group; Drug Combination; Drug Tolerance; Comparative; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance, Combination and single drug therapy, Combination and single pharmacokinetics. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 2 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 84 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV-1 seropositivity. 2. CD4 count <= 300 cells/mm3. 3. No active or acute (onset within the past month) opportunistic infections such as active cryptococcosis, pneumocystis carinii, herpes zoster, histoplasmosis, or cytomegalovirus (CMV). 4. Consent of parent or guardian if less than 18 years of age. 5. Understanding of potential risk to fetus related to study participation. 6. Acceptable medical history, physical exam, EKG, and chest x-ray during screening. NOTE: Patients with cutaneous Kaposi's sarcoma requiring no systemic therapy are permitted. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 300 cells/mm3. ( 0 - 100 - 200 - 300 ). PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT AGE AGE: 14 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 15 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: AZT therapy at some time prior to screening. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: AZT. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of pancreatitis within the past 2 years. 2. History of clinically significant nervous system or muscle disease, seizure disorder, AIDS dementia, or psychiatric disorder that would preclude study compliance. 3. History of grade 2 or worse peripheral neuropathy. 4. Intolerance to ddI in previous treated patients. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 13 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 15 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. More than 4 months total of prior ddI. 2. Any prior ddC, d4T, or 3TC. 3. Prior nonnucleoside reverse transcriptase inhibitors, including L-drugs, nevirapine, TIBO, HEPT, delavirdine, atevirdine, and alpha-APA. 4. Other investigational antiretroviral medications (including foscarnet) or immunomodulators (including all interferons) within 21 days prior to initial study drug dose. 5. Prior prophylactic or therapeutic HIV-1 gp120 or 160 vaccines. 6. Rifampin, rifabutn, astemizole, loratadine, or terfenadine within 21 days prior to initial study drug dose. 7. Any unapproved investigational medication for any indication within 21 days prior to initial study drug dose. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active tuberculosis that is sensitive to rifampin. 2. Inability to swallow numerous tablets. 3. Clinically significant active or acute medical problems, including progressive multifocal leukoencephalopathy, lymphoma, or malignancy requiring systemic therapy. 4. Clinically significant hypersensitivity to piperazine-type drugs (e.g., Antepar and Stelazine). 5. Grade 2 or worse baseline organ function. NOTE: Hemophiliacs with grade 2 bilirubin, alkaline phosphatase, SGOT, or SGPT will be considered if these values have been stable over the past year. NOTE: Patients with suspected Gilbert's syndrome will be considered if bilirubin is grade 2 or better. SUBSTANCE IDENTIFICATION Drug 1 DRG-0166 U-90152 SUBSTANCE IDENTIFICATION Drug 2 DRG-0016 Didanosine MANUFACTURERS Drug 1: The Upjohn Company 7000 Portage Road Kalamazoo, MI 49001 Contact: James VanSweden (616) 323-4696. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, compressed film-coated tablets SUPPORTING AGENCY The Upjohn Company. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/ADVERSE EFFECTS/ PHARMACOKINETICS/*THERAPEUTIC USE MESH HEADING Didanosine/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 940315 ENTRY MONTH 9404 ALABAMA University of Alabama at Birmingham 933 19th Street S/1917 Research Clinic Room 219 Birmingham, AL 35294-2041 Contact: Robin Noles (205) 934-7349 OPEN 940315. CALIFORNIA CARE / UCLA Medical Center / Department of Medicine 10833 Le Conte Avenue / Room BH 413 / CHS Los Angeles, CA 90024 Contact: Lori Bort (310) 206-6414 OPEN 940315. CALIFORNIA University of Southern California / LAC - USC Medical Cntr 1175 North Cummings Street / 5021 Clinic Los Angeles, CA 90033-1079 Contact: Novella Quesada (213) 343-8277 OPEN 940315. CALIFORNIA King / Drew Medical Center 12021 South Wilmington Avenue Los Angeles, CA 90059 Contact: Bessie Hughes (310) 603-4213 OPEN 940315. CALIFORNIA Harbor / UCLA Medical Center PO Box 449 / 1000 W Carson St Torrance, CA 90509 Contact: Jeannette Shelly (310) 222-3848 OPEN 940315. CALIFORNIA Shared Medical Research Foundation 5620 Wilbur / S 322 Tarzana, CA 91356 Contact: Eve Zisman (818) 345-2172 OPEN 940315. CALIFORNIA UCSD / Center for Special Immunology 2918 Fifth Ave / Suite 300 San Diego, CA 92103 Contact: Dr Scott Loss (619) 543-8080 OPEN 940315. CALIFORNIA UCI Medical Center Building 53 Route 81 / 101 City Drive South Orange, CA 92668 Contact: Josephine Mosquara (714) 456-7612 OPEN 940315. CALIFORNIA California Medical Research Group 8636 North First Street / Suite 120 Fresno, CA 93726 Contact: Margaret Northrop (209) 221-1327 OPEN 940315. CALIFORNIA ACRC AIDS Community Research Consortium 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harriss (415) 364-6564 OPEN 940315. CALIFORNIA ViRx Medical Group 1375 Sutter Street Suite 407 San Francisco, CA 94102 Contact: Joyce Amann (415) 474-4440 OPEN 940315. CALIFORNIA St Francis Hospital / Clinical Research 909 Hyde Street San Francisco, CA 94109 Contact: Max Huckabee (415) 353-6299 OPEN 940315. CALIFORNIA Davies Medical Center / Institute for HIV Treatment and Rsch Castro and Duboce Streets San Francisco, CA 94114 Contact: Sue Kelly (415) 565-6153 OPEN 940315. CALIFORNIA East Bay AIDS Center 3031 Telegraph Avenue / Suite 235 Berkeley, CA 94705 Contact: Sherry Lyman (510) 204-1870 Contact: Dr Carol Brosgart (510) 204-1201 OPEN 940315. CALIFORNIA U of CA / Davis Med Ctr / AIDS and Related Disorders Clinic 2221 Stockton Blvd / PCC Rm 3107 Sacramento, CA 95817 Contact: Sheila Enders (916) 734-7004 OPEN 940315. COLORADO University Hospital / Univ of Colorado Health Sci Ctr Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: Graham Ray (303) 270-8551 OPEN 940315 ACTU: 0105. DISTRICT OF COLUMBIA Georgetown University / Medical Center 3800 Reservoir Road Washington, DC 20007 Contact: Sara Swartzendruber (202) 687-1079 OPEN 940315. DISTRICT OF COLUMBIA George Washington University / Medical Faculty Associates 2150 Pennsylvania Avenue / Suite 5-419 Washington, DC 20037 Contact: Barbara Lewis (202) 994-2417 OPEN 940315. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue 1st Floor Eliot Building Miami, FL 33136 Contact: Janie Reese (305) 547-3840 OPEN 940315. FLORIDA Caremark Incorporated 3345 Burns Road / Suite 302 Palm Beach Gardens, FL 33410 Contact: Unspecified (407) 775-7544 OPEN 940315. FLORIDA St Josephs Hospital / Infectious Disease Research Institute 4600 N Habana Ave / Suite 14 Tampa, FL 33614 Contact: Allis Emmett (813) 870-4760 OPEN 940315. GEORGIA Southeast Clinical Resources 1758 A Century Boulevard Atlanta, GA 30345 Contact: Kym Prieto (404) 325-4677 OPEN 940315. IOWA University of Iowa 200 Hawkins Drive / Southwest 54 GH Iowa City, IA 52242 Contact: Unspecified (319) 356-3168 OPEN 940315. ILLINOIS Rush Presbyterian / St Luke's Medical Center Room 140 - 143 Academic Facility / 600 South Paulina Chicago, IL 60612 Contact: Marilyn Ashmann (312) 942-5865 OPEN 940315. ILLINOIS University of Illinois 840 South Wood Street Chicago, IL 60612 Contact: Unspecified (312) 996-6732 OPEN 940315. INDIANA Infectious Diseases Research Clinic 550 N University Blvd / Room 5550 Indianapolis, IN 46202 Contact: Jean Craft (317) 274-8456 OPEN 940315. KANSAS University of Kansas School of Med / University Hospital 39th at Rainbow Kansas City, KS 66160-7354 Contact: Jane Harms (913) 588-6035 Contact: (913) 588-3896 OPEN 940315. KANSAS Univ of Kansas School of Medicine - Wichita / Clinical Rsch 1010 North Kansas Wichita, KS 67214-3199 Contact: Dal Harrison (316) 261-2855 OPEN 940315. KENTUCKY University of Kentucky Medical Center 800 Rose Street / Room MN633A Lexington, KY 40536 Contact: Karen Bowen (606) 257-5473 OPEN 940315. LOUISIANA Tulane University Medical School / AIDS Clinical Trials Unit 1430 Tulane Avenue New Orleans, LA 70112-2699 Contact: Russell Strada (504) 584-3605 OPEN 940315. MASSACHUSETTS Baystate Medical Center / Infectious Disease Division 759 Chestnut Street Springfield, MA 01199 Contact: Deborah Prescod (413) 784-3046 OPEN 940315. MASSACHUSETTS University of Massachusetts Medical School 55 Lake Avenue North / Div Infectious Diseases Worcester, MA 01655 Contact: Joan L Avto (508) 856-2456 Contact: (508) 856-2666 OPEN 940315 ACTU: 3001. MASSACHUSETTS Massachusetts General Hospital Gray 5 / Infectious Disease Unit Boston, MA 02114 Contact: Ellen Godfrey (617) 726-5598 Contact: Teri Flynn (617) 726-3819 OPEN 940315. MASSACHUSETTS Brigham Women's Hospital / Infectious Disease Division 75 Francis Street Boston, MA 02115 Contact: Ann Elperin (617) 732-5885 OPEN 940315. MASSACHUSETTS Boston City Hospital / FGH-1 818 Harrison Avenue / Thorndike Room 209 Boston, MA 02118 Contact: Nancy Reinhalter (617) 534-5404 OPEN 940315. MASSACHUSETTS New England Deaconess Hospital 185 Pilgrim Road Boston, MA 02215 Contact: Helen Fitch (617) 735-0785 OPEN 940315 ACTU: 0103. MAINE AIDS Consultation Service / Maine Medical Center 22 Bramhall Street Portland, ME 04102 Contact: Sandy Putnam (207) 871-2995 OPEN 940315. MARYLAND University of Maryland / SOM / Department of Med / Adult HIV Box 165 / 22 S Green Street Baltimore, MD 21201 Contact: Andrea Fisch (410) 706-1806 OPEN 940315. MICHIGAN University of Michigan / Division of Infectious Diseases 3116 B Taubman Center Ann Arbor, MI 48109 Contact: unspecified (313) 936-5205 OPEN 940315. MICHIGAN Harper Hospital Harper Professional Bldg / Suite 202 / 4160 John R Detroit, MI 48201 Contact: Dr Crane (313) 745-9131 OPEN 940315. MICHIGAN Henry Ford Hospital / Infectious Diseases 2799 West Grand Blvd / CFP 111 Detroit, MI 48202 Contact: Ann Marie Krystoforsky (313) 876-2798 OPEN 940315. MINNESOTA St Paul Ramsey Medical Center / HIV Program Office 640 Jackson Street St Paul, MN 55101 Contact: Holly Melroe (612) 221-1280 OPEN 940315. MISSOURI Washington University Clinical Trials Unit 4511 Forest Park Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0058 OPEN 940315. MISSOURI University of Missouri Kansas City / School of Medicine 2411 Holmes Kansas City, MO 64108 Contact: Donna Simpson (816) 556-3478 OPEN 940315. NORTH CAROLINA University of NC / School of Medicine / Div Infec Diseases 547 Burnett Womack Building / CB7030 Chapel Hill, NC 27599-7030 Contact: Barbara Longmeyer (919) 966-7883 OPEN 940315. NORTH CAROLINA Duke University Medical Center / Infectious Diseases Clinic PO Box 3284 Durham, NC 27710 Contact: Ken Ship (919) 684-5260 OPEN 940315. NORTH CAROLINA Carolinas Medical Center / Department of Internal Medicine 1000 Blythe Blvd AHEC Room 507 Charlotte, NC 28203 Contact: Joan Connell (704) 355-5292 Contact: (704) 355-3165 OPEN 940315 ACTU: 3204. NEBRASKA University of Nebraska Medical Center / HIV Clinic 600 South 42nd Street Omaha, NE 68198-5130 Contact: Colleen R Kelly (402) 559-8163 OPEN 940315. NEW JERSEY Jersey Shore Medical Center 1945 Route #33 Neptune, NJ 07754 Contact: Susan Bataille (908) 776-4700 OPEN 940315. NEW YORK CRIA of New York 275 Seventh Avenue / 20th Floor New York, NY 10001 Contact: Bette Smith (212) 924-3934 OPEN 940315. NEW YORK Beth Israel Medical Center / Department of Medicine First Avenue and 16th Street New York, NY 10003 Contact: Alice Fox (212) 420-4519 OPEN 940315. NEW YORK St Vincents Hospital and Medical Center 412 Sixth Ave / 4th Floor New York, NY 10011 Contact: Noel George (212) 604-7625 OPEN 940315. NEW YORK St Luke / Roosevelt Hospital Center / Dir HIV / AIDS CTP 428 West 59th Street New York, NY 10019 Contact: Julie Rivera (212) 523-6723 OPEN 940315. NEW YORK New York Hospital / Cornell Medical Center 505 East 70th Street New York, NY 10021 Contact: Paul Douglas (212) 746-4177 OPEN 940315. NEW YORK Mount Sinai Hospital / Clinical Trials Unit 1 Gustave Levy Place New York, NY 10029 Contact: Eileen Chusid (212) 241-0433 OPEN 940315. NEW YORK Westchester County Medical Center / Department of Infec Dis 209 South East / Macy Pavillion Valhalla, NY 10595 Contact: Gilda Forseter (914) 285-1561 Contact: Diane Holmgren (914) 285-7400 Contact: Dr Marissa Montecalvo (914) 285-8865 Contact: Dr Gary Wormser (914) 285-8865 OPEN 940315. NEW YORK SUNY at Stony Brook Health Sciences Center / Div Infect Dis HSC T 15 Room 080 Stony Brook, NY 11794-8153 Contact: Ruth Ann Burk (516) 444-1658 OPEN 940315. NEW YORK Albany Medical College / Div Med Oncology 47 New Scotland Avenue / Div Med Oncology A52 Albany, NY 12208-6752 Contact: Patricia Amsler (518) 262-6759 OPEN 940315 ACTU: 7401. NEW YORK SUNY at Buffalo / Erie County Medical Center 462 Grider Street Buffalo, NY 14215 Contact: David Meger (716) 898-4482 OPEN 940315. NEW YORK Community Health Network 758 South Avenue Rochester, NY 14620 Contact: Lorraine Newcomb (716) 244-9000 OPEN 940315. NEW YORK University of Rochester Medical Center 601 Elmwood Avenue / Box 689 Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 940315. OHIO University of Cincinnati Medical Center / Holmes Division Eden and Bethesda Avenues Cincinnati, OH 45267 Contact: Jill Leonard (513) 558-8373 OPEN 940315. OREGON Research and Education Group 2701 NW Vaughn Streets / 770 Portland, OR 97210 Contact: Sallie Israelit (503) 229-8428 OPEN 940315. OTHER University of Puerto Rico / Department of Medicine Medical Science Center / Room A 838 San Juan, PR 00936 Contact: Unspecified (809) 754-3755 OPEN 940315. PENNSYLVANIA University of Pittsburgh / School of Medicine 3515 Fifth Avenue Pittsburgh, PA 15261 Contact: Rosella Rosener (412) 647-8125 OPEN 940315. PENNSYLVANIA Pennsylvania State University / Hershey Medical Center 500 Univ Drive / PO Box 850 / Biomedical Rsrch Bldg C-6833 Hershey, PA 17033 Contact: Francine Damianos (717) 531-7488 OPEN 940315. PENNSYLVANIA University of Pennsylvania / Dept of Infect Dis / HIV Clinic 536 Johnson Pavilion / 6073 Philadelphia, PA 19104 Contact: Heidi Lehman (215) 662-6932 OPEN 940315. PENNSYLVANIA Childrens Hospital of Philadelphia / Division of General Ped 34th Street and Civic Center Boulevard / 2nd Floor Room 2015 Philadelphia, PA 19104 Contact: Dr Richard Rutstein (215) 590-1466 OPEN 940315. PENNSYLVANIA Buckley Braffman Stern Medical Associates PC 822 Pine Street / Suite 3A Philadelphia, PA 19107 Contact: Nancy Pietroski (215) 925-8010 OPEN 940315. PENNSYLVANIA Oncology and Hematology Association 1840 South Street / 2nd Floor Philadelphia, PA 19146 Contact: Barbara Rensman (215) 893-7541 OPEN 940315. RHODE ISLAND Memorial Hospital of Rhode Island 111 Brewster Street Pawtucket, RI 02860 Contact: Francis Betencourt (401) 729-2918 OPEN 940315. SOUTH CAROLINA Medical University of South Carolina 171 Ashley Avenue Charleston, SC 29425 Contact: Unspecified (803) 792-4541 OPEN 940315. 95 UNIQUE IDENTIFIER FDA/00646 PROTOCOL ID NUMBERS FDA 227B PROTOCOL TITLE A Randomized, Open-Label Trial of High Dose Atovaquone Versus Low Dose Atovaquone Versus Aerosolized Pentamidine for Prophylaxis of Pneumocystis carinii Pneumonia in Patients With HIV Infection Who Are Intolerant of TMP/SMX. VERSION NUMBER & DATE (940802) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To assess whether high dose or low dose atovaquone suspension is more effective than aerosolized pentamidine as prophylaxis against Pneumocystis carinii pneumonia (PCP) in high-risk HIV-infected patients. To compare the safety of chronic administration of the three regimens in patients with advanced HIV disease. To determine the relationship between steady state atovaquone plasma concentrations and prophylactic efficacy against PCP. Methodology: Patients are randomized to receive oral atovaquone at either 1500 or 750 mg once daily or aerosolized pentamidine at 300 mg once every 4 weeks. Treatment continues until 18 months after the last patient is enrolled. Patients are stratified into primary or secondary prophylaxis strata based on prior occurrence of a PCP episode. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive oral atovaquone at either 1500 or 750 mg once daily or aerosolized pentamidine at 300 mg once every 4 weeks. Treatment continues until 18 months after the last patient is enrolled. Patients are stratified into primary or secondary prophylaxis strata based on prior occurrence of a PCP episode. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940501) DISEASE STUDIED Pneumocystis carinii pneumonia ( PCP ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV positive by ELISA or Western blot. 2. Prior PCP (histologically confirmed) OR documented CD4 count < 200 cells/mm3 OR constitutional symptoms such as thrush or unexplained fever (> 100 F) for 2 or more weeks. 3. No current or suspected active PCP, and no signs of active PCP on chest x-ray. 4. Prior intolerance to TMP/SMX or other trimethoprim or sulfa-containing regimens. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Randomized; Open Label; Dose Comparison; Drug Comparison; Multicenter; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Primary prophylaxis, Secondary prophylaxis, Drug efficacy, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 615 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Until 18 months after enrollment of last patient. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 4 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV positivity. 2. Prior PCP (histologically confirmed) OR documented CD4 count < 200 cells/mm3 OR constitutional symptoms such as thrush or unexplained fever (> 100 F) for 2 or more weeks. 3. No current or suspected active PCP, and no signs of active PCP on chest x-ray. 4. Prior intolerance to TMP/SMX or other trimethoprim or sulfa-containing regimens. 5. Life-expectancy of at least 6 months. NOTE: Pregnant women are eligible at the discretion of the investigator. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.0 g/dl. (Transfusion permitted). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 80000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. (Patients who qualify for study entry based on CD4 count alone must have < 200 cells/mm3). ( 0 - 100 ). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: Serum amylase < 2 x ULN. Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Transfusion. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Antimicrobial agents not specifically prohibited. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of severe or intractable intolerance to atovaquone or aerosolized pentamidine. 2. Prior hypoglycemia, pancreatitis, arrhythmias, or severe hypotension associated with any form of pentamidine. 3. Prior enrollment in this protocol. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active substance abuse that would preclude study compliance. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Rifampin. 2. Other investigational agents except for drugs available through Treatment INDs or expanded access programs. 3. Medications likely to have anti-pneumocystis effect (e.g., dapsone, trimethoprim, pyrimethamine, trimetrexate, other DHFR inhibitors, sulfadiazine, sulfamethoxazole, other sulfonamides, primaquine, clindamycin, and sulfonylureas. 4. Corticosteroids in greater than physiologic replacement doses for more than 21 consecutive days. 5. Systemic therapy for CNS toxoplasmosis, Kaposi's sarcoma, lymphoma, other active malignancies, or other disease that may decrease life expectancy or confound assessment. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Significant psychosis or emotional disorder that would preclude study compliance. 2. Severe chronic diarrhea (e.g., > five stools/day) that may negatively affect absorption of oral medication. 3. Unable to take oral medication or unable or unwilling to take medication with food. SUBSTANCE IDENTIFICATION Drug 1 DRG-0084 Atovaquone SUBSTANCE IDENTIFICATION Drug 2 DRG-0025 Pentamidine TRADE NAME OF SUBSTANCE Drug 1‰ Mepron MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Lisa Behrens (800) 722-9292 X 3633. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1500 or 750 mg once daily with a meal, for 78 weeks. Drug 2: 300 mg q 4 weeks over a 78-week period, administered vinebulizer at a flow rate of 5-7 l/min over 30-45 min SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 1500 or 750 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Inhalation OTHER TREATMENT INFO. TREATMENT DURATION: Until 18 months after enrollment of last patient. OTHER TREATMENT INFO. END POINT: Primary: Occurrence of breakthrough PCP (including both histologically confirmed or presumed PCP and histologically confirmed extrapulmonary P. carinii infection). Secondary: Dose-limiting adverse effects, death. SUPPORTING AGENCY Burroughs Wellcome. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antifungal Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Naphthoquinones/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Pentamidine/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Pneumonia, Pneumocystis carinii/COMPLICATIONS/ *PREVENTION & CONTROL CAS REGISTRY NUMBER 0 (Antifungal Agents) CAS REGISTRY NUMBER 100-33-4 (Pentamidine) CAS REGISTRY NUMBER 94015-53-9 (atovaquone) LAST REVISION DATE 940501 ENTRY MONTH 9408 FLORIDA Dr Goodgame and Hopkins 340 N Maitland Avenue Maitland, FL 32751 Contact: Chuck DeMarzo (407) 647-6000 OPEN 940802. FLORIDA Bay Area AIDS Consortium 2901 Swann Avenue / Suite 107 Tampa, FL 33609 Contact: Clinical Trials Director (813) 877-5696 OPEN 940802. NEW YORK St Vincent's Hospital AIDS Center 412 Sixth Avenue / 4th Floor New York, NY 10011 Contact: Kerry McIntyre (212) 741-0784 OPEN 940802. OHIO Holmes Hospital Eden and Bethesda Avenues Cincinnati, OH 45267-0405 Contact: Dr Michael Dohn (513) 558-6977 OPEN 940802. 96 UNIQUE IDENTIFIER FDA/00668 PROTOCOL ID NUMBERS FDA 226D PROTOCOL TITLE Phase I Study of the Clinical Pharmacology of Azithromycin in Buffy Coat of HIV-Infected Subjects. VERSION NUMBER & DATE (940927) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To compare the uptake of azithromycin in white cells relative to plasma concentrations in HIV-infected patients. Methodology: Patients are randomized to receive azithromycin orally or intravenously, with crossover to the alternate treatment after a 21-day wash-out period. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive azithromycin orally or intravenously, with crossover to the alternate treatment after a 21-day wash-out period. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940801) DISEASE STUDIED Bacterial infections. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by Western blot confirmed by ELISA. 2. CD4 count <= 200 cells/mm3. 3. No active AIDS-defining opportunistic infection (unless discussed with Pfizer Clinician). ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 066-062 STUDY DESIGN Open Label; Randomized; Crossover; Comparative administration route PROTOCOL DETAILS STUDY INTENT: Pharmacokinetics, Administration route comparison. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CD4 count <= 200 cells/mm3. 3. No active opportunistic infection (pending discussion with Pfizer Clinician). [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 200 cells/mm3. ( 0 - 100 - 200 ). PATIENT INCLUSION CRIT. BILIRUBIN: < 1.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 75 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase < 3 x ULN. Absolute neutrophils > 750 cells/mm3. Negative urine drug screen. Negative ethanol breath test. PATIENT AGE AGE: 18 Years - 65 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception during the study and for 90 days after. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior antiretroviral agents. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Antiretroviral agents, provided regimen has been stable for at least 1 month. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of clinically signficant allergic, hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or neurological disease. 2. Clinically important change in baseline status within 4 weeks prior to study entry. 3. Condition affecting drug absorption (e.g., ulcers, gastrectomy, HIV-associated enteropathies) within 4 weeks prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 66 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Known drug or alcohol dependence. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Investigational drugs including treatment IND drugs within 4 weeks prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active intercurrent illness (pending discussion with the Pfizer Clinician). 2. Allergies to macrolide antibiotics. 3. Signs and symptoms of severe illness that would preclude treatment. SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin TRADE NAME OF SUBSTANCE Drug 1‰ Zithromax MANUFACTURERS Drug 1: Pfizer Central Research Eastern Point Road Groton, CT 06340 Contact: Dr Aron Stein (203) 441-6106. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1200 mg per treatment SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral and intravenous (IV) SUPPORTING AGENCY Pfizer Central Research. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Azithromycin/ADMINISTRATION & DOSAGE/ *PHARMACOKINETICS MESH HEADING Bacterial Infections/COMPLICATIONS/ *PREVENTION & CONTROL MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 940801 ENTRY MONTH 9409 KANSAS Center for Phase I Research 1100 North St Francis / Suite 200 Wichita, KS 67214 Contact: Dr Donna Sweet (316) 268-5984 OPEN 940801. 97 UNIQUE IDENTIFIER FDA/00660 PROTOCOL ID NUMBERS FDA 226C PROTOCOL TITLE Double-Blind Crossover Study Assessing the Dose Proportionality of Azithromycin Tablets in HIV-Infected Subjects. VERSION NUMBER & DATE (940909) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To assess the dose proportionality of azithromycin concentrations and toleration when delivered in tablet formulation to HIV-infected patients. GENERAL DESCRIPTION RATIONALE: The need exists to further assess the antibacterial agent azithromycin at differing doses in an HIV-infected population. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive azithromycin at 600 or 1200 mg in a two-treatment, two-period, cross-over study. Dosing visits are separated by at least 14-day wash-out periods. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940601) DISEASE STUDIED Bacterial infections. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by Western blot and ELISA. 2. CD4 count <= 500 cells/mm3. 3. NO active AIDS opportunistic infection. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS 066-060 STUDY DESIGN 2-Arm; Double-Blind; Dose Comparison; Crossover; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug dosing schedule, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 12 patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. CD4 count <= 500 cells/mm3. 3. NO active AIDS opportunistic infection. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 500 cells/mm3. ( 0 - 100 - 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: < 1.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 75 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 750 cells/mm3. Alkaline phosphatase < 3 x ULN. Negative urine drug screen and blood alcohol test. PATIENT AGE AGE: 18 Years - 65 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: Clinically important change in baseline status within 4 weeks prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 66 Years - 99 Years. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Known drug or alcohol dependence. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Investigational drugs including treatment IND drugs within 4 weeks prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Other active intercurrent illness. 2. Any condition possibly affecting drug absorption (e.g., ulcers, gastrectomy, HIV-associated enteropathies. 3. Signs or symptoms of severe illness that would preclude study participation. 4. Known allergies to macrolide antibiotics. SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin MANUFACTURERS Drug 1: Pfizer Central Research Eastern Point Road Groton, CT 06340 Contact: Dr Aron Stein (203) 441-6106. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 600 or 1200 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, tablets SUPPORTING AGENCY Pfizer Central Research. MESH HEADING Adult MESH HEADING Azithromycin/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS MESH HEADING Bacterial Infections/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 940601 ENTRY MONTH 9409 ARIZONA Harris Laboratories Inc 4639 South 36th Street Phoenix, AZ 85040 Contact: Dr Wayne Colburn (602) 437-0097 OPEN 940909. 98 UNIQUE IDENTIFIER FDA/00673 PROTOCOL ID NUMBERS FDA 226B PROTOCOL TITLE A Randomized, Double-Blind, Comparative Study of Azithromycin Versus Clarithromycin in Combination with Ethambutol for the Treatment of Disseminated Mycobacterium Avium Complex (MAC). VERSION NUMBER & DATE (940323) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the efficacy and safety of two different doses of azithromycin in combination with ethambutol for the treatment of patients with Mycobacterium Avium Complex (MAC) infection, and to determine whether an azithromycin-containing regimen is at least as safe and effective as the same regimen containing clarithromycin. Methodology: Patients are randomized to receive azithromycin at one of two doses in combination with ethambutol or clarithromycin in combination with ethambutol for 24 weeks, after which they are evaluated for entry into a maintenance phase of treatment. Clinical, microbiologic, and safey assessments are performed every 3 weeks for the first 12 weeks, then monthly for the remaining 12 weeks. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive azithromycin at one of two doses in combination with ethambutol or clarithromycin in combination with ethambutol for 24 weeks, after which they are evaluated for entry into a maintenance phase of treatment. Clinical, microbiologic, and safey assessments are performed every 3 weeks for the first 12 weeks, then monthly for the remaining 12 weeks. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940728) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA and/or Western blot and/or PCR. 2. Disseminated MAC by positive blood culture within 2 months prior to study entry. 3. No MAC therapy between time of last positive blood culture draw and study entry (single-agent prophylaxis allowed). ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 066-189. 189/189B STUDY DESIGN Randomized; Double-Blind; Comparative; Drug Combination; Dose Comparison PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Combination drug therapy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 18 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. Disseminated MAC. 3. No MAC therapy between time of last positive blood culture draw and study entry (single-agent prophylaxis allowed). 4. Life expectancy of at least 2 months. 5. Consent of parent or guardian if below legal age of consent. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 3.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 3.0. PATIENT INCLUSION CRIT. OTHER: Neutrophils > 500 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception during the study and for 90 days after. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: MAC therapy between time of last positive blood culture draw and study entry (although single-agent prophylaxis is allowed). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Another investigational drug started in the week prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known hypersensitivity to macrolide antibiotics (erythromycin, azithromycin, or clarithromycin) or ethambutol. 2. Inability to take oral medications. 3. Condition likely to interfere with drug absorption (e.g., gastrectomy, malabsorption syndromes). SUBSTANCE IDENTIFICATION Drug 1 DRG-0099 Clarithromycin SUBSTANCE IDENTIFICATION Drug 2 DRG-0104 Azithromycin SUBSTANCE IDENTIFICATION Drug 3 DRG-0111 Ethambutol TRADE NAME OF SUBSTANCE Drug 2‰ Zithromax MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. MANUFACTURERS Drug 2: Pfizer Central Research Eastern Point Road Groton, CT 06340 Contact: Dr Aron Stein (203) 441-6106. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 500 mg BID for 24 weeks. Drug 2: 250 or 600 mg daily for 24 weeks. Drug 3: 800 mg (if < 65 kg) or 1200 mg (if >= 65 kg) daily for weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 1000 mg. Drug 2: 250 or 600 mg. Drug 3: 800 or 1200 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Oral. Drug 3: Oral OTHER TREATMENT INFO. TREATMENT DURATION: At least 24 weeks. SUPPORTING AGENCY Pfizer Central Research. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Azithromycin/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Clarithromycin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Ethambutol/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 74-55-5 (Ethambutol) CAS REGISTRY NUMBER 81103-11-9 (Clarithromycin) CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 940728 ENTRY MONTH 9410 CALIFORNIA University of California Irvine / Dept of Med / Infect Disea 101 City Drive South / Building 53 / Route 53 Orange, CA 92668 Contact: Bobi Keenan (714) 456-7612 OPEN 941103. CALIFORNIA HIV Research Unit / Kaiser Permanente Medical Group 2590 Geary Boulevard San Francisco, CA 94115 Contact: Joe Thatcher (415) 202-3480 Contact: Dr W Jeffrey Fessel OPEN 941103. CALIFORNIA Infectious Disease Medical Gp / Adult Immunology Clinic 3012 Summit Street Sixth Floor Oakland, CA 94609 Contact: Jamie Carroll (510) 420-6014 Contact: Doctors office (510) 834-2800 OPEN 941103. CALIFORNIA East Bay AIDS Center 3031 Telegraph Avenue Suite 235 Berkeley, CA 94705 Contact: Nancy Orcutt (510) 204-1291 OPEN 940915. CALIFORNIA Santa Clara Valley Medical Center / AIDS Program 751 South Bascom Avenue San Jose, CA 95128-2699 Contact: Carol Kane (408) 885-4316 Contact: Dr Carol Kemper (assoc dir) (408) 885-4300 OPEN 940915. DISTRICT OF COLUMBIA Georgetown University 110 Kober-Cogan Building / 3800 Reservoir Road Northwest Washington, DC 20007-2197 Contact: Sharon Boone (202) 687-7387 Contact: Dr Princy Kumar (202) 687-6845 OPEN 941103. DISTRICT OF COLUMBIA Whitman Walker Clinic 1701 NW 14th Street Washington, DC 20009 Contact: Christiane Jones (202) 745-6151 OPEN 940915. FLORIDA Medical Service (111-1) 1201 NW 16 Street Miami, FL 33125 Contact: Karen Cleven (305) 324-3267 Contact: Tommie Stapleton (305) 324-3267 Contact: Dr Gordon Dickinson (305) 324-3267 OPEN 941103. FLORIDA Bay Area AIDS Consortium 2901 Swann Avenue / Suite 107 Tampa, FL 33609 Contact: Clinical Trials Director (813) 877-5696 OPEN 940728. FLORIDA Dr Robert Wallace 2663 First Avenue North St Petersburg, FL 33713 Contact: Becky Tarbett - key contact (813) 877-5696 Contact: (Bay Area AIDS Consortium) Contact: Doctor's office (813) 327-5188 OPEN 940915. ILLINOIS Northwestern Univ Medical School / Comp AIDS Ctr / Infec Dis 303 East Superior Street / Passavant Room 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 940915. ILLINOIS Dr Neel French / Louis A Weiss Memorial Hospital 4640 North Marine Drive Suite 4 Chicago, IL 60640 Contact: Dr Neel French (312) 275-2562 OPEN 941103. MISSOURI Trinity Lutheran Hospital / Infectious Disease Clinic 3030 Baltimore Kansas City, MO 64108 Contact: Maithe E. Fowler (816) 751-2792 Contact: (816) 751-2332 OPEN 940915. 99 UNIQUE IDENTIFIER FDA/00609 PROTOCOL ID NUMBERS FDA 226A PROTOCOL TITLE A Randomized Study of Daily and Intermittent Prophylactic Regimens for the Prevention of Disseminated Mycobacterium avium Complex (MAC) and Fungal Infections in HIV-Infected Patients. VERSION NUMBER & DATE (940323) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: PRIMARY: To determine the efficacy of azithromycin and rifabutin alone and in combination for the prevention of disseminated Mycobacterium avium Complex (MAC) infection in HIV-infected patients. To determine the efficacy of daily versus weekly fluconazole for the prevention of deep fungal infections in this patient population. SECONDARY: To determine the incidence of bacterial (including mycobacterial) infections, cryptosporidiosis, and toxoplasmosis in azithromycin versus non-azithromycin containing regimens. To determine the incidence of oropharyngeal and vaginal candidiasis in patients treated with daily versus weekly fluconazole. To compare survival and outcomes of primary endpoints in the treatment arms. Methodology: Patients are randomized to receive azithromycin alone, rifabutin alone, or the two drugs in combination for MAC prophylaxis. Patients in each treatment group further receive one of two doses of concomitant fluconazole for deep fungal prophylaxis, unless specifically excluded for fluconazole randomization. Patients are followed for 1 to 2 years. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive azithromycin alone, rifabutin alone, or the two drugs in combination for MAC prophylaxis. Patients in each treatment group further receive one of two doses of concomitant fluconazole for deep fungal prophylaxis, unless specifically excluded for fluconazole randomization. Patients are followed for 1 to 2 years. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (921201) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ), Fungal infections (Myco DISEASES STATUS Patients have the following symptoms and conditions: 1. Laboratory evidence of HIV infection or history of an AIDS-defining condition by CDC criteria. 2. One documented CD4 count < 100 cells/mm3 within 12 months prior to study entry. 3. NO known or disseminated MAC disease or MAC bacteremia or active nontuberculous mycobacterial infection. 4. NO known or suspected M. tuberculosis infection. 5. Chest radiograph within 1 month prior to study entry that shows no evidence of active disease. 6. NO acute opportunistic infection (although patients receiving maintenance therapy for CMV retinitis are permitted). ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 066-174 STUDY DESIGN Randomized; Double-Blind; Multicenter; Drug Comparison; Dose Comparison PROTOCOL DETAILS STUDY INTENT: Drug prophylaxis, Drug efficacy, Combination drug therapy, Comparative drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 720 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 2 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 12 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection or history of an AIDS-defining condition by CDC criteria. 2. One documented CD4 count < 100 cells/mm3 within 12 months prior to study entry. 3. NO active MAC disease, MAC bacteremia, or active mycobacterial infection (tuberculous or nontuberculous). 4. NO acute opportunistic infection. 7. Life expectancy of more than 6 months. 8. Consent of parent or guardian if less than legal age of consent. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: < 100 cells/mm3. ( 0 ). One documented count within 12 months prior to study entry. PATIENT INCLUSION CRIT. BILIRUBIN: < 3 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 3 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 500 cells/mm3. PATIENT AGE AGE: 12 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Preventive therapy with isoniazid for M. tuberculosis. 2. Maintenance therapy for CMV retinitis. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 11 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded for fluconazole randomization: 1. Maintenance therapy for deep fungal infections. 2. Chronic therapy with ketoconazole or fluconazole. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: ALL PATIENTS - 1. Unexplained fevers, elevation in alkaline phosphatase, pancytopenia, abnormal liver function tests, or odynophagia for which the diagnoses of MAC and fungal infections have not been excluded. 2. Serious hypersensitivity reactions to macrolides or rifampin. 3. Unable to tolerate oral medications. FOR FLUCONAZOLE RANDOMIZATION - 1. Serious hypersensitivity reaction to fluconazole. 2. Active fungal infection (cryptococcosis, histoplasmosis, blastomycosis, aspergillosis, Candida esophagitis, thrush, vaginal candidiasis). 3. Positive baseline urine cryptococcal culture. SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin SUBSTANCE IDENTIFICATION Drug 2 DRG-0005 Fluconazole SUBSTANCE IDENTIFICATION Drug 3 DRG-0085 Rifabutin TRADE NAME OF SUBSTANCE Drug 1‰ Zithromax TRADE NAME OF SUBSTANCE Drug 2‰ Diflucan MANUFACTURERS Drug 1: Pfizer Central Research Eastern Point Road Groton, CT 06340 Contact: Dr Aron Stein (203) 441-6106. MANUFACTURERS Drug 2: Pfizer Central Research Eastern Point Road Groton, CT 06340 Contact: Dr Aron Stein (203) 441-6106. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1200 mg weekly. Drug 2: 200 mg daily or 400 mg weekly. Drug 3: 300 mg daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 3: 300 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 600 mg lactose-free tablets. Drug 2: Oral, 200 mg tablets. Drug 3: Oral, 150 mg capsules SUPPORTING AGENCY Pfizer Central Research. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Azithromycin/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Fluconazole/ADMINISTRATION & DOSAGE/ *THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*PREVENTION & CONTROL MESH HEADING Mycoses/COMPLICATIONS/*PREVENTION & CONTROL MESH HEADING Rifabutin/*THERAPEUTIC USE CAS REGISTRY NUMBER 72559-06-9 (Rifabutin) CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) CAS REGISTRY NUMBER 86386-73-4 (Fluconazole) LAST REVISION DATE 921201 ENTRY MONTH 9403 CALIFORNIA Los Angeles County / Univ of Southern California Medical Ctr Building 5P21 / Room 349 / 1175 Cummings Street Los Angeles, CA 90033 Contact: Dr Michael Dube (213) 226-7504 OPEN 921201. CALIFORNIA Harbor UCLA Medical Center / Department of Medicine 1000 West Carson Street Torrance, CA 90509 Contact: Sally Kruger (310) 222-3848 OPEN 921201. CALIFORNIA University of California / San Diego Treatment Center 2760 Fifth Avenue / Suite 300 San Diego, CA 92103 Contact: Cathy Nuffer (619) 543-8080 Contact: Dr Diane Havir (619) 543-8080 OPEN 921201. CALIFORNIA University of California Irvine / Dept of Med / Infect Disea 101 City Drive South / Building 53 / Route 53 Orange, CA 92668 Contact: Bobi Keenan (714) 456-7612 OPEN 921201. CALIFORNIA Santa Clara Valley Medical Center / AIDS Program 751 South Bascom Avenue San Jose, CA 95128-2699 Contact: Carol Kane (408) 885-4316 Contact: Dr Carol Kemper (assoc dir) (408) 885-4300 OPEN 921201. DISTRICT OF COLUMBIA Georgetown University Medical Center 3800 Reservoir Rd / Kober-Cogan Bldg / Suite 100 Washington, DC 20007 Contact: Jeanne Trembeth (202) 687-5378 OPEN 921201. DISTRICT OF COLUMBIA George Washington University / Medical Center / Div Inf Dise 2150 Pennsylvania Ave NW Washington, DC 20037 Contact: Susan LeLacheruri (202) 994-2417 OPEN 921201. MASSACHUSETTS University of Massachusetts Medical School 55 Lake Avenue North / Div Infectious Diseases Worcester, MA 01655 Contact: Joan L Avto (508) 856-2456 Contact: (508) 856-2666 OPEN 921201 ACTU: 3001. NEW YORK Memorial Sloan Kettering Cancer Center / Cornell Medical Col 525 East 68th Street New York, NY 10021 Contact: Trisha Seroko (212) 746-4177 Contact: Dr Kent Sepkowitz (212) 746-4177 OPEN 921201. PENNSYLVANIA University of Pennsylvania / Depart of Infectious Diseases 6073 36th Street and Hamilton Walk/536 Johnson Pavillion G2 Philadelphia, PA 19104 Contact: Amy Graziani (215) 662-2900 OPEN 921201. 100 UNIQUE IDENTIFIER FDA/00605 PROTOCOL ID NUMBERS FDA 224A PROTOCOL TITLE Randomized Phase I Study of Trimetrexate Glucuronate (TMTX) With Leucovorin (LCV) Protection Plus Dapsone Versus Trimethoprim / Sulfamethoxazole (TMP/SMX) for Treatment of Moderately Severe Episodes of Pneumocystis carinii Pneumonia. VERSION NUMBER & DATE (940713) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the safety of the combination of trimetrexate glucuronate (TMTX) and dapsone with leucovorin protection versus trimethoprim/sulfamethoxazole (TMP/SMX) in patients with AIDS and moderately severe Pneumocystis carinii pneumonia (PCP). To determine the pharmacokinetic parameters of TMTX, leucovorin, and dapsone and of TMP/SMX when given to patients with AIDS and moderately severe PCP. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940124) DISEASE STUDIED Pneumocystis carinii pneumonia ( PCP ). DISEASES STATUS Patients have the following symptoms and conditions: 1. AIDS by CDC criteria. 2. Confirmed diagnosis of PCP by morphologic confirmation of three or more typical Pneumocystis carinii organisms in sputum, bronchoalveolar lavage fluid, or lung tissue within 10 days prior to study entry. (If PCP is highly suspected but diagnosis has not been made, confirmation may be established within the first 10 days of study.) 3. Alveolar-arterial differences in dissolved oxygen >= 35 mm Hg but < 55 mm Hg on room air. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS TMTX A009 STUDY DESIGN Prospective; Randomized; Double-Blind; Drug Comparison; Drug Tolerance; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug safety, Combination drug therapy, Pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 20 patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS. 2. Confirmed diagnosis of PCP. 3. Alveolar-arterial differences in dissolved oxygen >= 35 mm Hg but < 55 mm Hg on room air. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. (Transfusion permitted). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 3 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Abstinence or effective method of birth control / contraception during the study and for 14 days after. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Empiric therapy for other opportunistic pulmonary infection (TB or fungi) for the first 72 hours of study enrollment ONLY, until presence of suspected pathogens can be confidently excluded. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: Prior history of serious or life-threatening intolerance to TMP/SMX. (NOTE: Patients with less severe reactions may be included at the discretion of the investigator and primary care provider.) [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. No abstinence or no agreement to use effective method of birth control during study and for 14 days after. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: More than 24 hours of systemic anti-PCP therapy within 2 weeks prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Induction therapy with bone marrow suppressive drugs (e.g., ganciclovir) or hepatotoxic drugs (e.g., chemotherapy). 2. AZT, ddI, ddC, d4T, or other antiretroviral therapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Severe renal or hepatic dysfunction. 2. Serious or life-threatening intolerance to TMP/SMX, TMTX, or dapsone. 3. Concurrent pneumothorax. 4. Active pulmonary tuberculosis or other inadequately treated opportunistic pulmonary infection (e.g., Cryptocococcus neoforms, CMV). NOTE: Identification of Mycobacterium avium or CMV in sputum or BAL fluid does not exclude, since these organisms may be present without causing disease. 5. Pulmonary Kaposi's sarcoma. 6. Active opportunistic infections or malignancies requiring induction therapy with bone marrow suppressive drugs (e.g., ganciclovir) or hepatotoxic drugs (e.g., chemotherapy). 7. Unable to have arterial blood gases on room air obtained at baseline. 8. Unwilling to undergo bronchoscopy, if sputum induction does not reveal Pneumocystis carinii. 9. Suspected malabsorption (e.g., ileus or severe diarrhea with > 6 stools/day). 10. Known absence of G6PD activity. 11. Large volume (1.0 to 1.5 liters) of intravenous fluid (5 percent in water) per 24 hours is medically inadvisable. 12. Unwilling to comply with study design. SUBSTANCE IDENTIFICATION Drug 1 DRG-0183 Trimetrexate glucuronate SUBSTANCE IDENTIFICATION Drug 2 DRG-0002 Leucovorin calcium SUBSTANCE IDENTIFICATION Drug 3 DRG-0036 Dapsone SUBSTANCE IDENTIFICATION Drug 4 DRG-0030 Trimethoprim SUBSTANCE IDENTIFICATION Drug 5 DRG-0031 Sulfamethoxazole MANUFACTURERS Drug 1: US Bioscience Incorporated One Tower Bridge 100 Front Street West Conshohocken, PA 19428 Contact: Dr Edith Mitchell (610) 832-4525. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Jacobus Pharmaceutical Company PO Box 5290 / 37 Cleveland Lane Princeton, NJ 08540 Contact: Dr David Jacobus (609) 921-7447. MANUFACTURERS Drug 4: Drugs are provided by each participating unit site. MANUFACTURERS Drug 5: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous OTHER TREATMENT INFO. TREATMENT DURATION: 24 days. OTHER TREATMENT INFO. END POINT: Survival; dose-limiting toxicity at 10 days, completion of therapy (21 days +/- 3 days), and 1 month following completion of therapy; differences in arterial blood gases (ABGs) after 10 and 21 days (+/- 3 days) of study therapy. SUPPORTING AGENCY US Bioscience Incorporated, Jacobus Pharmaceutical Company. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Dapsone/*ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Leucovorin/PHARMACOKINETICS/*THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Pneumonia, Pneumocystis carinii/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Trimethoprim-Sulfamethoxazole Combination/ *ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Trimetrexate/*ADVERSE EFFECTS/ PHARMACOKINETICS CAS REGISTRY NUMBER 52128-35-5 (Trimetrexate) CAS REGISTRY NUMBER 58-05-9 (Leucovorin) CAS REGISTRY NUMBER 80-08-0 (Dapsone) CAS REGISTRY NUMBER 8064-90-2 (Trimethoprim-Sulfamethoxazole Combination) LAST REVISION DATE 940124 ENTRY MONTH 9403 CALIFORNIA University of Southern California Medical Center 1175 N Cummings Street / Bldg 5P21 / Room 349 Los Angeles, CA 90033 Contact: Diane Ramos (213) 343-8288 OPEN 940124. 101 UNIQUE IDENTIFIER FDA/00606 PROTOCOL ID NUMBERS FDA 223A PROTOCOL TITLE Diethylhomospermine (DEHSPM) for Refractory AIDS-Related Diarrhea. VERSION NUMBER & DATE (940222) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To perform preliminary clinical testing of diethylhomospermine (DEHSPM), a polyamine analog, for refractory AIDS-related diarrhea. GENERAL DESCRIPTION RATIONALE: Possibly, DEHSPM will reduce stool volume and frequency in patients with refractory AIDS-related diarrhea. GENERAL DESCRIPTION METHODOLOGY: Patients are initially hydrated for 24 hours, followed by a 3-day baseline period. They then receive intravenous infusions of DEHSPM three times per day for 3 days, followed by observation for 3 days. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940214) DISEASE STUDIED Diarrhea. DISEASES STATUS Patients have the following symptoms and conditions: 1. ARC or AIDS by CDC criteria. 2. Uncontrolled diarrhea defined as more than 500 ml liquid stool daily for at least 4 weeks duration despite at least 2 weeks of high-dose, nonspecific antidiarrheal therapy (i.e., loperamide, diphenoxylate hydrochloride-atropine sulfate, or opiates) at maximally tolerable doses. NOTE: Patients with cytomegalovirus colitis or enteritis are permitted if they are unresponsive to ganciclovir therapy. Patients with Mycobacterium avium-intracellulare, Cryptosporidium parvum, or microsporidial infection are permitted only if they are receiving no other experimental drugs. NOTE: Patients must have none of the gastrointestinal disorders that are specifically excluded. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Open Label; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 10 days. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. ARC or AIDS by CDC criteria. 2. Uncontrolled diarrhea unresponsive to high-dose, nonspecific antidiarrheal therapy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 18 Years - 65 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Postmenopausal or infertile because of tubal ligation, hysterectomy, bilateral oophorectomy, or oral contraceptives. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: At least 2 weeks of prior high-dose, nonspecific antidiarrheal therapy (i.e., loperamide, diphenoxylate hydrochloride-atropine sulfate, or opiates) at maximally tolerable doses. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 66 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Reproductive potential. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Other experimental drugs within 1 month prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other experimental antidiarrheal drugs. 2. Antibiotic therapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known idiopathic ulcerative colitis or Crohn colitis. 2. Acute stool-culture-positive bacterial colitis. 3. Acute amoebic colitis. 4. Pseudomembranous colitis with Clostridium difficile toxin positivity. 5. Short-gut syndrome. 6. Chronic pancreatitis. 7. Ischemic bowel disease. 8. Enteroenteric fistulae. 9. Other gastrointestinal tract disorders known to cause diarrhea. 10. Underlying evidence of immunosuppression other than that related to HIV infection. 11. Unable or unwilling to have subcutaneous injections. 12. Clinically significant CNS, hepatic, or renal disease. SUBSTANCE IDENTIFICATION Drug 1 DRG-0203 Diethylhomospermine TRADE NAME OF SUBSTANCE Drug 1‰ DEHSPM MANUFACTURERS Drug 1: Gainesville Veterans Administration Medical Center Gastroenterology Section 111-C Gainesville, FL 32608 Contact: Dr Charles A Sninsky (904) 374-6055. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 30 mg/m2 daily for 3 days SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 30 mg/m2 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV) OTHER TREATMENT INFO. TREATMENT DURATION: 3 days. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Development of an excluded condition. 2. Requirement for antibiotics. SUPPORTING AGENCY Gainesville Veterans Administration Medical Center. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Antidiarrheals/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Diarrhea/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Spermine/ANALOGS & DERIVATIVES/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antidiarrheals) CAS REGISTRY NUMBER 119422-08-1 (N(1),N(14)-bis(ethyl)homospermine) LAST REVISION DATE 940214 ENTRY MONTH 9403 FLORIDA Gainesville Veterans Administration Medical Center Gastroenterology Section 111-C Gainesville, FL 32608 Contact: Dr Charles A Sninsky (904) 374-6055 OPEN 940214. 102 UNIQUE IDENTIFIER FDA/00604 PROTOCOL ID NUMBERS FDA 222A PROTOCOL TITLE A Phase I/II Clinical Study of WF 10 IV Solution (Oxoferin; TCDO) in Patients With HIV Infection. VERSION NUMBER & DATE (940309) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the clinical toxicity, safety, and MTD of oxoferin (WF 10; TCDO) intravenous solution administered to patients with HIV infection. To evaluate the potential anti-HIV activity of TCDO. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940309) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV positive by ELISA. 2. Absolute CD4 count of 150 - 500 cells/mm3 in two determinations within 15 days prior to study entry. 3. At least 6 months of prior zidovudine therapy. 4. No active opportunistic infection requiring ongoing therapy. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS WF10-92-US-001 STUDY DESIGN Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug toxicity, Maximum tolerated dose (MTD), Drug efficacy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV positivity. 2. Absolute CD4 count of 150 - 500 cells/mm3. 3. At least 6 months of prior zidovudine therapy. 4. No active opportunistic infection requiring ongoing therapy. 5. Life expectancy of at least 6 months. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 10 g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: > 1000 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 150 - 500 cells/mm3. ( 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: < 1.95 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 3.0 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 3.0 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 2.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: > 70. PATIENT INCLUSION CRIT. OTHER: Normal PT and PTT. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: At least 6 months of prior zidovudine. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: Aerosolized pentamidine (300 mg monthly) as prophylaxis for PCP only in patients with CD4 count <= 200 cells/mm3. Allowed: PCP prophylaxis with aerosolized pentamidine in patients with CD4 count > 200 cells/mm3, only at the discretion of the treating physician. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of myocardial infarction or arrhythmias. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active drug or alcohol abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 2 weeks prior to study entry: 1. Antiretroviral agent or interferon. 2. Systemic biologic response modifiers, corticosteroids, cytotoxic chemotherapeutic agents, or other drugs that can cause neutropenia or significant nephrotoxicity. 3. Rifampin or rifampin derivatives. 4. Systemic anti-infectives. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Neoplasm other than basal cell carcinoma of the skin. 2. Clinically significant cardiac disease. 3. Abnormal neurological status by a standardized assessment including strength, reflex testing, and sensory testing. 4. Unwilling to comply with protocol requirements. SUBSTANCE IDENTIFICATION Drug 1 DRG-0204 Oxoferin TRADE NAME OF SUBSTANCE Drug 1‰ WF 10 MANUFACTURERS Drug 1: Oxo Chemie GmbH Im Neuenheimer Feld 517 Heidelberg, GE Contact: Unspecified. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV), solution SUPPORTING AGENCY Oxo Chemie GmbH. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Chlorine/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Oxides/*ADVERSE EFFECTS/THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 92047-76-2 (oxoferin) LAST REVISION DATE 940309 ENTRY MONTH 9403 103 UNIQUE IDENTIFIER FDA/00603 PROTOCOL ID NUMBERS FDA 221A PROTOCOL TITLE A Randomized, Placebo-Controlled, Double-Blind, Single and Multiple Oral Dose-Tolerance Study of Oral MDL 28,574A Solution in HIV-Positive Patients. VERSION NUMBER & DATE (940302) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To characterize the safety profile of MDL 28574A following both acute and subchronic dosing in HIV-positive patients. To determine the MTD of both acute and subchronic doses of this drug when administered as oral solution. To determine the pharmacokinetic profile of MDL 28574A and castanospermine (from which MDL 28574A is derived) following both acute and subchronic dosing. Methodology: In Part A of the study, patients receive a single oral dose of MDL 28574A on day 1 and are followed through day 7. In Part B, patients receive single daily doses of the drug on days 1 through 14 and are followed through day 21. GENERAL DESCRIPTION METHODOLOGY: In Part A of the study, patients receive a single oral dose of MDL 28574A on day 1 and are followed through day 7. In Part B, patients receive single daily doses of the drug on days 1 through 14 and are followed through day 21. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940314) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Two positive tests for HIV antibody (ELISA plus Western blot-identified p24, gp41, or gp120/160). 2. CD4 count >= 500 cells/mm3. 3. No evidence of AIDS. 4. No antiretroviral therapy within 30 days prior to study entry. NOTE: Presence of lymphadenopathy in two or more extrainguinal sites, at least 1 cm in diameter for 3 or more months, is permitted. ELIGIBILITY ASYM. OTHER PROTOCOL NUMBERS NDPR0002 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Drug Tolerance; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug safety, Maximum tolerated dose (MTD), Pharmacokinetics, Drug dosing schedule. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 7 - 14 days. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CD4 count >= 500 cells/mm3. 3. No evidence of AIDS. 4. No antiretroviral therapy within 30 days prior to study entry. NOTE: Presence of lymphadenopathy in two or more extrainguinal sites, at least 1 cm in diameter for 3 or more months, is permitted. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 500 cells/mm3. ( 500 - 600 - 700 - 800 - plus ). PATIENT AGE AGE: 18 Years - 50 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Prior participation in this trial. 2. Serious physical or mental illness within 1 year prior to study entry that would confound interpretation of data. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 51 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: History of alcohol or drug abuse within the past year. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Antiretroviral therapy within 30 days prior to study entry. 2. Known medications that alter renal, hepatic, or hematologic/immunologic function (such as barbiturates, phenothiazines, cimetidine, and immunomodulators) within 14 days prior to study entry. 3. Routine treatment with nonprescription medications within 3 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Routine treatment with nonprescription medications. 2. Treatment with other medications except with approval of the investigator. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Clinically significant abnormalities on routine hematology (other than CD4 count and Western blot), serum chemistry, and urinalysis. 2. Abnormal EKG. 3. Positive stool guaiac. 4. Abnormal medical history or physical exam including temperature, heart rate, and blood pressure. 5. Clinically significant organ abnormality or disease. 6. Positive urine drug screen for illicit drugs. 7. Inability to comply with study procedures. PATIENT EXCLUSION CRIT. AVAILABILITY: Unavailable for inpatient stay or for outpatient followup. SUBSTANCE IDENTIFICATION Drug 1 DRG-0202 MDL 28574 MANUFACTURERS Drug 1: Marion Merrell Dow Inc 9300 Ward Parkway Kansas City, MO 64114 Contact: David Katterhenrich (816) 966-3482. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Part A: Single dose administered on day 1. Part B: Daily doses administered on days 1 through 14 SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, solution OTHER TREATMENT INFO. TREATMENT DURATION: 1 to 14 days. SUPPORTING AGENCY Marion Merrell Dow Inc. MESH HEADING Adult MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Indolizines/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 121104-96-9 (MDL 28574) LAST REVISION DATE 940314 ENTRY MONTH 9403 CALIFORNIA Saint Francis Memorial Hospital 900 Hyde Street San Francisco, CA 94109 Contact: Mark Bowers (415) 353-6215 OPEN 940314. 104 UNIQUE IDENTIFIER FDA/00598 PROTOCOL ID NUMBERS FDA 220A PROTOCOL TITLE A Randomized, Open-Label Study of Alternative Treatment Combinations of Dideoxycytidine (HIVID; ddC) and Zidovudine (AZT) in Patients With HIV Infection. VERSION NUMBER & DATE (940209) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To investigate the appropriate dideoxycytidine (ddC) dose and zidovudine (AZT) schedule for use in combination therapy in patients with HIV infection. Methodology: Patients are randomized to one of four treatment arms. ddC is administered at either 0.375 or 0.75 mg every 8 hours. AZT is administered at 100 mg every 4 hours while awake (500 mg/day) or at 200 mg every 8 hours (600 mg/day). GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to one of four treatment arms. ddC is administered at either 0.375 or 0.75 mg every 8 hours. AZT is administered at 100 mg every 4 hours while awake (500 mg/day) or at 200 mg every 8 hours (600 mg/day). PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940209) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection. 2. CD4 count 100 - 500 cells/mm3. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS NV 14257 STUDY DESIGN Randomized; Open Label; Multicenter PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Combination drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 528 patients. (Half of patients are AZT-naive and half are AZT-experienced). PROTOCOL DETAILS STUDY DURATION: 12 months after enrollment of last patient, up to 18 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 24 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CD4 count 100 - 500 cells/mm3. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 100 - 500 cells/mm3. ( 100 - 200 - 300 - 400 - 500 ). PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. SUBSTANCE IDENTIFICATION Drug 1 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 2 DRG-0015 Dideoxycytidine TRADE NAME OF SUBSTANCE Drug 1‰ Retrovir TRADE NAME OF SUBSTANCE Drug 2‰ HIVID MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 100 mg q 4 h while awake (500 mg/day) or 200 mg q 8 h (600 mg/day). Drug 2: 0.375 or 0.75 mg q 8 h SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 500 or 600 mg. Drug 2: 1.125 or 2.25 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, capsules. Drug 2: Oral, tablets OTHER TREATMENT INFO. END POINT: Immunologic and virologic surrogate markers, survival, occurrence of opportunistic infections and neoplasms, adverse experiences, laboratory parameters. SUPPORTING AGENCY Hoffmann-La Roche, Incorporated, Burroughs Wellcome. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zalcitabine/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Zidovudine/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 7481-89-2 (Zalcitabine) LAST REVISION DATE 940209 ENTRY MONTH 9402 CALIFORNIA Kaiser Permanente HIV Specialty Clinic 1505 North Edgemont Street Los Angeles, CA 90027 Contact: Karole Velzy (213) 667-5332 OPEN 940215. CALIFORNIA Kaiser Foundation Hospital 25825 South Vermont Avenue Harbor City, CA 90710 Contact: Larry Rick (310) 530-8420 OPEN 940215. CALIFORNIA Sharp Rees - Stealy Medical Group 2001 Fourth Avenue San Diego, CA 92101 Contact: Peggy Hammerdinger (619) 234-6261 X 302OPEN 940215. CALIFORNIA University of California San Francisco / Department of Med 995 Potrero Avenue Ward 84 Building 80 San Francisco, CA 94110 Contact: Diane Davies (415) 476-4082 X 846Contact: Rowena Mah (415) 476-4082 X 840Contact: Kathy Dybeck (415) 476-4082 X 840OPEN 940215. COLORADO Denver Disease Control 605 Bannock Street Denver, CO 80204 Contact: Ron Schimmel (303) 436-7282 Contact: Patrick Gourley (303) 436-7240 OPEN 940215. DISTRICT OF COLUMBIA Howard University Clinial Trials Unit 2112 Georgia Avenue NW Washington, DC 20060 Contact: Shella Taylor (202) 808-4786 Contact: Vikoria Trimmer (202) 808-4755 OPEN 940215. DISTRICT OF COLUMBIA Veterans Administration Medical Center 50 Irving Street N W Washington, DC 20422 Contact: Dr Fred Gordon (202) 745-8695 Contact: Patricia Ackerson (202) 745-8695 OPEN 940215. FLORIDA Miami Veterans Administration Medical Center 1201 NW 16 Street Miami, FL 33125 Contact: Alyce Bishop (305) 324-3929 OPEN 940215. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue 1st Floor Eliot Building Miami, FL 33136 Contact: Janie Reese (305) 547-3840 OPEN 940215. GEORGIA Intergrated Care Center 3280 Howell Mill Road Atlanta, GA 30327 Contact: Bill Emery (404) 355-6681 OPEN 940215. ILLINOIS Rush Presbyterian St Luke's Medical Center 600 South Pauline Street Suite 143 Chicago, IL 60612 Contact: Pam Urbanski (312) 942-5865 OPEN 940215. KANSAS Univ of Kansas School of Medicine - Wichita / Clinical Rsch 1010 North Kansas Wichita, KS 67214-3199 Contact: Dal Harrison (316) 261-2855 OPEN 940215. MASSACHUSETTS New England Medical Center / Division of Infectious Diseases 750 Washington Street Box NEMCH 67 Boston, MA 02111 Contact: Christine Sullivan (617) 956-7008 OPEN 940215. MINNESOTA St Paul Ramsey Medical Center / HIV Program Office 640 Jackson Street St Paul, MN 55101 Contact: Holly Melroe (612) 221-1280 OPEN 940215. MISSOURI Washington University Clinical Trials Unit 4511 Forest Park Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0058 OPEN 940215. NEW MEXICO University of New Mexico School of Medicine HSSB 302 Albuquerque, NM 87131 Contact: Carolyn Williams (505) 277-5775 OPEN 940215. NEW YORK St Luke's - Roosevelt Hospital Center HIV / AIDS Clinical Antenucci Medical Research Building 432 West 58th Street New York, NY 10019 Contact: Jim O'Connor (212) 523-6585 Contact: Juli Rivera (212) 523-6723 OPEN 940215. NEW YORK Bronx Veteran's Affairs Medical Center 130 West Kingsbridge Road Bronx, NY 10466 Contact: Eileen Mclaughlin (718) 584-9000 X 586OPEN 940215. NEW YORK SUNY at Brooklyn / Department of Medicine 450 Clarkson Avenue - Box 77 Brooklyn, NY 11203 Contact: Don Smith (718) 270-3370 Contact: Adrian Marcel (718) 245-2800 OPEN 940215. OHIO Ohio State University Hospital Clinic 456 West 10th Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judy Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 940215 ACTU: 2301. OREGON Oregon Health Sciences University 3181 SW Sam Jackson Park Road Portland, OR 97201 Contact: Jan Weyeneth (503) 295-0850 OPEN 940215. 105 UNIQUE IDENTIFIER FDA/00597 PROTOCOL ID NUMBERS FDA 219A PROTOCOL TITLE A Phase I/II Study of the Safety and Efficacy of Topical 1-(S)-(3-Hydroxy-2-phosphonylmethoxypropyl)cy- tosine Dihydrate ( Cidofovir; HPMPC ) in the Treatment of Condyloma Acuminatum in Patients With HIV Infection. VERSION NUMBER & DATE (940204) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the safety and tolerance of topical cidofovir (HPMPC) therapy for condyloma acuminatum in patients with HIV infection. To investigate whether topical HPMPC therapy can induce regression of condyloma acuminatum in patients with HIV infection. Methodology: Four groups of 10 patients each receive topical HPMPC at 0.3 percent concentration for 5 or 10 days total or 1.0 percent concentration for 5 or 10 days total, followed by 2 weeks of rest. When six patients at a given dose and schedule have completed treatment and follow-up without significant toxicity, subsequent patients are entered at the next higher dose level. Patients are evaluated twice weekly during treatment and once weekly during the rest period. HPMPC may be extended for up to two additional courses in patients who experience no significant toxicity. GENERAL DESCRIPTION METHODOLOGY: Four groups of 10 patients each receive topical HPMPC at 0.3 percent concentration for 5 or 10 days total or 1.0 percent concentration for 5 or 10 days total, followed by 2 weeks of rest. When six patients at a given dose and schedule have completed treatment and follow-up without significant toxicity, subsequent patients are entered at the next higher dose level. Patients are evaluated twice weekly during treatment and once weekly during the rest period. HPMPC may be extended for up to two additional courses in patients who experience no significant toxicity. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940415) DISEASE STUDIED Condyloma acuminatum ( Venereal wart ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA and Western blot. 2. Mean CD4 count >= 100 cells/mm3 on two serial measurements at least 1 week apart. 3. External anogenital condyloma acuminatum confirmed by biopsy, present for less than 1 year. NOTE: Warts on anal, urethral, or vaginal mucosa will not be studied. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS GS-93-302 STUDY DESIGN Dose Escalating; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Drug dosing schedule. PROTOCOL DETAILS PROJECTED ACCRUAL: 40 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 12 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 3 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. Mean CD4 count >= 100 cells/mm3. 3. External anogenital condyloma acuminatum confirmed by biopsy, present for less than 1 year. NOTE: Warts on anal, urethral, or vaginal mucosa will not be studied. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 100 cells/mm3. ( 100 - 200 - 300 - 400 - 500 - 600 - 700 - 800 plus ). PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: < 1+ proteinuria. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. AZT, ddI, ddC, d4T, or 3TC. 2. Oral trimethoprim/sulfamethoxazole. 3. Aerosolized pentamidine. 4. Dapsone. 5. Fluconazole. 6. Rifabutin. 7. Clarithromycin. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of untreated syphilis or Bowenoid papulosis. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Substance abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 4 weeks prior to study entry: 1. Treatment for anogenital warts. 2. Immunomodulators (including interferons or systemic corticosteroids). 3. Lymphocyte replacement therapy. 4. Biologic response modifiers. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Podofilox or any podophyllum resin preparation. 2. Liquid nitrogen treatment. 3. Interferon alpha. 4. Trichloracetic acid. 5. Other treatments, topical or systemic, surgical or ablative, known to have anti-papilloma activity. 6. Other investigative drugs (except d4T or 3TC) unless approved by the sponsor. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active lesions of genital herpes, other skin wounds, or active inflammatory skin disorders in the same area as warts to be treated. 2. Active medical problems sufficient to hinder study compliance. SUBSTANCE IDENTIFICATION Drug 1 DRG-0145 HPMPC MANUFACTURERS Drug 1: Gilead Sciences Inc 353 Lakeside Drive Foster City, CA 94404 Contact: Dr John Boggs (415) 573-4745. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Groups A and C: 0.3 and 1.0 percent, respectively, applied once daily for 5 consecutive days, with possible extensfor 2 additional courses. Groups B and D: 0.3 and 1.0 percent, respectively, applied oncefor 5 consecutive days per week for 2 weeks (10 days total), wipossible extension for 2 additional courses SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 0.3 or 1.0 percent SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Topical SUPPORTING AGENCY Gilead Sciences Inc. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/ADMINISTRATION & DOSAGE/ *ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Condylomata Acuminata/COMPLICATIONS/*DRUG THERAPY MESH HEADING Cytosine/ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Opportunistic Infections/COMPLICATIONS/*DRUG THERAPY MESH HEADING Organophosphorus Compounds/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS/THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 113852-37-2 (1-(3-hydroxy-2-phosphonylmethoxypropyl)cytos- ine) LAST REVISION DATE 940415 ENTRY MONTH 9402 CALIFORNIA Conant Medical Group C/O Clinical Research 1635 Divisadero Street / Suite 606 San Francisco, CA 94115 Contact: Tanya Kocian (415) 923-1333 Contact: (415) 661-2613 Contact: (415) 923-0222 OPEN 940215. 106 UNIQUE IDENTIFIER FDA/00596 PROTOCOL ID NUMBERS FDA 218A PROTOCOL TITLE A Phase I/II Study of the Safety and Efficacy of Topical 1-(S)-(3-Hydroxy-2-phosphonylmethoxypropyl)cy- tosine Dihydrate ( Cidofovir; HPMPC ) in the Treatment of Refractory Mucocutaneous Herpes Simplex Disease in Patients With AIDS. VERSION NUMBER & DATE (940223) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the safety and tolerance of topical cidofovir (HPMPC) therapy for refractory mucocutaneous herpes simplex virus disease in AIDS patients. To determine whether topical HPMPC therapy can induce re-epithelialization and healing of refractory mucocutaneous herpes simplex virus disease in AIDS patients. To evaluate the virologic effects of topical HPMPC therapy on herpes simplex virus shedding from refractory lesions. Methodology: Patients are randomized to receive topical therapy with placebo (vehicle alone) or HPMPC at either 0.3 or 1.0 percent once daily for 5 days. Patients are assessed to day 15; those with no significant toxicity are eligible to receive open-label topical HPMPC for up to 6 months. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive topical therapy with placebo (vehicle alone) or HPMPC at either 0.3 or 1.0 percent once daily for 5 days. Patients are assessed to day 15; those with no significant toxicity are eligible to receive open-label topical HPMPC for up to 6 months. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940617) DISEASE STUDIED Herpes simplex, mucocutaneous. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA and Western blot OR a diagnosis of AIDS by CDC criteria. 2. Mucocutaneous herpes simplex virus (HSV) infection confirmed by previous viral culture and persisting without improvement despite at least 10 days of acyclovir at a minimum dose of 1 g/day (oral) or 15 mg/kg/day (intravenous). 3. Lesions that are accessible to serial measurement of surface area or serial photography. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS GS-93-301 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Multicenter; Drug Tolerance; 3-Arm PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 30 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 6 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 9 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. Mucocutaneous herpes simplex virus (HSV) infection confirmed by previous viral culture and persisting without improvement despite at least 10 days of acyclovir at a minimum dose of 1 g/day (oral) or 15 mg/kg/day (intravenous). 3. Measurable lesions. 4. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 6.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 20000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CREATININE: < 2.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Proteinase < 2+ (10 g/l). Neutrophils > 500 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: At least 10 days of prior acyclovir at a minimum dose of 1 g/day (oral) or 15 mg/kg/day (intravenous). OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antiretroviral therapy with AZT, ddI, ddC, or d4T. 2. Oral trimethoprim/sulfamethoxazole. 3. Dapsone. 4. Atovaquone. 5. Fluconazole. 6. Rifabutin. 7. Clarithromycin. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Substance abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 14 days prior to study entry: 1. Immunomodulators (such as corticosteroids or interferons). 2. Lymphocyte replacement therapy. 3. Biologic response modifiers. 4. Ganciclovir. 5. Foscarnet. 6. Vidarabine. 7. Topical trifluridine. 8. Other investigational drugs with potential anti-HSV activity. 9. Amphotericin. 10. Intravenous therapy for PCP. Excluded within 4 weeks prior to study entry: Chemotherapeutic agents. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Acyclovir. 2. Immunomodulators (such as corticosteroids or interferons). 3. Lymphocyte replacement therapy. 4. Biologic response modifiers. 5. Ganciclovir. 6. Foscarnet. 7. Vidarabine. 8. Topical trifluridine. 9. Other investigational drugs (except d4T). 10. Amphotericin. 11. Intravenous therapy for PCP. 12. Chemotherapeutic agents. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Active medical problems sufficient to hinder study compliance or assessment of treatment effect. SUBSTANCE IDENTIFICATION Drug 1 DRG-0145 HPMPC MANUFACTURERS Drug 1: Gilead Sciences Inc 353 Lakeside Drive Foster City, CA 94404 Contact: Dr John Boggs (415) 573-4745. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 0.3 or 1.0 percent (or placebo) once daily for 5 days, then possible extension for up to 6 months SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 0.3 or 1.0 percent SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Topical OTHER TREATMENT INFO. TREATMENT DURATION: Minimum of 5 days, with possible extension of up to 6 months. SUPPORTING AGENCY Gilead Sciences Inc. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Cytosine/ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Herpes Simplex/COMPLICATIONS/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Organophosphorus Compounds/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 113852-37-2 (1-(3-hydroxy-2-phosphonylmethoxypropyl)cytos- ine) LAST REVISION DATE 940617 ENTRY MONTH 9402 CALIFORNIA University of Southern California / LAC - USC Medical Center 1178 North Cummings Los Angeles, CA 90033 Contact: Andrea Martelli (213) 343-8280 OPEN 940617. CALIFORNIA San Francisco General Hospital 995 Potrero Street San Francisco, CA 94110 Contact: Rowena Mah (415) 476-9296 OPEN 940617. CALIFORNIA Mt Zion Medical Center / University California San Francisco 1600 Divisadero Street San Francisco, CA 94115 Contact: Dr Jacob Lalezari (415) 476-6356 OPEN 940617. ILLINOIS Rush Presbyterian - St Lukes Medical Ctr / Sec of Infect Dis 1725 West Harrison Ave Suite 143 Academic Facility Chicago, IL 60612 Contact: Donna Samano (312) 942-5865 OPEN 940617. MARYLAND The Johns Hopkins Hospital 600 North Wolfe Street / Wilmer 300 Baltimore, MD 21205 Contact: Linda Apuzzo (410) 614-1069 OPEN 940617. NORTH CAROLINA University of North Carolina Hospitals 547 Burnett - Womack Chapel Hill, NC 27599 Contact: Dr Sabina Lee (919) 966-6712 OPEN 940617. OTHER University of British Columbia / University Hospital 2211 Westbrook Mall Vancouver, BC V6T 1Z3 Contact: April Bishop 604/822-7565 OPEN 940617. 107 UNIQUE IDENTIFIER FDA/00595 PROTOCOL ID NUMBERS FDA 217B PROTOCOL TITLE A Phase I/II Study of the Safety, Tolerance, and Pharmacokinetics of Combination Zidovudine (AZT) and 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) Treatment in HIV-Infected Patients. VERSION NUMBER & DATE (940204) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To study the safety, tolerance, pharmacokinetics, and anti-HIV effects of combination zidovudine (AZT) and PMEA therapy. Methodology: Patients receive AZT daily and intravenous PMEA three times weekly for 4 weeks. An MTD will be defined for this regimen. GENERAL DESCRIPTION METHODOLOGY: Patients receive AZT daily and intravenous PMEA three times weekly for 4 weeks. An MTD will be defined for this regimen. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940415) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA and Western blot. 2. Mean CD4 count <= 500 cells/mm3 on two measurements at least 1 day apart. 3. Been receiving AZT at 500 mg daily for at least 4 weeks prior to study entry. NOTE: Kaposi's sarcoma is permitted provided patient has not received any systemic therapy for KS within the past 4 weeks. Patients with a history of another malignancy must be disease free for 6 months or more prior to study entry. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS GS-93-204 STUDY DESIGN Drug Combination; Drug Tolerance; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Drug efficacy, Pharmacokinetics, Combination drug therapy, Maximum tolerated dose (MTD). PROTOCOL DETAILS PROJECTED ACCRUAL: 20 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 4 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. Mean CD4 count <= 500 cells/mm3. 3. Been receiving AZT at 500 mg daily for at least 4 weeks prior to study entry. 4. Life expectancy of at least 3 months. NOTE: Kaposi's sarcoma is permitted provided patient has not received any systemic therapy for KS within the past 4 weeks. Patients with a history of another malignancy must be disease free for 6 months or more prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 500 cells/mm3. ( 0 - 100 - 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 750 cells/mm3. <= 2+ proteinuria. Prothrombin time < 14 sec. Partial thromboplastin < 35 sec. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: AZT at a stable dose for at least 4 weeks prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Prophylactic therapy with aerosolized pentamidine, oral trimethoprim/sulfamethoxazole (Bactrim, Septra) or dapsone, and fluconazole or ketoconazole IF on a stable regimen for at least 4 weeks prior to study entry. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Current use of illicit drugs (e.g., heroin or cocaine). Ingestion of substantial alcohol. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 2 weeks prior to study entry: 1. ddI or ddC. 2. Interferon alpha. 3. Ganciclovir. 4. Foscarnet. 5. Diuretics. 6. Investigational agents including d4T. 7. Chemotherapeutic agents. 8. Amphotericin B. 9. Aminoglycoside antibiotics. 10. Other nephrotoxic agents. 11. Immunomodulatory agents. Excluded within 4 weeks prior to study entry: Systemic therapy for Kaposi's sarcoma. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. ddI or ddC. 2. Interferon alpha. 3. Ganciclovir. 4. Foscarnet. 5. Diuretics. 6. Investigational agents including d4T. 7. Chemotherapeutic agents. 8. Amphotericin B. 9. Aminoglycoside antibiotics. 10. Other nephrotoxic agents. 11. Immunomodulatory agents. 12. Parenteral therapy for an active, serious infection (other than HIV infection). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Inadequate venous access. 2. Active, serious infections (other than HIV infection) requiring parenteral antibiotic therapy. 3. Clinically significant cardiac disease, including symptoms of ischemia, congestive heart failure, or clinically significant arrhythmia. 4. Active malignancy other than Kaposi's sarcoma. 5. Mental incapacity or illness that may affect compliance. SUBSTANCE IDENTIFICATION Drug 1 DRG-0156 PMEA SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir MANUFACTURERS Drug 1: Gilead Sciences Inc 353 Lakeside Drive Foster City, CA 94404 Contact: Dr Jay Toole (415) 573-4751. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Three times weekly for 4 weeks. Drug 2: 500 mg daily for 4 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 2: 500 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV). Drug 2: Oral OTHER TREATMENT INFO. TREATMENT DURATION: 4 weeks. SUPPORTING AGENCY Gilead Sciences Inc. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adenine/ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Adult MESH HEADING Antiviral Agents/ADMINISTRATION & DOSAGE/ *ADVERSE EFFECTS/PHARMACOKINETICS MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zidovudine/*ADVERSE EFFECTS/PHARMACOKINETICS CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 106941-25-7 (9-(2-phosphonylmethoxyethyl)adenine) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 940415 ENTRY MONTH 9402 MARYLAND National Cancer Institute 9000 Rockville Pike Clinical Center Bethesda, MD 20892 Contact: Sergio Bauza (301) 496-9054 OPEN / USA accrual 940204. 108 UNIQUE IDENTIFIER FDA/00594 PROTOCOL ID NUMBERS FDA 217A PROTOCOL TITLE A Phase I/II Study of the Safety, Tolerance, and Pharmacokinetics of 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) in Patients With Advanced HIV Disease. VERSION NUMBER & DATE (940204) TRIAL CATEGORY HIV Infection GENERAL DESCRIPTION PURPOSE: To study the safety, tolerance, pharmacokinetics, and anti-HIV effects of PMEA when administered daily by intravenous (IV) and/or subcutaneous (SC) injection in patients with advanced HIV disease. Methodology: Patients receive a single IV or SC dose of PMEA daily for 4 weeks. A maximum tolerated dose will be defined for these regimens. GENERAL DESCRIPTION METHODOLOGY: Patients receive a single IV or SC dose of PMEA daily for 4 weeks. A maximum tolerated dose will be defined for these regimens. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940415) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA and Western blot. 2. Elevated p24 antigen (> 40 pg/ml). 3. Mean CD4 count <= 100 cells/mm3 on two measurements at least 1 week apart. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS GS-92-202 STUDY DESIGN Drug Tolerance; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug tolerance, Drug efficacy, Pharmacokinetics, Maximum tolerated dose (MTD). PROTOCOL DETAILS PROJECTED ACCRUAL: 20 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 4 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. Elevated p24 antigen (> 40 pg/ml). 3. Mean CD4 count <= 100 cells/mm3. 4. Life expectancy of at least 3 months. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8.5 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 100 cells/mm3. ( 0 - 100). PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: <= 2+ proteinuria. Absolute neutrophils >= 750 cells/mm3. Prothrombin time < 14 sec. Partial thromboplastin time < 35 sec. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: 1. Other prior antiretroviral therapy. 2. Prophylactic therapy with aerosolized pentamidine, oral trimethoprim/sulfamethoxazole (Bactrim, Septra) or dapsone, and fluconazole or ketoconazole. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Other antiretroviral therapy IF on a stable dose for at least 4 weeks prior to study entry. 2. Prophylactic therapy with aerosolized pentamidine, oral trimethoprim/sulfamethoxazole (Bactrim, Septra) or dapsone, and fluconazole or ketoconazole IF on a stable prophylactic regimen for at least 4 weeks prior to study entry. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Substance abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 2 weeks prior to study entry: 1. Investigational agents other than stavudine (d4T). 2. Interferon-alpha. 3. Ganciclovir. 4. Foscarnet. 5. Diuretics. 6. Amphotericin B. 7. Aminoglycoside antibiotics. 8. Other nephrotoxic agents. Excluded within 4 weeks prior to study entry: Systemic therapy for Kaposi's sarcoma. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Investigational agents other than stavudine (d4T). 2. Interferon-alpha. 3. Ganciclovir. 4. Foscarnet. 5. Diuretics. 6. Amphotericin B. 7. Aminoglycoside antibiotics. 8. Other nephrotoxic agents. 9. Acyclovir at doses >= 2 g/day. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Inadequate venous access. 2. Active serious infection (other than HIV infection) requiring parenteral antibiotic therapy. 3. Clinically significant cardiac disease, including symptoms of ischemia, congestive heart failure, or arrhythmia. 4. Psychiatric disturbance or illness that may affect compliance. 5. Malignancy other than Kaposi's sarcoma. SUBSTANCE IDENTIFICATION Drug 1 DRG-0156 PMEA MANUFACTURERS Drug 1: Gilead Sciences Inc 353 Lakeside Drive Foster City, CA 94404 Contact: Dr John Boggs (415) 573-4745. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV) or Subcutaneous (SC) OTHER TREATMENT INFO. TREATMENT DURATION: 4 weeks. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Requirement for parenteral therapy for a serious illness during the study. SUPPORTING AGENCY Gilead Sciences Inc. MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adenine/ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS/PHARMACOKINETICS/ THERAPEUTIC USE MESH HEADING Adult MESH HEADING Antiviral Agents/ADMINISTRATION & DOSAGE/ *ADVERSE EFFECTS/PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 106941-25-7 (9-(2-phosphonylmethoxyethyl)adenine) LAST REVISION DATE 940415 ENTRY MONTH 9402 109 UNIQUE IDENTIFIER FDA/00684 PROTOCOL ID NUMBERS FDA 216B PROTOCOL TITLE An Open-Label Study of the Safety and Efficacy of Cidofovir ( HPMPC ) for the Treatment of Relapsing Cytomegalovirus Retinitis in Patients With AIDS. VERSION NUMBER & DATE (941011) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the safety and tolerance of cidofovir (HPMPC) infusions in AIDS patients with relapsing cytomegalovirus (CMV) retinitis. To determine the time to retinitis progression in this patient population. To evaluate the impact of cidofovir therapy on visual acuity. Methodology: Patients are randomized to receive intravenous HPMPC either at 5 mg/kg/dose for both induction and maintenance or at 5 mg/kg/dose for induction and 3 mg/kg/dose for maintenance. Induction consists of two consecutive weekly doses followed by maintenance every other week. All patients receive concomitant probenecid and saline hydration. Treatment continues until retinitis progression, as assessed by retinal photographs, or treatment-limiting toxicity occurs. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive intravenous HPMPC either at 5 mg/kg/dose for both induction and maintenance or at 5 mg/kg/dose for induction and 3 mg/kg/dose for maintenance. Induction consists of two consecutive weekly doses followed by maintenance every other week. All patients receive concomitant probenecid and saline hydration. Treatment continues until retinitis progression, as assessed by retinal photographs, or treatment-limiting toxicity occurs. OPEN/CLOSED INDICATOR Open: Actively accruing patients (941028) DISEASE STUDIED Cytomegalovirus retinitis ( CMV retinitis ). DISEASES STATUS Patients have the following symptoms and conditions: 1. AIDS by CDC criteria. 2. CMV retinitis as assessed by presence of white, fluffy, or granular retinal infiltrates with or without hemorrhage. 3. Visual acuity in an affected eye of three or more lines on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart at 1 meter distance (Snellen equivalent 8/200). 4. NO retinal detachment. 5. NO media opacity that precludes visualization of the fundus of both eyes. 6. If retinitis involves retinal zone 1, patient must have had prior disease progression while receiving at least 4 weeks of systemic ganciclovir and 4 weeks of systemic foscarnet, given as single drugs or in combination, or while receiving at least 4 weeks of one drug with intolerance of the other drug. If retinitis involves only zone 2 and/or zone 3, patient must have had prior disease progresssion while receiving at least 4 weeks of systemic ganciclovir OR foscarnet. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS GS-93-107 STUDY DESIGN Open Label; Randomized; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 100 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Until disease progression or unacceptable toxicity occurs. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS. 2. CMV retinitis, with severity as specified in the Disease Status field. 3. Life expectancy of at least 3 months. 4. Consent of parent or guardian if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.5 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 3.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 55 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Proteinuria < 1+. Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antiretroviral agents. 2. Oral trimethoprim/sulfamethoxazole. 3. Aerosolized pentamidine. 4. Dapsone. 5. Fluconazole. 6. Rifabutin. 7. Filgrastim (G-CSF). 8. Itraconazole. 9. HIV vaccines. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Drug or alcohol abuse that is considered sufficient to hinder study compliance. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 2 days prior to study entry: 1. Ganciclovir or foscarnet. Excluded within one week prior to study entry: 1. Amphotericin B. 2. Aminoglycoside antibiotics. 3. Vidarabine. 4. Intravenous pentamidine. 5. CMV hyperimmune immunoglobulin. 6. Other nephrotoxic agents. 7. Other investigational agents with anti-CMV activity. Excluded at any time: Prior systemic or intravitreal HPMPC. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Amphotericin B. 2. Aminoglycoside antibiotics. 3. Vidarabine. 4. Intravenous pentamidine. 5. CMV hyperimmune immunoglobulin. 6. Other nephrotoxic or potentially nephrotoxic agents. 7. Other investigational agents with anti-CMV activity. 8. Ganciclovir. 9. Intravenous or oral acyclovir (except following development of herpetic lesion). 10. Foscarnet. 11. Diuretics. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known clinically significant allergy to probenecid. 2. Clinically significant cardiac disease, including symptoms of ischemia, congestive heart failure, or arrhythmia. 3. Other active medical problems sufficient to hinder study compliance. SUBSTANCE IDENTIFICATION Drug 1 DRG-0145 HPMPC SUBSTANCE IDENTIFICATION Drug 2 DRG-0053 Probenecid TRADE NAME OF SUBSTANCE Drug 1‰ Cidofovir MANUFACTURERS Drug 1: Gilead Sciences Incorporated 353 Lakeside Drive Foster City, CA 94404 Contact: Dr Robert Stagg (415) 572-6566. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 5 mg/kg weekly for 2 weeks (induction) followed by eith5 or 3 mg/kg q other week (maintenance) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV). Drug 2: Oral OTHER TREATMENT INFO. TREATMENT DURATION: Until disease progression or unacceptable toxicity occurs. OTHER TREATMENT INFO. END POINT: Safety, time to retinitis progression or death, changes in visual acuity. SUPPORTING AGENCY Gilead Sciences Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Antiviral Agents/ADMINISTRATION & DOSAGE/ *ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Cytomegalovirus Infections/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Cytosine/ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Organophosphorus Compounds/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Probenecid/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Retinitis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 113852-37-2 (1-(3-hydroxy-2-phosphonylmethoxypropyl)cytos- ine) CAS REGISTRY NUMBER 57-66-9 (Probenecid) LAST REVISION DATE 941028 ENTRY MONTH 9411 NEW JERSEY Besselaar Associates 103 College Road East Princeton, NJ 08540-6681 Contact: Alan Boylan (609) 452-8550 OPEN / USA accrual 941028. 110 UNIQUE IDENTIFIER FDA/00593 PROTOCOL ID NUMBERS FDA 216A PROTOCOL TITLE A Phase II/III Study of the Safety and Efficacy of 1-(S)-(3-Hydroxy-2-phosphonylmethoxypropyl)cy- tosine Dihydrate ( Cidofovir; HPMPC ) for the Treatment of Peripheral Cytomegalovirus Retinitis in Patients With AIDS. VERSION NUMBER & DATE (940503) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To determine whether cidofovir (HPMPC) therapy administered by intravenous infusion can extend the time to progression of peripheral cytomegalovirus (CMV) retinitis in AIDS patients. To evaluate the safety and tolerance of HPMPC therapy when administered by intravenous infusion in AIDS patients with CMV retinitis that is not immediately sight-threatening. To evaluate the virologic effects of intravenous HPMPC therapy on CMV shedding in urine, blood, and/or semen. To evaluate the impact of HPMPC therapy on visual acuity. Methodology: Patients are randomized to one of two treatment arms. Group A receives HPMPC by IV infusion weekly for 2 consecutive weeks (induction) and then every other week (maintenance) with oral probenecid and IV hydration. Group B receives no treatment until the time of retinitis progression (deferred treatment), at which time they receive the same regimen as Group A, provided retinitis progression is not immediately sight-threatening. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to one of two treatment arms. Group A receives HPMPC by IV infusion weekly for 2 consecutive weeks (induction) and then every other week (maintenance) with oral probenecid and IV hydration. Group B receives no treatment until the time of retinitis progression (deferred treatment), at which time they receive the same regimen as Group A, provided retinitis progression is not immediately sight-threatening. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940415) DISEASE STUDIED Cytomegalovirus retinitis ( CMV retinitis ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Diagnosis of AIDS by CDC criteria. 2. Diagnosis of peripheral (not immediately sight-threatening) CMV retinitis. Lesions must be at least 1500 micrometers from the margin of the optic disc and 3000 micrometers from the center of the fovea. One lesion must be at least one-quarter disc area such that it can be photographed. 3. Visual acuity in the affected eye of >= three lines on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart at 1 m distance. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS GS-93-106 STUDY DESIGN Randomized; Controlled; Multicenter PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 48 patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 8 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Diagnosis of AIDS by CDC criteria. 2. Diagnosis of peripheral (not immediately sight-threatening) CMV retinitis. 3. Visual acuity in the affected eye of >= three lines on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart at 1 m distance. 4. Life expectancy of at least 3 months. 5. Consent of parent or guardian in patients less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.5 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 3.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 55 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: < 1+ proteinuria. Absolute neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 13 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: 1. Acyclovir. 2. Prior ganciclovir, foscarnet, or CMV hyperimmune immunoglobulin if given solely as prophylaxis. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antiretroviral agents. 2. Oral trimethoprim/sulfamethoxazole. 3. Aerosolized pentamidine. 4. Dapsone. 5. Fluconazole. 6. Rifabutin. 7. Filgrastim (G-CSF). 8. p24 vaccine. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Not breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Drug or alcohol abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Prior ganciclovir, foscarnet, or CMV hyperimmune immunoglobulin as therapy for CMV disease (although permitted if previously received solely as prophylaxis). Excluded within 1 week prior to study entry: 1. Amphotericin B. 2. Vidarabine. 3. Other nephrotoxic agents. 4. Aminoglycoside antibiotics. 5. Intravenous pentamidine. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Acyclovir (may be reinstituted following development of herpetic lesions). 2. Ganciclovir. 3. Foscarnet. 4. Amphotericin B. 5. Diuretics. 6. Aminoglycoside antibiotics. 7. CMV hyperimmune immunoglobulin. 8. Intravenous pentamidine. 9. Other nephrotoxic agents. 10. Other investigational drugs with potential nephrotoxicity. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Media opacity that precludes visualization of the fundus of both eyes. 2. Retinal detachment. 3. Clinically significant cardiac disease, including symptoms of ischemia, congestive heart failure, or arrhythmia. 4. Active medical problems considered sufficient to hinder study compliance. 5. Known clinically significant allergy to probenecid. SUBSTANCE IDENTIFICATION Drug 1 DRG-0145 HPMPC SUBSTANCE IDENTIFICATION Drug 2 DRG-0053 Probenecid MANUFACTURERS Drug 1: Gilead Sciences Incorporated 353 Lakeside Drive Foster City, CA 94404 Contact: Dr Robert Stagg (415) 572-6566. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 5 mg/kg weekly for 2 consecutive weeks, followed by 5 mg/kg q other week SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV). Drug 2: Oral SUPPORTING AGENCY Gilead Sciences Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Antiviral Agents/ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Cytomegalovirus Infections/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Cytosine/ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Organophosphorus Compounds/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Probenecid/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Retinitis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 113852-37-2 (1-(3-hydroxy-2-phosphonylmethoxypropyl)cytos- ine) CAS REGISTRY NUMBER 57-66-9 (Probenecid) LAST REVISION DATE 940415 ENTRY MONTH 9402 CALIFORNIA University of Southern California / LAC - USC Medical Center 1175 North Cummings Street Los Angeles, CA 90033 Contact: Dr Francoise Kramer (213) 343-8316 OPEN 940215. CALIFORNIA University of California / Irvine Medical Center 101 The City Drive Orange, CA 92668 Contact: Dr Baruch Kuppermann (714) 856-6256 OPEN 940215. CALIFORNIA Mt Zion Medical Center 1600 Divisadero Street San Francisco, CA 94115 Contact: Eileen Glutzer (415) 476-6356 OPEN 940215. MASSACHUSETTS Beth Israel Hospital 330 Brookline Avenue Boston, MA 02215 Contact: Dr David Ives (617) 735-3661 OPEN 940215. NORTH CAROLINA University of North Carolina Hospitals 547 Burnett - Womack Chapel Hill, NC 27599 Contact: Dr Joseph Eron (919) 966-2537 OPEN 940215. NEW YORK University of Rochester Medical Center 30 North Union Street Rochester, NY 14607 Contact: Kathy Champagne (716) 232-2560 OPEN 940215. OTHER Chelsea & Westminster Hospital / St Stephen's Clinic 369 Fulham Road London, UK SW10 9NH Contact: Dr Michael Youle 011-44-81-746-5594 OPEN 940215. 111 UNIQUE IDENTIFIER FDA/00611 PROTOCOL ID NUMBERS FDA 214A PROTOCOL TITLE A Randomized Open-Label Study of the Tolerability and Efficacy of Clarithromycin and Ethambutol in Combination With or Without Clofazimine for the Treatment of Disseminated MAC (dMAC) in Patients With AIDS. VERSION NUMBER & DATE (940414) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: PRIMARY: To assess the tolerability of the combination regimen of clarithromycin plus ethambutol with or without clofazimine in patients with disseminated Mycobacterium avium Complex (dMAC). SECONDARY: To determine the proportion of patients achieving a sterile blood culture along with the time required to achieve it. To determine the duration of bacteriological response, defined as length of time that blood cultures remain sterile. OPEN/CLOSED INDICATOR Open: Actively accruing patients (931222) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. History of HIV seropositivity. 2. Clinical signs and symptoms consistent with disseminated MAC (e.g., diarrhea, periodic fevers, night sweats, weight loss, hepatomegaly, and/or splenomegaly). 3. Positive blood culture for MAC within 4 weeks prior to study entry. NOTE: Patients with active opportunistic infections other than dMAC are permitted if dosage and clinical parameters have been stable for 4 weeks prior to enrollment. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS M93-069 STUDY DESIGN Randomized; Open Label; Drug Tolerance; Drug Combination; Multicenter PROTOCOL DETAILS STUDY INTENT: Drug tolerance, Drug efficacy, Combination drug therapy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 18 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. History of HIV seropositivity. 2. Disseminated MAC. 3. Positive blood culture for MAC within 4 weeks prior to study entry. 4. Consent of parent or guardian if less than 18 years of age. 5. Ability to complete the study. NOTE: Patients with active opportunistic infections other than dMAC are permitted if dosage and clinical parameters have been stable for 4 weeks prior to enrollment. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 2.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 10 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): < 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.0 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: <= 40. PATIENT INCLUSION CRIT. OTHER: Total neutrophils >= 600 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of allergy or hypersensitivity to macrolides, ethambutol, or clofazimine. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Other antimycobacterials, including aminoglycosides, ansamycin (rifabutin), other macrolides (such as clindamycin), quinolones, and rifampin, between screening and study entry. 2. Clarithromycin or azithromycin as prophylaxis or treatment (for any cause) for more than 14 days cumulative within the past 2 months. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Active therapy with carbamazepine or theophylline, unless investigator agrees to carefully monitor blood levels. 2. Active therapy with investigational drugs other than treatment for HIV disease, except with approval of the sponsor. 3. Concomitant terfenadine (Seldane or Seldane-D) or astemizole (Hismanal). 4. Amikacin. 5. Azithromycin. 6. Capreomycin. 7. Ciprofloxacin. 8. Cycloserine. 9. Ethionamide. 10. Gentamicin. 11. Kanamycin. 12. Levofloxacin. 13. Lomefloxacin. 14. Ofloxacin. 15. Rifampin. 16. Rifabutin. 17. Sparfloxacin. 18. Streptomycin. 19. Any other aminoglycosides, quinolones, and macrolides. SUBSTANCE IDENTIFICATION Drug 1 DRG-0099 Clarithromycin SUBSTANCE IDENTIFICATION Drug 2 DRG-0111 Ethambutol SUBSTANCE IDENTIFICATION Drug 3 DRG-0067 Clofazimine TRADE NAME OF SUBSTANCE Drug 1‰ Biaxin MANUFACTURERS Drug 1: Abbott Laboratories One Abbott Park Road / Department 422 Abbott Park, IL 60064-3500 Contact: Medical Services (708) 938-0601. MANUFACTURERS Drug 2: Lederle Laboratories Professional Services Department Pearl River, NY 10965 Contact: Professional Services (914) 735-2815. MANUFACTURERS Drug 3: Ciba Pharmaceutical Company 556 Morris Avenue Summit, NJ 07901 Contact: Medical Services Department (908) 277-5000. SUPPORTING AGENCY Abbott Laboratories. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Clarithromycin/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Clofazimine/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Ethambutol/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 2030-63-9 (Clofazimine) CAS REGISTRY NUMBER 74-55-5 (Ethambutol) CAS REGISTRY NUMBER 81103-11-9 (Clarithromycin) LAST REVISION DATE 931222 ENTRY MONTH 9403 CALIFORNIA Kaiser Permanente Medical Center 1505 North Edgemont Street Los Angeles, CA 90027 Contact: Dr Joel Ruskin (213) 667-3715 OPEN 931222. CALIFORNIA Kaiser Permanente Medical Center / HIV Research Unit 2590 Geary Blvd San Francisco, CA 94115 Contact: Gretchen Van Raalte (415) 202-3482 Contact: Barbara LeMaire (415) 202-3480 Contact: Dr Jeffrey Fessel (415) 202-3486 OPEN 931222. CALIFORNIA Santa Clara Valley Medical Center / AIDS Program 751 South Bascom Avenue San Jose, CA 95128-2699 Contact: Carol Kane (408) 885-4316 Contact: Dr Carol Kemper (assoc dir) (408) 885-4300 OPEN 931222. CALIFORNIA University of California Davis / Medical Center 2221 Stockton Boulevard PCC Room 3107 Sacramento, CA 95817 Contact: Sheila Enders (916) 734-7004 OPEN 931222. DISTRICT OF COLUMBIA George Washington University / Hemophilia Treatment Center 2150 Pennsylvania Avenue N W Washington, DC 20037 Contact: Charlotte Quinlan (202) 994-3076 OPEN 931222. FLORIDA Dr Margaret Fischel Elliott Building / 1st Floor / 1800 Northwest 10th Avenue Miami, FL 33136 Contact: Dr Margaret Fischel (305) 547-3848 OPEN 931222. FLORIDA Dr Bienvenido Yangco Suite 14 Tampa, FL 33614 Contact: Vicky Kenyon (813) 870-4760 OPEN 931222. ILLINOIS Rush Presbyterian St Luke's Medical Center 600 South Pauline Street Suite 143 Chicago, IL 60612 Contact: Pam Urbanski (312) 942-5865 OPEN 931222. LOUISIANA Tulane University Medical School / AIDS Clinical Trials Unit 1430 Tulane Avenue New Orleans, LA 70112-2699 Contact: Russell Strada (504) 584-3605 OPEN 931222. MARYLAND Johns Hopkins University / School of Medicine 1830 East Monument Street / Suite 7400 Baltimore, MD 21205 Contact: Sara Lynn Elkin (410) 955-1754 OPEN 931222. NORTH CAROLINA University of North Carolina at Chapel Hill / UNC CTU 516 Burnett Womack / CB# 7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-7883 OPEN 931222. NEW YORK Beth Israel Medical Center First Avenue at 16th Street / Div Inf Dis / DAZIAN New York, NY 10003 Contact: Ann Marshak (212) 420-4432 OPEN 931222. NEW YORK Mount Sinai Hospital / Clinical Trials Unit One Gustave L Levy Place / Box 1042 New York, NY 10029-6574 Contact: Dr Eileen Chusid (212) 241-8254 OPEN 931222. OTHER Dr Javier Morales 1451 Ashford Avenue / 2nd Floor / Suite H Condado San Juan, PR 00907 Contact: Carmen DeJesus (809) 722-0455 OPEN 931222. PENNSYLVANIA Dr Stephen Hauptman 1015 Chestnut Street / Suite 610 Philadelphia, PA 19107 Contact: Lyle Jew (215) 955-7785 OPEN 931222. 112 UNIQUE IDENTIFIER FDA/00588 PROTOCOL ID NUMBERS FDA 213A PROTOCOL TITLE A Pilot Study of Fluconazole Plus Flucytosine for the Treatment of AIDS Patients With Acute Cryptococcal Meningitis. VERSION NUMBER & DATE (940104) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate and estimate the safety and efficacy of the combination of fluconazole and flucytosine as treatment for acute cryptococcal meningitis in patients with AIDS. GENERAL DESCRIPTION RATIONALE: Fluconazole and flucytosine have different mechanisms of action. Since fluconazole has not been associated with hematologic suppression and does not produce renal impairment that can result in higher serum flucytosine levels, this combination may be better tolerated than is amphotericin B plus flucytosine. GENERAL DESCRIPTION METHODOLOGY: Patients in each cohort receive a lower dose of fluconazole alone or in combination with flucytosine, or a higher dose of fluconazole alone. Doses in subsequent cohorts are escalated if safety data in the previous cohort is satisfactory. Patients are evaluated weekly for the first 4 weeks and every 2 weeks thereafter. Therapy continues until 8 weeks after the CSF becomes culture negative, up to a maximum of 26 weeks. PROTOCOL PHASE Pilot Study OPEN/CLOSED INDICATOR Open: Actively accruing patients (940413) DISEASE STUDIED Cryptococcal meningitis. DISEASES STATUS Patients have the following symptoms and conditions: 1. AIDS by CDC criteria. 2. One of the following: o Identification of Cryptococcal neoformans in culture or lumbar CSF. o Clinical and CSF findings compatible with crytococcal meningitis plus a) positive CSF India ink exam; OR b) culture or biopsy evidence of extraneural cryptococcal infection; OR c) positive serum or CSF cryptococcal antigen test; OR d) biopsy evidence of CNS cryptococcal infection. 3. No evidence of acute or chronic meningitis of any etiology other than cryptococcosis. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS R-0202 STUDY DESIGN Drug Tolerance; Randomized PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Combination and single drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 64 patients. (24 patients in cohorts one and two and 16 patients in cohort three) PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 3 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS. 2. Evidence of Cryptococcal neoformans in culture or lumbar CSF OR clinical and CSF findings compatible with crytococcal meningitis. 3. No evidence of acute or chronic meningitis of any etiology other than cryptococcosis. 4. Life expectancy of at least 2 weeks. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1250 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 3 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 40 ml/min. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 3 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR TREATMENT: Allowed: Prior radiation therapy for mucocutaneous Kaposi's sarcoma. OTHER PATIENT INCL. CH. CONCURRENT TREATMENT: Allowed: Radiation therapy for mucocutaneous Kaposi's sarcoma. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: 1. Prior antiviral therapy (AZT, DHPG). 2. Prophylaxis for Pneumocystis carinii pneumonia. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Antiviral therapy (AZT, DHPG). 2. Prophylaxis for Pneumocystis carinii pneumonia. 3. Treatment for intercurrent opportunistic infection. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of allergy to or intolerance of imidazoles, azoles, or flucytosine. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. More than 1 mg/kg amphotericin B. 2. Systemic antifungal agents within 7 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Concomitant use of any antifungal agent other than study drug. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Relapsing on maintenance triazole therapy for cryptococcal meningitis. 2. Unable to take oral medication. SUBSTANCE IDENTIFICATION Drug 1 DRG-0005 Fluconazole SUBSTANCE IDENTIFICATION Drug 2 DRG-0049 Flucytosine TRADE NAME OF SUBSTANCE Drug 1‰ Diflucan MANUFACTURERS Drug 1: Pfizer Incorporated / Roerig Division 235 East 42nd Street New York, NY 10017-7851 Contact: Professional Information (212) 573-2187. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: First cohort: 800 or 1200 mg daily until 8 weeks after the CSF becomes culture negative, up to a maximum of 26 weeks. Second cohort; 1200 or 1600 mg daily until 8 weeks after the CSbecomes culture negative, up to a maximum of 26 weeks. Third cohort: 1600 mg daily until 8 weeks after the CSF becomesculture negative, up to a maximum of 26 weeks. Drug 2: 150 mg/kg daily for 4 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 800 - 1600 mg. Drug 2: 150 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous OTHER TREATMENT INFO. TREATMENT DURATION: Maximum of 26 weeks. SUPPORTING AGENCY Pfizer Incorporated / Roerig Division. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Cryptococcosis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Fluconazole/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Flucytosine/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Meningitis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Middle Age CAS REGISTRY NUMBER 2022-85-7 (Flucytosine) CAS REGISTRY NUMBER 86386-73-4 (Fluconazole) LAST REVISION DATE 940413 ENTRY MONTH 9401 CALIFORNIA Los Angeles County USC Medical Center / Dr. Robert Larson 1129 North State Street Los Angeles, CA 90033 Contact: DeAnn Diamond (213) 226-3580 OPEN 940107. CALIFORNIA University of California / UCSD Treatment Center 2760 Fifth Avenue / Suite 300 San Diego, CA 92103-6325 Contact: Chris Fegan (619) 543-8080 Contact: Ben Freeman (619) 543-8080 OPEN 940107. CALIFORNIA UCI Medical Center / Division of Infectious Diseases 101 City Drive South / Building 53 Route 81 Orange, CA 92668 Contact: Marlene Fugate (714) 456-7612 Contact: Sheila Fitzgibbons (714) 456-7747 OPEN 940107. 113 UNIQUE IDENTIFIER FDA/00585 PROTOCOL ID NUMBERS FDA 212A PROTOCOL TITLE A Dose-Escalating Study of Ro 31-8959 (HIV Protease Inhibitor) in Patients With HIV Disease. VERSION NUMBER & DATE (940104) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To investigate the toxicity, antiviral activity, and pharmacokinetics in HIV-infected patients receiving 16 weeks of oral Ro 31-8959 at one of two doses. Methodology: Cohorts of 16 patients receive either 600 or 1200 mg Ro 31-8959 six times per day for 20 weeks. Administration of the higher dose will proceed only after 2-week safety data for the first eight patients on the lower dose has been reviewed. GENERAL DESCRIPTION METHODOLOGY: Cohorts of 16 patients receive either 600 or 1200 mg Ro 31-8959 six times per day for 20 weeks. Administration of the higher dose will proceed only after 2-week safety data for the first eight patients on the lower dose has been reviewed. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940101) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by ELISA confirmed by Western blot. 2. CD4 count 200 - 500 cells/mm3. 3. No evidence of viral mutation at codon 48, 74, 90, or 215. 4. HIV RNA quantifiable by PCR. NOTE: Fifty percent of patients must have measurable p24 antigen levels (> 31 pg/ml). ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS EV 14757 STUDY DESIGN Open Label; Drug Tolerance; Dose Comparison PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Pharmacokinetics. PROTOCOL DETAILS PROJECTED ACCRUAL: 32 patients. (16 patients per treatment arm) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 20 weeks. PROTOCOL DETAILS STUDY DURATION: 1 year. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. CD4 count 200 - 500 cells/mm3. 3. No evidence of viral resistance. 4. HIV RNA quantifiable by PCR. 5. Negativity for HBsAg, HBeAg, and anti-HBc. NOTE: Fifty percent of patients must have measurable p24 antigen levels (> 31 pg/ml). [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.0 g/dl. (Must not be transfusion dependent). PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1000 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 500 cells/mm3. ( 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: < 1.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 1.25 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): < 1.25 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils 750 cells/mm3. Total serum amylase < 2 x ULN (unless fractionation reveals that elevated fraction is salivary amylase OR patient has macroamylasemia OR has a normal lipase value). PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR TREATMENT: Allowed: Transfusion, provided patient has not received more than three units of blood within a 21-day period. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Unexplained temperature >= 38.5 C (101.5 F) persisting for 14 days or more within a 30-day period. 2. Unexplained, chronic diarrhea persisting for 14 days or more within a 30-day period. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy other than local skin radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior treatment with an HIV proteinase inhibitor. 2. AZT within 30 days prior to study entry OR lasting more than 1 year. 3. Other antiretroviral therapy (besides AZT) within 30 days prior to study entry OR lasting more than 14 days. 4. Acute therapy for an opportunistic infection within 14 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antineoplastic agents. 2. Concomitant or maintenance treatment with excluded experimental drugs and drugs with known nephrotoxic or hepatotoxic potential. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Active opportunistic infection requiring immediate treatment, such as tuberculosis, cytomegalovirus, cerebral toxoplasmosis, and Pneumocystis carinii pneumonia. 2. Unable to maintain adequate oral intake. 3. Clinically significant vomiting and/or diarrhea. 4. Malignancy, visceral Kaposi's sarcoma, or lymphoma that will require systemic chemotherapy within the next 12 months. 5. Unable to comply with protocol requirements, in the judgment of the investigator. 6. Any grade 3 or worse laboratory or clinical abnormality. SUBSTANCE IDENTIFICATION Drug 1 DRG-0164 Ro 31-8959 MANUFACTURERS Drug 1: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 600 or 1200 mg six times per day for 20 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 3600 or 7200 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral OTHER TREATMENT INFO. TREATMENT DURATION: 20 weeks. SUPPORTING AGENCY Stanford University Medical Center. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Isoquinolines/*ADVERSE EFFECTS/ PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age MESH HEADING Quinolines/*ADVERSE EFFECTS/PHARMACOKINETICS/ THERAPEUTIC USE CAS REGISTRY NUMBER 127779-20-8 (Ro 31-8959) LAST REVISION DATE 940101 ENTRY MONTH 9401 CALIFORNIA Stanford University Medical Center SUMC S-156 Stanford, CA 94305 Contact: Jane Norris (415) 723-2805 Contact: (415) 723-6231 OPEN 940101. 114 UNIQUE IDENTIFIER FDA/00583 PROTOCOL ID NUMBERS FDA 211A PROTOCOL TITLE A Phase II/III Study of Cysteamine (Mercaptoethylamine) and Zidovudine for the Treatment of HIV Disease. VERSION NUMBER & DATE (931215) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To determine the safety and tolerance of low-dose versus high-dose cysteamine administered concurrently with zidovudine (AZT). To determine the pharmacokinetics and effects on immune function and viral load in patients receiving these drug regimens. Methodology: Patients receive high or low doses of cysteamine plus AZT or placebo plus AZT. The target dose of cysteamine is determined by titration of the dose over a 6-week period, after which the patient receives 24 additional weeks of treatment. An initial cohort of 36 patients will be enrolled in a 10-week pilot phase. Accrual will be temporarily suspended while data from the pilot phase is assessed. GENERAL DESCRIPTION METHODOLOGY: Patients receive high or low doses of cysteamine plus AZT or placebo plus AZT. The target dose of cysteamine is determined by titration of the dose over a 6-week period, after which the patient receives 24 additional weeks of treatment. An initial cohort of 36 patients will be enrolled in a 10-week pilot phase. Accrual will be temporarily suspended while data from the pilot phase is assessed. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940503) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by ELISA confirmed by Western blot. 2. CD4 count 300 - 500 cells/mm3. 3. Prior AZT therapy for at least 3 months but less than 12 months prior to study entry. 4. No past or current AIDS-defining opportunistic infection by CDC definition. ELIGIBILITY ASYM. ARC. OTHER PROTOCOL NUMBERS CYST-9304 STUDY DESIGN Randomized; Double-Blind; 3-Arm; Dose Comparison; Drug Tolerance; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Pharmacokinetics, Combination and single drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 300 patients. (100 patients in each of three treatment arms) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: At least 31 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 6 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. CD4 count 300 - 500 cells/mm3. 3. Prior AZT therapy for at least 3 months but less than 12 months prior to study entry. 4. No past or current AIDS-defining opportunistic infection. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9.5 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 300 - 500 cells/mm3. ( 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: < 2.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 70. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 1000 cells/mm3. Alkaline phosphatase < 3 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: AZT for at least 3 months but no more than 12 months prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Chemoprophylaxis for Pneumocystis carinii pneumonia, candidiasis, Mycobacterium tuberculosis, and herpes as prescribed by the investigator. 2. Recombinant erythropoietin and G-CSF if clinically indicated. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of treatment-limiting intolerance to 500-600 mg AZT daily as manifested by the same recurrent grade 3 toxicity or any prior grade 4 toxicity. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiation therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Prior antiretroviral therapy other than AZT. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antiretroviral therapy other than AZT. 2. Immunosuppressive drugs. 3. Investigational HIV drugs/therapies other than study drug. 4. Interferon. 5. Steroids. 6. Hematopoietins. 7. Cytotoxic chemotherapy including Adriamycin, bleomycin, and vincristine. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Kaposi's sarcoma requiring systemic therapy. 2. Active malignancy other than basal cell carcinoma or in situ cervical carcinoma. SUBSTANCE IDENTIFICATION Drug 1 DRG-0003 Cysteamine SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir MANUFACTURERS Drug 1: Mylan Laboratories Inc 1030 Century Building Pittsburgh, PA 15222 Contact: Kristine Hartman (800) 858-8490 Contact: (412) 232-0100. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 2: 200 mg thrice daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 2: 600 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, capsules. Drug 2: Oral SUPPORTING AGENCY Mylan Laboratories Inc. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Cysteamine/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Zidovudine/ADVERSE EFFECTS/PHARMACOKINETICS/ *THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 60-23-1 (Cysteamine) LAST REVISION DATE 940503 ENTRY MONTH 9312 FLORIDA Saint Josephs Hospital / Infectious Disease Research Unit 4600 N Habana Suite 14 Tampa, FL 33614 Contact: Vicki Kenyon (813) 870-4760 Contact: (Tampa Gen Hospital) (813) 870-4759 OPEN 931215. LOUISIANA Tulane University Medical School / AIDS Clinical Trials Unit 1430 Tulane Avenue New Orleans, LA 70112-2699 Contact: Russell Strada (504) 584-3605 OPEN 931215. NORTH CAROLINA Bowman Gray School of Medicine / North Carolina Baptist Hosp Medical Center Boulevard Winston-Salem, NC 27157-1042 Contact: Mary Green (910) 716-4584 OPEN 931215. NEW YORK SUNY at Stony Brook Health Sciences Center / Div Infect Dis HSC T 15 Room 080 Stony Brook, NY 11794-8153 Contact: Ruth Ann Burk (516) 444-1658 OPEN 931215. RHODE ISLAND Independent Research Nurses Inc 769 Park Avenue Cranston, RI 02910 Contact: Dr Dennis Mikolich (401) 467-7760 OPEN 940503. 115 UNIQUE IDENTIFIER FDA/00574 PROTOCOL ID NUMBERS FDA 210A PROTOCOL TITLE Randomized, Double-Blind, Placebo-Controlled Comparative Dose-Response Study of Two Doses of Atevirdine Mesylate (U-87201E) in Combination With Fixed Doses of Zidovudine (AZT) in HIV+ Patients. VERSION NUMBER & DATE (931119) TRIAL CATEGORY HIV Infection GENERAL DESCRIPTION PURPOSE: PRIMARY: To determine the tolerance and antiviral response of two different doses of atevirdine mesylate (U-87201E) in symptomatic HIV-positive patients with CD4 counts of 50-350 cells/mm3, who also take zidovudine (AZT) at 500-600 mg total daily dose. SECONDARY: To determine time to a 10-fold increase in IC50 in patients on U-87201E, time to a 1-log decrease in viremia, and effect on the pharmacokinetics of U-87201E; to determine time to new/recurrent AIDS-defining illness and survival at 1 year. Methodology: Patients are randomized to one of three treatment groups: U-87201E at 200 or 600 mg or placebo administered every 8 hours. Patients must have taken AZT for at least 3 months prior to randomization. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to one of three treatment groups: U-87201E at 200 or 600 mg or placebo administered every 8 hours. Patients must have taken AZT for at least 3 months prior to randomization. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (930831) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV positive by ELISA confirmed by Western blot, RIA, HIV culture, or another method. 2. Symptomatic (currently or prior to enrollment) for Category B or C of CDC classification, although THE FOLLOWING CURRENT ACUTE MEDICAL CONDITIONS ARE NOT ALLOWED: - Cryptococcosis - Pneumocystis carinii pneumonia - Herpes zoster - Histoplasmosis - CMV - Hepatic or renal disease - Lymphoma. 3. CD4 count 50 - 350 cells/mm3 within 14 days prior to study entry. 4. Ongoing therapy with AZT at 500 - 600 mg total daily dose for at least 3 months prior to study entry. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS M/3330/0018 STUDY DESIGN Randomized; Multicenter; Parallel-Group; Double-Blind; Placebo-Controlled; 3-Arm; Dose Comparison; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug tolerance, Drug efficacy, Combination drug therapy, Pharmacokinetics. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 54 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 12 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Symptoms (currently or prior to enrollment) included in Category B or C of CDC classification, although THE FOLLOWING CURRENT ACUTE MEDICAL CONDITIONS ARE NOT ALLOWED: - Cryptococcosis - Pneumocystis carinii pneumonia - Herpes zoster - Histoplasmosis - CMV - Hepatic or renal disease - Lymphoma. 3. CD4 count 50 - 350 cells/mm3 within 14 days prior to study entry. 4. Ongoing therapy with AZT at 500 - 600 mg total daily dose for at least 3 months prior to study entry. 5. Consent of parent, guardian, or person with power of attorney if less than 18 years of age. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.5 g/dl. (men); >= 9.0 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 50 - 350 cells/mm3. ( 100 - 200 - 300 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 2.5 x ULN. If etiology is unknown. OR <= 5 x ULN if etiology is known. (ULN = upp PATIENT INCLUSION CRIT. SGPT(ALT): <= 2.5 x ULN. If etiology is unknown. OR <= 5 x ULN if etiology is known. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 50 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. Alkaline phosphatase <= 2.5 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: AZT for at least 3 months prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Primary or secondary prophylaxis for opportunistic infections. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Present use of excessive alcohol or illicit drugs. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Cytotoxic chemotherapy within 1 month prior to study entry. 2. Prior U-87201E or any other nonnucleoside antiretroviral medications, including but not limited to nevirapine, TIBO R-82150 or TIBO R-82913, L-697639 or L-696229, U-90152S, or any protease inhibitors. 3. Antiretroviral agents other than AZT within 3 months prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Any other investigational drugs. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following conditions are excluded: 1. Intolerance to AZT. 2. Current diagnosis of malignancy for which systemic therapy will be required during the study. SUBSTANCE IDENTIFICATION Drug 1 DRG-0144 U-87201E SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine MANUFACTURERS Drug 1: The Upjohn Company 7000 Portage Road Kalamazoo, MI 49001 Contact: James VanSweden (616) 323-4696. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 or 600 mg (or placebo) q 8 h for up to 54 weeks. Drug 2: 500 - 600 mg daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 600 or 1800 mg. Drug 2: 500 - 600 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, compressed tablets. Drug 2: Oral OTHER TREATMENT INFO. TREATMENT DURATION: Up to 54 weeks. SUPPORTING AGENCY The Upjohn Company. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antiviral Agents) LAST REVISION DATE 930831 ENTRY MONTH 9312 CALIFORNIA University of Southern California / LAC - USC Medical Cntr 1175 North Cummings Street / 5021 Clinic Los Angeles, CA 90033-1079 Contact: Novella Quesada (213) 343-8277 OPEN 930831. CALIFORNIA UCI Medical Center / Division of Infectious Diseases 101 City Drive South / Building 53 Route 81 Orange, CA 92668 Contact: Marlene Fugate (714) 456-7612 Contact: Sheila Fitzgibbons (714) 456-7747 OPEN 930831. CALIFORNIA Davies Medical Center / Institute for HIV Treatment and Rsch Castro and Duboce Streets San Francisco, CA 94114 Contact: Sue Kelly (415) 565-6153 OPEN 930831. FLORIDA Saint Josephs Hospital / Infectious Disease Research Unit 4600 N Habana Suite 14 Tampa, FL 33614 Contact: Vicki Kenyon (813) 870-4760 Contact: (Tampa Gen Hospital) (813) 870-4759 OPEN 930831. MASSACHUSETTS Boston City Hospital / FGH-1 818 Harrison Avenue / Thorndike Room 209 Boston, MA 02118 Contact: Nancy Reinhalter (617) 534-5404 OPEN 930831. MARYLAND Johns Hopkins University Hospital Richard Starr Ross Rsch Bldg / 720 Rutland Avenue Room 1159 Baltimore, MD 21205-2196 Contact: Becky Becker (410) 955-4370 OPEN 930831. NEW JERSEY Veterans Administration Medical Center / Infectious Disease 285 Tremont Ave East Orange, NJ 07018 Contact: Mayra LaTorre (201) 676-1000 X 214OPEN 930831. PENNSYLVANIA Buckley Braffman Stern Medical Associates PC 822 Pine Street / Suite 3A Philadelphia, PA 19107 Contact: Nancy Pietroski (215) 925-8010 OPEN 930831. RHODE ISLAND Memorial Hospital of Rhode Island 111 Brewster Street Pawtucket, RI 02860 Contact: Francis Betencourt (401) 729-2918 OPEN 930831. 116 UNIQUE IDENTIFIER FDA/00578 PROTOCOL ID NUMBERS FDA 200C PROTOCOL TITLE A Multi-Center, Placebo-Controlled, Double-Blind, Randomized Trial Comparing the Activity, Safety, and Tolerance of 1) 400 mg Nevirapine in Combination With 500-600 mg Zidovudine Versus Zidovudine Alone in Asymptomatic HIV-1 Infected Patients With 3-24 Months of Prior Zidovudine Therapy and 200-500 CD4+ Cells/mm3 and 2) 400 mg Nevirapine Versus Nev VERSION NUMBER & DATE (940404) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: PRIMARY: To compare the effect of nevirapine versus placebo alone or in combination with zidovudine (AZT) on CD4 T-cell count and percentage after 3 and 6 months of treatment. To evaluate the safety and tolerance of nevirapine alone or in combination with AZT. SECONDARY: To compare the effects of the various treatment combinations on virologic and immunologic markers. Methodology: In Part I, patients who have had prior AZT therapy receive either nevirapine or placebo in combination with AZT. In Part II, patients who are nucleoside naive receive either nevirapine or matching placebo. After 6 months, patients receive open-label nevirapine. GENERAL DESCRIPTION METHODOLOGY: In Part I, patients who have had prior AZT therapy receive either nevirapine or placebo in combination with AZT. In Part II, patients who are nucleoside naive receive either nevirapine or matching placebo. After 6 months, patients receive open-label nevirapine. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940404) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Asymptomatic HIV-1 infection, with positive serum antibody to HIV-1 as determined by ELISA or Western blot. 2. CD4 count 200-500 cells/mm3 within 4-28 days prior to study entry. 3. No conditions indicative of AIDS. 4. Per 04/04/94 amendment, NO history of HIV-related oropharyngeal thrush or vaginal candidiasis (UNLESS occurred prior to start of AZT treatment), compatible clinical syndrome with documented response to antifungal therapy, excessive weight loss, persistent fever, or diarrhea. NOTE: Patients with a past or present history of oral hairy leukoplakia lymphadenopathy, night sweats, fatigue, bullous impetigo, and/or HIV-related zoster (shingles) are NOT excluded. 5. If enrolled in Part I, must have tolerated 500-600 mg AZT daily for at least the preceding 3 months but no greater than 24 months (per 04/04/94 amendment) prior to study entry OR if enrolled in Part II, must be AZT naive, i.e., have had < 2 months prior AZT experience that ended more than 6 months prior to study entry. ELIGIBILITY ASYM. ARC. OTHER PROTOCOL NUMBERS 1038 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Multicenter; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance, Combination and single drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 250 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 52 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 18 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Asymptomatic HIV-1 infection, with positive serum antibody to HIV-1 as determined by ELISA or Western blot. 2. CD4 count 200-500 cells/mm3 within 4-28 days prior to study entry. 3. No conditions indicative of AIDS. 4. None of the constitutional symptoms that are specifically excluded. 5. Prior AZT for 3-24 months (amended 04/04/94) immediately prior to study entry (Part I) OR no prior AZT (Part II). 6. Consent of parent or guardian if less than 18 years of age. NOTE: Co-enrollment in a protocol involving another investigational drug or biologic is not permitted. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.5 g/dl. (men); >= 9.0 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 80000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 500 cells/mm3. ( 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 80. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3 (without use of leukoproliferative drugs). GGT <= 5 x ULN. Alkaline phosphatase <= 2.5 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required (for patients in Part I): Prior AZT at 500-600 mg daily for at least 3 months but not more than 24 months immediately prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. PCP prophylaxis (trimethoprim-sulfamethoxazole, dapsone, or aerosolized pentamidine), at the discretion of the investigator. 2. Antifungal prophylaxis with oral fluconazole or ketoconazole. 3. Antiviral prophylaxis for herpes simplex virus with <= 1000 mg/day oral acyclovir. 4. Dilantin for prevention and treatment of seizures. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following condition are excluded: History of other clinically important disease (i.e., one that precludes participation in the study). [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Chronic use of alcohol or drugs sufficient to impair compliance with protocol requirements. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Antiretroviral medications other than AZT. Excluded within 4 weeks prior to study entry: 1. Immunosuppressive or cytotoxic drugs or other experimental drugs. 2. Systemic glucocorticoids and steroid hormones. 3. Dicumarol, warfarin, and other anticoagulant medications. 4. Cimetidine. 5. Tolbutamide. 6. Doxycycline. 7. Chloramphenicol. 8. Phenobarbital and other barbiturates. 9. Foscarnet. 10. Erythromycin. 11. Amoxicillin-clavulanate (Augmentin). 12. Ticarcillin clavulanate (Timentin). 13. Biologic response modifiers (alpha interferon, IL-2, immune modulators). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Investigational drugs other than study drugs. 2. Systemic glucocorticoids and steroid hormones. 3. Dicumarol, warfarin, and other anticoagulant medications. 4. Cimetidine. 5. Tolbutamide. 6. Doxycycline. 7. Chloramphenicol. 8. Phenobarbital and other barbiturates. 9. Foscarnet. 10. Erythromycin. 11. Amoxicillin-clavulanate (Augmentin). 12. Ticarcillin clavulanate (Timentin). 13. Biologic response modifiers (alpha interferon, IL-2, immune modulators). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Malignancy other than limited cutaneous basal cell carcinoma. 2. Psychiatric condition sufficient to impair compliance with protocol requirements. SUBSTANCE IDENTIFICATION Drug 1 DRG-0116 Nevirapine SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine TRADE NAME OF SUBSTANCE Drug 1‰ BI-RG-587 TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir MANUFACTURERS Drug 1: Boehringer Ingelheim Pharmaceuticals Inc 900 Ridgebury Road / PO Box 368 Ridgefield, CT 06877 Contact: David Numberger (203) 798-4700. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg (or placebo) once daily for 14 days, then 200 mgtwice daily. Drug 2: 500 - 600 mg daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 200 mg for 14 days, then 400 mg. Drug 2: 500 - 600 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Oral SUPPORTING AGENCY Boehringer Ingelheim Pharmaceuticals Inc. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Pyridines/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Zidovudine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 129618-40-2 (BI-RG 587) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 940404 ENTRY MONTH 9312 CALIFORNIA UCSD Treatment Center 2760 Fifth Avenue / Suite 300 San Diego, CA 92103 Contact: Ron Synder (619) 543-8080 Contact: Candace McIvor (619) 298-0177 OPEN 940404. CALIFORNIA Saint Francis Memorial Hospital 900 Hyde Street San Francisco, CA 94109 Contact: Brian Goodroad (415) 353-6218 Contact: Ellen LaPointe (415) 353-6299 OPEN 931207. DELEWARE Wilmington Hospital / Infectious Disease Research Laboratory 501 West 14th Street Wilmington, DE 19801 Contact: Arlene Bincsik (302) 428-2538 OPEN 940404. FLORIDA Dr Goodgame and Hopkins 340 N Maitland Avenue Maitland, FL 32751 Contact: Chuck DeMarzo (407) 647-6000 OPEN 940404. FLORIDA CRI South Florida 1508 San Ignacio Avenue / Suite 200 Coral Gables, FL 33146 Contact: Rick Siclari (305) 667-9296 Contact: Lisa Giordano (305) 667-9296 OPEN 931207. KANSAS Univ of Kansas School of Medicine - Wichita / Clinical Rsch 1010 North Kansas Wichita, KS 67214-3199 Contact: Dal Harrison (316) 261-2855 OPEN 931207. KENTUCKY Chandler Medical Center / Dept of Medicine 800 Rose Street / Room MN 632 Lexington, KY 40536-0084 Contact: Karen Bowen (606) 257-5473 Contact: Vernon Hackworth (606) 233-6107 OPEN 931207. MISSOURI Kansas City AIDS Research Consortium 2411 Holmes Blue IV Kansas City, MO 64108-2792 Contact: Gary R. Johnson (816) 235-5366 Contact: Dr. Lawrence Dall (816) 235-1964 OPEN 940404. NEW YORK CRIA of New York 275 Seventh Avenue / 20th Floor New York, NY 10001 Contact: Bette Smith (212) 924-3934 OPEN 931207. OHIO Medical College of Ohio / Department of Medicine 3000 Arlington Avenue Toledo, OH 43699 Contact: Jan Kosmyna (419) 381-3726 OPEN 940404. OKLAHOMA Associates in Medical and Mental Health 1560 East 21st Street / Suite 210 Tulsa, OK 74114-1325 Contact: Virginia Butler (918) 743-1000 OPEN 940404. PENNSYLVANIA Philadelphia FIGHT 201 North Broad Street / 6th Floor Philadelphia, PA 19107 Contact: Carol Graeber (215) 557-8265 OPEN 931207. SOUTH CAROLINA Alfred F Burnside Jr M D 1640 St Julian Place Suite 300 Columbia, SC 29204 Contact: John Windham (803) 256-7282 OPEN 940404. 117 UNIQUE IDENTIFIER FDA/00577 PROTOCOL ID NUMBERS FDA 200B PROTOCOL TITLE A Multi-Center, Placebo-Controlled, Double-Blind, Randomized Trial Comparing the Virologic and Immunologic Activities of 400 mg Nevirapine in Combination With Zidovudine Versus Zidovudine Alone in Asymptomatic HIV-1 Infected Patients With 4-12 Months of Prior Zidovudine Therapy and 200-500 CD4+ Cells/mm3. VERSION NUMBER & DATE (931027) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: PRIMARY: To compare the virologic activity (quantitative RNA PCR, quantitative PBMC) of the combination of nevirapine and zidovudine (AZT) versus AZT alone after 3 and 6 months of treatment. To compare the effects of these two regimens on CD4 T-cell count and percentage. SECONDARY: To compare and evaluate other markers of immunologic and virologic activity in patients receiving nevirapine/AZT versus AZT alone. To compare the effects of the two regimens on clinical signs and symptoms. To evaluate the safety and tolerance of the two regimens. Methodology: Patients receive combination nevirapine/AZT or AZT alone. Patients are evaluated for virologic and immunologic activity at 3 and 6 months. GENERAL DESCRIPTION METHODOLOGY: Patients receive combination nevirapine/AZT or AZT alone. Patients are evaluated for virologic and immunologic activity at 3 and 6 months. OPEN/CLOSED INDICATOR Open: Actively accruing patients (930901) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Asymptomatic HIV infection confirmed by ELISA or Western blot. 2. CD4 count 200-500 cells/mm3 for two consecutive samples drawn at least 2 days apart during the screening period. 3. No prior AIDS. 4. No history of or active HIV-related thrush, vaginal candidiasis, zoster (shingles), excessive weight loss, persistent fever, or diarrhea. 5. Have tolerated 500-600 mg AZT daily for at least 4 months but no more than 12 months immediately prior to study entry. ELIGIBILITY ASYM. OTHER PROTOCOL NUMBERS BIPI 1037 STUDY DESIGN Multicenter; Placebo-Controlled; Double-Blind; Randomized; Comparative; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Combination and single drug therapy, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 60 patients. (Twelve patients at each of five sites) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: At least 6 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 5 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Asymptomatic HIV infection. 2. CD4 count 200-500 cells/mm3. 3. No prior AIDS. 4. No history of or active HIV-related thrush, vaginal candidiasis, zoster (shingles), excessive weight loss, persistent fever, or diarrhea. 5. Tolerated 500-600 mg AZT daily for at least 4 months but no more than 12 months immediately prior to study entry. 6. Consent of parent or guardian if less than 18 years of age. NOTE: Patients may not co-enroll in another protocol involving other investigational drugs or biologics. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 9.5 g/dl. (men); >= 9.0 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 80000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 500 cells/mm3. ( 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.5 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 80. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3 (without use of leukoproliferative drugs). GGT <= 5 x ULN. Alkaline phosphatase <= 2.5 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: AZT at 500-600 mg/day for at least 4 months but no more than 12 months immediately preceding study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. PCP prophylaxis (trimethoprim-sulfamethoxazole, dapsone, or aerosolized pentamidine), at the discretion of the investigator. 2. Antifungal prophylaxis with oral fluconazole or ketoconazole. 3. Antiviral prophylaxis for herpes simplex virus with <= 1000 mg/day oral acyclovir. 4. Dilantin for prevention and treatment of seizures. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of clinically important disease other than HIV infection, that may put patient at risk because of participation in this study. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Chronic use of alcohol or drugs sufficient to impair study compliance. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Antiretroviral medications other than AZT. Excluded within 4 weeks prior to study entry: 1. Immunosuppressive or cytotoxic drugs or other experimental drugs. 2. Systemic glucocorticoids and steroid hormones. 3. Dicumarol, warfarin, and other anticoagulant medications. 4. Cimetidine. 5. Tolbutamide. 6. Doxycycline. 7. Chloramphenicol. 8. Phenobarbital and other barbiturates. 9. Foscarnet. 10. Erythromycin. 11. Amoxicillin-clavulanate (augmentin). 12. Ticarcillin clavulanate. 13. Biologic response modifiers (alpha interferon, IL-2, immune modulators). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Systemic glucocorticoids and steroid hormones. 2. Dicumarol, warfarin, and other anticoagulant medications. 3. Cimetidine. 4. Tolbutamide. 5. Doxycycline. 6. Chloramphenicol. 7. Phenobarbital and other barbiturates. 8. Foscarnet. 9. Erythromycin. 10. Amoxicillin-clavulanate (Augmentin). 11. Ticarcillin clavulanate. 12. Biologic response modifiers (alpha interferon, IL-2, immune modulators). 13. Any investigational drugs other than study drugs. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Malignancy other than limited cutaneous basal cell carcinoma. 2. Psychiatric condition sufficient to impair study compliance. SUBSTANCE IDENTIFICATION Drug 1 DRG-0116 Nevirapine SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine TRADE NAME OF SUBSTANCE Drug 1‰ BI-RG-587 TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir MANUFACTURERS Drug 1: Boehringer Ingelheim Pharmaceuticals Incorporated 90 East Ridge / PO Box 368 Ridgefield, CT 06877 Contact: Dr Inder Kaul (203) 791-6215. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 400 mg daily for at least 6 months. Drug 2: 500 - 600 mg daily for at least 6 months SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 400 mg. Drug 2: 500 - 600 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Oral OTHER TREATMENT INFO. TREATMENT DURATION: At least 6 months. SUPPORTING AGENCY Boehringer Ingelheim Pharmaceuticals Incorporated. MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Pyridines/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Zidovudine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 129618-40-2 (BI-RG 587) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 930901 ENTRY MONTH 9312 CALIFORNIA General Hospital / AIDS Clinical Trials Unit 995 Potrero Avenue / Bldg 80 / Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 846OPEN 930901 ACTU: 0808. ILLINOIS Northwestern Univ Medical School / Comp AIDS Ctr / Infec Dis 303 East Superior Street / Passavant Room 823 Chicago, IL 60611 Contact: Baiba Berzins (312) 908-9636 OPEN 930901. MARYLAND Johns Hopkins University Hospital 1830 E Monument St \ 8th Floor Baltimore, MD 21205 Contact: Louis Grue (410) 955-2898 OPEN 931013. MISSOURI Washington University School of Medicine Campus Box 8011 / 4511 Forest Park Parkway / Suite 304 St Louis, MO 63108 Contact: Dr William Powderly (314) 361-5231 Contact: Mark Myers (314) 454-0058 OPEN 930901. 118 UNIQUE IDENTIFIER FDA/00555 PROTOCOL ID NUMBERS FDA 136A PROTOCOL TITLE Study of the Activity of Thymic Humoral Factor (THF gamma 2) on HIV Load in HIV-Positive Individuals With CD4+ Cell Counts in the Range of 200-500 Cells/mm3. VERSION NUMBER & DATE (940420) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To investigate the safety of thymic humoral factor (THF gamma 2), its effect on HIV load based on at least a 75 percent decrease in HIV quantitative PCR RNA copies/ml, and its persistence when administered in combination with an antiretroviral nucleoside derivative (zidovudine; AZT). To assess the effects of THF gamma 2 on T-cells, quality of life, and progression of disease. Methodology: All patients receive 12 weeks of AZT before being randomized to self-administer one of two doses of THF gamma 2 (500 ng or 40 mcg) or placebo for 15 consecutive days and then twice weekly for an additional 50 weeks. GENERAL DESCRIPTION METHODOLOGY: All patients receive 12 weeks of AZT before being randomized to self-administer one of two doses of THF gamma 2 (500 ng or 40 mcg) or placebo for 15 consecutive days and then twice weekly for an additional 50 weeks. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (931105) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive by ELISA confirmed by Western blot. 2. Either asymptomatic or with persistent generalized lymphadenopathy (PGL). 3. No history of symptoms in Category B or C of 1993 Case Definition, other than oral candidiasis following previous broad-spectrum antibiotic therapy. 3. Mean CD4 of 200-500 cells/mm3 for counts taken at 4, 3, and 1 weeks prior to study entry. (At least two counts must be within range of 200-500 cells/mm3; other count must be within range of 150-600 cells/mm3.) AMENDED 04/20/94: AZT-treated patients need have only one CD4 count 200 - 500 cells/mm3 within 7 days prior to randomization. 4. HIV-1 positive PCR RNA. ELIGIBILITY ASYM. PGL. OTHER PROTOCOL NUMBERS CS 112010-999 STUDY DESIGN Randomized; Double-Blind; Placebo-Controlled; Multicenter; Dose Comparison; Drug Combination PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Combination drug therapy. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 64 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 10 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity and be either asymptomatic or have persistent generalized lymphadenopathy (PGL). 2. No history of symptoms in Category B or C of 1993 Case Definition, other than oral candidiasis following previous broad-spectrum antibiotic therapy. 3. Mean CD4 of 200-500 cells/mm3. 4. HIV-1 positive PCR RNA. 5. Ability to self-administer study drug by IM injection. 6. Ability to tolerate AZT at 600 mg daily during first 8 weeks of run-in period (if AZT naive) OR tolerated AZT at >= 500 mg daily for at least 3 months but no more than 12 months prior to randomization. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 10 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 500 cells/mm3. ( 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 2.5 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: >= 90. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 5 x ULN. Creatine phosphokinase <= 2 x ULN. Absolute neutrophils >= 1000 cells/mm3. PT <= 1.25 x ULN. PTT <= 1.6 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. AZT or another antiretroviral agent (marketed or investigational under a Treatment IND). 2. Primary prophylaxis for Pneumocystis carinii pneumonia (PCP), toxoplasmosis, and Mycobacterium avium-intracellulare (MAI) if patient's CD4 count decreases to < 200 cells/mm3. 3. Other marketed drugs as required. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: Myositis within the past 6 months. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active alcoholism, drug abuse, or a mental or psychiatric problem sufficient to prevent adequate compliance with study. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within 6 weeks prior to study entry: Blood transfusion or blood products. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Experimental therapy, including interleukin-2, interferon, erythropoietin, or filgastrim nucleoside within 6 weeks prior to study entry. 2. Prior antiretroviral therapy (AZT-naive patients only). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Non-antiretroviral agents with known or suspected activity against HIV. 2. Investigational new drugs that are not antiretroviral agents distributed under a Treatment IND. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Malignancy. 2. Hematuria. 3. Proteinuria > 1+. SUBSTANCE IDENTIFICATION Drug 1 DRG-0187 Thymic humoral factor (THF gamma 2) SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine TRADE NAME OF SUBSTANCE Drug 2‰ Retrovir MANUFACTURERS Drug 1: Adria Laboratories PO Box 16529 Columbus, OH 43216-6529 Contact: Dr Robert Nolan (614) 764-8192. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 500 ng or 40 mcg (or placebo) daily for 15 days, then twice weekly for 50 weeks. Drug 2: 600 mg daily for 12 weeks prior to randomization to THFplacebo SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 500 ng or 40 mcg. Drug 2: 600 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intramuscular (IM) SUPPORTING AGENCY Adria Laboratories. MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Oligopeptides/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Zidovudine/*THERAPEUTIC USE CAS REGISTRY NUMBER 107489-37-2 (thymic humoral factor gamma 2) CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) LAST REVISION DATE 931105 ENTRY MONTH 9309 CALIFORNIA SW Community Based AIDS Treatment Group-COMBAT 1800 North Highland Avenue / Suite 610 Los Angeles, CA 90028 Contact: Holly Boyd (213) 469-5888 Contact: Stacey Kobayashi (213) 469-5888 OPEN 931105. CALIFORNIA Michael S Gottleib M D 4929 Van Nuys Boulevard Sherman Oaks, CA 91403 Contact: Renee Potochan (818) 501-2600 OPEN 931105. CALIFORNIA University of California Medical Science 1-C240 Irvine, CA 92717 Contact: Pat Hunter (714) 856-8334 OPEN 940527. CALIFORNIA San Francisco Veterans' Administration Medical Center 4150 Clement Street #111W San Francisco, CA 94121 Contact: Manon Marovich (415) 221-4810 X 394Contact: Sandra Charles (415) 221-4810 X 394OPEN 931105 ACTU: 0807. FLORIDA Dr Goodgame and Hopkins 340 N Maitland Avenue Maitland, FL 32751 Contact: Chuck DeMarzo (407) 647-6000 OPEN 930811. FLORIDA Memorial Hospital Hollywood 4700 K Sheridan Street Hollywood, FL 33021 Contact: Sherry Balder (305) 962-0040 Contact: (305) 987-2000 OPEN 940527. NEW YORK Chelsea Village Medical Center 314 West 14th Street / 5th Floor New York, NY 10014 Contact: Pat Costello (212) 620-0145 OPEN 940527. OREGON The Research and Education Group 2701 NW Vaughn / Suite 770 Portland, OR 97210 Contact: Robin Larson (503) 229-8428 OPEN 931105. SOUTH CAROLINA Alfred F Burnside Jr M D 1640 St Julian Place Suite 300 Columbia, SC 29204 Contact: John Windham (803) 256-7282 OPEN 930811. 119 UNIQUE IDENTIFIER FDA/00544 PROTOCOL ID NUMBERS FDA 134C PROTOCOL TITLE Open Trial of DOX-SL (Stealth Liposomal Doxorubicin Hydrochloride) in the Treatment of Moderate to Severe AIDS-Related Kaposi's Sarcoma. VERSION NUMBER & DATE (930625) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: To evaluate the safety and effectiveness of Stealth liposomal doxorubicin hydrochloride (DOX-SL) in the long-term treatment of AIDS-related Kaposi's sarcoma (KS) in patients who previously had good responses to DOX-SL in controlled studies of limited duration, or those with KS who discontinued treatment with another Kaposi's sarcoma therapy because of inadequate efficacy or unacceptable toxicity. To provide a defined protocol for Kaposi's sarcoma patients for whom DOX-SL therapy is indicated. Methodology: Patients receive 20 mg/m2 DOX-SL every 3 weeks for a maximum of 20 cycles (including any cycles from a previous DOX-SL study). KS lesions are evaluated prior to administration of each treatment, at the end of the final treatment cycle, and at 4 weeks following the end of the final treatment. Patients who respond will be followed every 2 months for up to 1 year. Study treatment may be interrupted for up to 4 months because of complete response, development of opportunistic infections, or adverse drug effects. GENERAL DESCRIPTION METHODOLOGY: Patients receive 20 mg/m2 DOX-SL every 3 weeks for a maximum of 20 cycles (including any cycles from a previous DOX-SL study). KS lesions are evaluated prior to administration of each treatment, at the end of the final treatment cycle, and at 4 weeks following the end of the final treatment. Patients who respond will be followed every 2 months for up to 1 year. Study treatment may be interrupted for up to 4 months because of complete response, development of opportunistic infections, or adverse drug effects. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940520) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. AIDS-related Kaposi's sarcoma of a severity requiring systemic chemotherapy. 2. Anti-HIV antibody on ELISA confirmed by an appropriate validation method. 3. No active opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, Pneumocystis carinii, or other microorganisms (if under treatment with myelotoxic drugs). NOTE: Eligible KS patients include those who have discontinued therapy in the control arm of a DOX-SL KS study because of side effects or inadequate efficacy OR other KS patients for whom DOX-SL is believed to be indicated. Patients must not be eligible for other Liposome Technology protocols comparing DOX-SL with established therapies. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS LTI-30-12 STUDY DESIGN Open Label; Noncomparative PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: UNLIMITED patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 33 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Moderate to severe AIDS-related Kaposi's sarcoma. 2. Documented anti-HIV antibody. 3. No active opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, Pneumocystis carinii, or other microorganisms (if under treatment with myelotoxic drugs). NOTE: Eligible KS patients include those who have discontinued therapy in the control arm of a DOX-SL KS study because of side effects or inadequate efficacy OR other KS patients for whom DOX-SL is believed to be indicated. Patients must not be eligible for other Liposome Technology protocols comparing DOX-SL with established therapies. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: < 2 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: >= 40. PATIENT INCLUSION CRIT. OTHER: Neutrophils > 1200 cells/mm3. PT < 2 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Prophylaxis for PCP, cryptococcal, and herpes infections, and antiretroviral therapy provided these doses have been stable for at least 1 month. 2. Maintenance therapy for tuberculosis, fungal, and herpes infections. 3. Therapy for new episodes of tuberculosis, fungal, and herpes infections except with potentially myelotoxic chemotherapy. 4. Foscarnet or ganciclovir for CMV infection. 5. Colony stimulating factors and erythropoietin. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Prior neoplasms treated with extensive chemotherapy that, in the investigator's opinion, has led to an irreversibly compromised marrow function. 2. History of idiosyncratic or allergic reaction to anthracyclines. 3. History of major psychiatric illness. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within the past 3 weeks: Radiation or electron beam therapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within the past 4 weeks: 1. Cytotoxic chemotherapy (other than in a qualifying Liposome Technology protocol). 2. Interferon treatment. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Other cytotoxic cancer chemotherapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Clinically significant cardiac disease. 2. Confusion or disorientation. PATIENT EXCLUSION CRIT. AVAILABILITY: Must not be eligible for other Liposome Technology protocols comparing DOXIL with established therapies. SUBSTANCE IDENTIFICATION Drug 1 DRG-0185 Doxorubicin hydrochloride (liposomal) TRADE NAME OF SUBSTANCE Drug 1‰ DOX-SL MANUFACTURERS Drug 1: Liposome Technology Incorporated 1050 Hamilton Court Menlo Park, CA 94025 Contact: Melody Anderson (415) 323-9011. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 20 mg/m2 over 30 min q 3 months for a maximum of twenty3-month cycles (including any cycles from a previous study) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous, vials OTHER TREATMENT INFO. TREATMENT DURATION: Maximum of twenty 3-week treatment cycles (including any cycles from a previous study). SUPPORTING AGENCY Liposome Technology Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Doxorubicin/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Drug Carriers MESH HEADING Female MESH HEADING Human MESH HEADING Liposomes MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/*DRUG THERAPY/ETIOLOGY CAS REGISTRY NUMBER 0 (Drug Carriers) CAS REGISTRY NUMBER 0 (Liposomes) CAS REGISTRY NUMBER 23214-92-8 (Doxorubicin) LAST REVISION DATE 940520 ENTRY MONTH 9307 CALIFORNIA Dr Becky Miller 8621 West Third Street Suite 600E Los Angeles, CA 90048 Contact: Jean Klein (310) 854-5841 OPEN 940520. CALIFORNIA Pacific Oaks Medical Group 150 N Robertson Suite 300 Beverly Hills, CA 90211 Contact: Rod Raphael (310) 652-2562 OPEN 940520. CALIFORNIA Pacific Oaks Medical Group 4940 Van Nuys Blvd Sherman Oaks, CA 91403 Contact: Rod Raphael (310) 652-2562 OPEN 940520. CALIFORNIA Tarzana Medical Center 16133 Ventura Boulevard Suite 470 Encino, CA 91436 Contact: Mary Hillner (818) 981-4156 OPEN 940520. CALIFORNIA Apogee Medical Group 3415 Sixth Avenue SW San Diego, CA 92103 Contact: Steve Anderson (619) 295-4448 OPEN 940520. CALIFORNIA San Francisco General Hospital / UCSF 995 Potrero Avenue / Building 80 Ward 84 San Francisco, CA 94110 Contact: Carol Arri (415) 476-9296 X 840OPEN 940520. CALIFORNIA Kaiser Permanente / HIV Research Unit 2590 Geary Boulevard San Francisco, CA 94115 Contact: Kate Fitzgerald (415) 202-3480 OPEN 940520. CALIFORNIA University of California/San Francisco 350 Parnassus Avenue Suite 701 San Francisco, CA 94117 Contact: Anita Harrison (415) 566-3431 OPEN 940520. CALIFORNIA VA San Francisco Hematology/Oncology Clinic 4150 Clement Street 111H1 San Francisco, CA 94121 Contact: Anita Harrison (415) 502-0873 OPEN 940520. CALIFORNIA Univrsity of California/San Francisco 400 Parnassus Avenue 5th Floor Room A502 San Francisco, CA 94143-0324 Contact: Julie Russel (415) 476-8911 OPEN 940520. CALIFORNIA East Bay AIDS Clinic 3031 Telegraph Avenue Berkeley, CA 94705 Contact: Nancy Orcutt (510) 204-1870 OPEN 940520. DISTRICT OF COLUMBIA Dr Mahmoud Mustafa 2311 M Street Suite 401 Washington, DC 20037 Contact: Cathi Carlise (202) 331-3762 OPEN 940520. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue 1st Floor Eliot Building Miami, FL 33136 Contact: Janie Reese (305) 547-3840 OPEN 940520. FLORIDA H Lee Moffit Cancer Center and Research Institute 12902 Magnolia Drive Tampa, FL 33612 Contact: Jeane Richard (813) 972-8477 OPEN 940520. GEORGIA American Medical Research Institute 1677 Tullie Circle Suite 118 Atlanta, GA 30329 Contact: Jane Green (404) 395-0009 OPEN 940520. GEORGIA Infectious Disease Consortium Southeast Clinical Resources 1758 Century Boulevard Suite A Atlanta, GA 30345 Contact: Kim Prieto (404) 388-3694 OPEN 940520. ILLINOIS Northwestern Medical Faculty Foundation 233 East Erie Suite 700 Chicago, IL 60611 Contact: Rebecca Sunenshine (312) 908-2250 OPEN 940520. ILLINOIS Rush Presbyterian Medical College 1725 W Harrison Room 809 Chicago, IL 60612 Contact: Jean Lydon (312) 942-5904 OPEN 940520. ILLINOIS Illinois Masonic Medical Center The Cancer Center 900 West Belmont Avenue Chicago, IL 60657 Contact: Helen Gereas (312) 296-7089 OPEN 940520. MICHIGAN Henry Ford Medical Center Division of Hematology/Oncology 2799 West Grand Boulevard 13th Floor Room 1305 Detroit, MI 48202 Contact: Carolyn Schmidt (313) 876-7277 OPEN 940520. MISSOURI Washington University 660 South Euclid B8125 St Louis, MO 63108 Contact: Mary Gould (314) 454-0058 OPEN 940520. NEW YORK St Vincent's Hospital and Medical Center 412 Sixth Avenue Suite 401 New York, NY 10011 Contact: Mary Catherine George (212) 228-4633 OPEN 940520. NEW YORK New York University Medical Center 530 First Avenue New York, NY 10016 Contact: Therese Powers (212) 263-6485 OPEN 940520. NEW YORK Memorial Sloan-Kettering Cancer Center Box 306 1275 York Avenue New York, NY 10021 Contact: Michael Pino (212) 639-7161 OPEN 940520. NEW YORK St Luke's-Roosevelt Hospital Center 126 West 60th Street New York, NY 10023 Contact: Diana Mott-Tierno (212) 316-9689 OPEN 940520. NEW YORK Mt Sinai Hospital One Gustave Levy Place Box 1042 New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: Alice Mercado (212) 241-8903 OPEN 940520. NEW YORK Roswell Park Cancer Institute Elm and Carlton Street Buffalo, NY 14263 Contact: Paula Grimes (716) 845-8965 OPEN 940520. PENNSYLVANIA The Tuttleman Center Graduate Hospital 1840 South Street 2nd floor Philadelphia, PA 19146 Contact: Barbara Rensman (215) 893-7541 OPEN 940520. 120 UNIQUE IDENTIFIER FDA/00543 PROTOCOL ID NUMBERS FDA 134B PROTOCOL TITLE Randomized, Comparative Trial of DOX-SL (Stealth Liposomal Doxorubicin Hydrochloride) Versus Bleomycin and Vincristine in the Treatment of AIDS-Related Kaposi's Sarcoma. VERSION NUMBER & DATE (930625) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: To determine the efficacy of Stealth liposomal doxorubicin hydrochloride (DOX-SL) in the treatment of moderate to severe AIDS-related Kaposi's sarcoma (KS) by comparison with the established therapy BV (bleomycin/vincristine). To evaluate the safety and tolerance of DOX-SL compared to BV in a population of AIDS patients with moderate to severe KS. Methodology: Patients are randomized to receive either DOX-SL or the BV combination. Infusions are given on day 1 and every 3 weeks for a total of six cycles. Kaposi's sarcoma lesions are evaluated prior to every cycle, at the end of the last treatment cycle, and 4 weeks following the end of the last treatment. Patients who respond to therapy will be followed every 2 months for up to 1 year. Patients must agree to have one or more representative KS lesions biopsied. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either DOX-SL or the BV combination. Infusions are given on day 1 and every 3 weeks for a total of six cycles. Kaposi's sarcoma lesions are evaluated prior to every cycle, at the end of the last treatment cycle, and 4 weeks following the end of the last treatment. Patients who respond to therapy will be followed every 2 months for up to 1 year. Patients must agree to have one or more representative KS lesions biopsied. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940520) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. Biopsy-proven, progressive, AIDS-related Kaposi's sarcoma, with any of the following: - At least 15 mucocutaneous lesions. - Six or more new lesions in the prior month. - Documented visceral disease with at least five accessible cutaneous lesions. 2. Anti-HIV antibody by ELISA confirmed by an appropriate validation method. 3. No active opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, Pneumocystis carinii, or other microorganisms (if REQUIRING treatment with myelotoxic drugs). NOTE: Patients who fail the BV combination or who relapse are eligible to enter the Liposome Technology open trial using DOX-SL alone. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS LTI-30-11 STUDY DESIGN 2-Arm; Prospective; Randomized; Multicenter; Comparative; Drug Combination PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance, Combination drug therapy, Comparative drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 220 patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 4 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Biopsy-proven, progressive, AIDS-related Kaposi's sarcoma, with any of the following: - At least 15 mucocutaneous lesions. - Six or more new lesions in the prior month. - Documented visceral disease with at least five accessible cutaneous lesions. 2. Documented anti-HIV antibody. 3. No active opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, Pneumocystis carinii, or other microorganisms (if REQUIRING treatment with myelotoxic drugs). 4. Life expectancy > 4 months. NOTE: Patients who fail the BV combination or who relapse are eligible to enter the Liposome Technology open trial using DOX-SL alone. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: < 2 x ULN. PATIENT INCLUSION CRIT. KARNOFSKY: >= 30. PATIENT INCLUSION CRIT. OTHER: Neutrophils > 1500 cells/mm3. PT < 2 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Prophylaxis for PCP, cryptococcal, and herpes infections, and antiretroviral therapy (e.g., AZT, ddC, ddI) provided these doses have been stable for at least 1 month. 2. Maintenance therapy for tuberculosis, fungal, and herpes infections. 3. Therapy for new episodes of tuberculosis, fungal, and herpes infection except with potentially myelotoxic chemotherapy. 3. Foscarnet for cytomegalovirus infection. 4. Erythropoietin. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Prior neoplasms treated with extensive chemotherapy that, in the investigator's opinion, has led to irreversibly compromised bone marrow function. 2. History of idiosyncratic or allergic reaction to anthracyclines, bleomycin, or vincristine. 3. History of major psychiatric illness. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Radiation or electron beam therapy within the past 3 weeks. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Cytotoxic chemotherapy or interferon therapy within the past 4 weeks. 2. More than one prior cycle of bleomycin/vincristine at any time. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other cytotoxic chemotherapy. 2. Colony-stimulating factors. 3. Ganciclovir. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Clinically significant cardiac disease. 2. Confusion, disorientation, CNS symptoms, or peripheral neuropathy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0185 Doxorubicin hydrochloride (liposomal) SUBSTANCE IDENTIFICATION Drug 2 DRG-0045 Bleomycin SUBSTANCE IDENTIFICATION Drug 3 DRG-0046 Vincristine TRADE NAME OF SUBSTANCE Drug 1‰ DOX-SL MANUFACTURERS Drug 1: Liposome Technology Incorporated 1050 Hamilton Court Menlo Park, CA 94025 Contact: Melody Anderson (415) 323-9011. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 20 mg/m2 over 30 min on day 1 and q 3 weeks for a totalof six cycles. Drug 2: 15 mg/m2 over 1 hr on day 1 and q 3 weeks for a total ocycles. Drug 3: 1.4 mg/m2 by bolus injection on day 1 and q 3 weeks fortotal of six cycles. Should be administered prior to bleomycin SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous, vials. Drug 2: Intravenous. Drug 3: Intravenous OTHER TREATMENT INFO. TREATMENT DURATION: 18 weeks. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Unacceptable toxicity. SUPPORTING AGENCY Liposome Technology Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Bleomycins/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Doxorubicin/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Drug Carriers MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Liposomes MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/*DRUG THERAPY/ETIOLOGY MESH HEADING Vincristine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Bleomycins) CAS REGISTRY NUMBER 0 (Drug Carriers) CAS REGISTRY NUMBER 0 (Liposomes) CAS REGISTRY NUMBER 23214-92-8 (Doxorubicin) CAS REGISTRY NUMBER 57-22-7 (Vincristine) LAST REVISION DATE 940520 ENTRY MONTH 9308 MASSACHUSETTS Beth Israel Hospital 330 Brookline Avenue Bosotn, MA 02215 Contact: Paul Marcoux (617) 735-4700 X 152OPEN 940520. NEW YORK Mt Sinai Hospital One Gustave Levy Place Box 1042 New York, NY 10029 Contact: Eileen Chusid (212) 241-8903 Contact: Alice Mercado (212) 241-8903 OPEN 940520. 121 UNIQUE IDENTIFIER FDA/00542 PROTOCOL ID NUMBERS FDA 134A PROTOCOL TITLE Randomized, Comparative Trial of DOX-SL (Stealth Liposomal Doxorubicin Hydrochloride) Versus Adriamycin, Bleomycin, and Vincristine (ABV) in the Treatment of Severe AIDS-Related Kaposi's Sarcoma. VERSION NUMBER & DATE (930625) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: To determine the efficacy of Stealth liposomal doxorubicin hydrochloride (DOX-SL) in the treatment of severe AIDS-related Kaposi's sarcoma (KS) by comparison with the established therapy ABV: Adriamycin (doxorubicin)/bleomycin/vincristine. To evaluate the safety and tolerance of DOX-SL compared to ABV in a population of AIDS patients with severe KS. Methodology: Patients are randomized to receive either DOX-SL or the ABV combination. Infusions are given on day 1 and every 2 weeks for a total of six cycles. Kaposi's sarcoma lesions are evaluated prior to every cycle, at the end of the last treatment cycle, and 4 weeks following the end of the last treatment. Patients must agree to have one or more representative KS lesions biopsied. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either DOX-SL or the ABV combination. Infusions are given on day 1 and every 2 weeks for a total of six cycles. Kaposi's sarcoma lesions are evaluated prior to every cycle, at the end of the last treatment cycle, and 4 weeks following the end of the last treatment. Patients must agree to have one or more representative KS lesions biopsied. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940520) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. Biopsy-proven, progressive, AIDS-related Kaposi's sarcoma, with any of the following: - At least 25 mucocutaneous lesions. - Ten or more new lesions in the prior month. - Documented visceral disease with at least two accessible cutaneous lesions. - Two accessible cutaneous lesions with edema. 2. Anti-HIV antibody by ELISA confirmed by an appropriate validation method. 3. No active opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, Pneumocystis carinii, or other microorganisms (if under treatment with myelotoxic drugs). NOTE: Patients who respond to therapy on this protocol, as well as those who fail the ABV combination, are eligible to enter the Liposome Technology open trial using DOX-SL alone. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS LTI-30-10 STUDY DESIGN 2-Arm; Prospective; Randomized; Multicenter; Comparative; Drug Combination PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance, Combination drug therapy, Comparative drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 225 patients. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 28 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Biopsy-proven, progressive, AIDS-related Kaposi's sarcoma, with any of the following: - At least 25 mucocutaneous lesions. - Ten or more new lesions in the prior month. - Documented visceral disease with at least two accessible cutaneous lesions. - Two accessible cutaneous lesions with edema. 2. Documented anti-HIV antibody. 3. No active opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, Pneumocystis carinii, or other microorganisms (if under treatment with myelotoxic drugs). 4. Life expectancy > 4 months. NOTE: Patients who respond to therapy on this protocol, as well as those who fail the ABV combination, are eligible to enter the Liposome Technology open trial using DOX-SL alone. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 8 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. KARNOFSKY: >= 50. (or >= 40 if decreased performance status is directly attributable to the KS). PATIENT INCLUSION CRIT. OTHER: Neutrophils > 1200 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Prophylaxis for PCP, cryptococcal, and herpes infections, and antiretroviral therapy (e.g., AZT, ddC, ddI) provided these doses have been stable for at least 1 month. 2. Therapy for tuberculosis, fungal, and herpes infections except with potentially myelotoxic chemotherapy. 3. Foscarnet for new episodes of cytomegalovirus infection. 4. Colony-stimulating factors and erythropoietin. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Prior neoplasms treated with extensive chemotherapy that, in the investigator's opinion, has led to irreversibly compromised bone marrow function. 2. History of idiosyncratic or allergic reaction to bleomycin or vincristine. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Radiation or electron beam therapy within the past 3 weeks. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior anthracycline therapy. 2. Cytotoxic chemotherapy or interferon treatment within the past 4 weeks. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other cytotoxic chemotherapy. 2. Ganciclovir. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Clinically significant cardiac, hepatic, or renal disease. 2. Peripheral neuropathy, signs of moderate to severe sensory loss, or moderate to marked motor loss. 3. Inability to comply with the study. SUBSTANCE IDENTIFICATION Drug 1 DRG-0185 Doxorubicin hydrochloride (liposomal) SUBSTANCE IDENTIFICATION Drug 2 DRG-0047 Doxorubicin SUBSTANCE IDENTIFICATION Drug 3 DRG-0046 Vincristine SUBSTANCE IDENTIFICATION Drug 4 DRG-0045 Bleomycin TRADE NAME OF SUBSTANCE Drug 1‰ DOX-SL TRADE NAME OF SUBSTANCE Drug 2‰ Adriamycin MANUFACTURERS Drug 1: Liposome Technology Incorporated 1050 Hamilton Court Menlo Park, CA 94025 Contact: Melody Anderson (415) 323-9011. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. MANUFACTURERS Drug 4: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 20 mg/m2 over 30 min on day 1 and q 2 weeks for a totalof six cycles. Drug 2: 20 mg/m2 over at least 3-5 min on day 1 and q 2 weeks ftotal of six cycles. Should be administered prior to bleomycin.Drug 3: 1.0 mg over 1 min on day 1 and q 2 weeks for a total ofcycles. Should be administered prior to bleomycin. Drug 4: 10 mg/m2 over 10 min on day 1 and q 2 weeks for a totalsix cycles SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous, vials. Drug 2: Intravenous. Drug 3: Intravenous. Drug 4: Intravenous OTHER TREATMENT INFO. TREATMENT DURATION: 12 weeks. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Unacceptable toxicity. SUPPORTING AGENCY Liposome Technology Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Bleomycins/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Doxorubicin/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Drug Carriers MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Liposomes MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/*DRUG THERAPY/ETIOLOGY MESH HEADING Vincristine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Bleomycins) CAS REGISTRY NUMBER 0 (Drug Carriers) CAS REGISTRY NUMBER 0 (Liposomes) CAS REGISTRY NUMBER 23214-92-8 (Doxorubicin) CAS REGISTRY NUMBER 57-22-7 (Vincristine) LAST REVISION DATE 940520 ENTRY MONTH 9307 CALIFORNIA Dr Becky Miller 8621 West Third Street Suite 600E Los Angeles, CA 90048 Contact: Jean Klein (310) 854-5841 OPEN 940520. CALIFORNIA Pacific Oaks Medical Group 150 N Robertson Suite 300 Beverly Hills, CA 90211 Contact: Rod Raphael (310) 652-2562 OPEN 940520. CALIFORNIA Pacific Oaks Medical Group 4940 Van Nuys Blvd Sherman Oaks, CA 91403 Contact: Rod Raphael (310) 652-2562 OPEN 940520. CALIFORNIA Tarzana Medical Center 16133 Ventura Boulevard Suite 470 Encino, CA 91436 Contact: Mary Hillner (818) 981-4156 OPEN 940520. CALIFORNIA Apogee Medical Group 3415 Sixth Avenue SW San Diego, CA 92103 Contact: Steve Anderson (619) 295-4448 OPEN 940520. CALIFORNIA San Francisco General Hospital / UCSF 995 Potrero Avenue / Building 80 Ward 84 San Francisco, CA 94110 Contact: Carol Arri (415) 476-9296 X 840OPEN 940520. CALIFORNIA Kaiser Permanente / HIV Research Unit 2590 Geary Boulevard San Francisco, CA 94115 Contact: Kate Fitzgerald (415) 202-3480 OPEN 940520. CALIFORNIA University of California/San Francisco 350 Parnassus Avenue Suite 701 San Francisco, CA 94117 Contact: Anita Harrison (415) 566-3431 OPEN 940520. CALIFORNIA VA San Francisco Hematology/Oncology Clinic 4150 Clement Street 111H1 San Francisco, CA 94121 Contact: Anita Harrison (415) 502-0873 OPEN 940520. CALIFORNIA Univrsity of California/San Francisco 400 Parnassus Avenue 5th Floor Room A502 San Francisco, CA 94143-0324 Contact: Julie Russel (415) 476-8911 OPEN 940520. CALIFORNIA East Bay AIDS Clinic 3031 Telegraph Avenue Berkeley, CA 94705 Contact: Nancy Orcutt (510) 204-1870 OPEN 940520. DISTRICT OF COLUMBIA Dr Mahmoud Mustafa 2311 M Street Suite 401 Washington, DC 20037 Contact: Cathi Carlise (202) 331-3762 OPEN 940520. FLORIDA University of Miami School of Medicine 1800 NW 10th Avenue 1st Floor Eliot Building Miami, FL 33136 Contact: Janie Reese (305) 547-3840 OPEN 940520. FLORIDA H Lee Moffit Cancer Center and Research Institute 12902 Magnolia Drive Tampa, FL 33612 Contact: Jeane Richard (813) 972-8477 OPEN 940520. GEORGIA American Medical Research Institute 1677 Tullie Circle Suite 118 Atlanta, GA 30329 Contact: Jane Green (404) 395-0009 OPEN 940520. GEORGIA Infectious Disease Consortium Southeast Clinical Resources 1758 Century Boulevard Suite A Atlanta, GA 30345 Contact: Kim Prieto (404) 388-3694 OPEN 940520. ILLINOIS Northwestern Medical Faculty Foundation 233 East Erie Suite 700 Chicago, IL 60611 Contact: Rebecca Sunenshine (312) 908-2250 OPEN 940520. ILLINOIS Rush Presbyterian Medical College 1725 W Harrison Room 809 Chicago, IL 60612 Contact: Jean Lydon (312) 942-5904 OPEN 940520. ILLINOIS Illinois Masonic Medical Center The Cancer Center 900 West Belmont Avenue Chicago, IL 60657 Contact: Helen Gereas (312) 296-7089 OPEN 940520. MICHIGAN Henry Ford Medical Center Division of Hematology/Oncology 2799 West Grand Boulevard 13th Floor Room 1305 Detroit, MI 48202 Contact: Carolyn Schmidt (313) 876-7277 OPEN 940520. MISSOURI Washington University 660 South Euclid B8125 St Louis, MO 63108 Contact: Mary Gould (314) 454-0058 OPEN 940520. NEW YORK St Vincent's Hospital and Medical Center 412 Sixth Avenue Suite 401 New York, NY 10011 Contact: Mary Catherine George (212) 228-4633 OPEN 940520. NEW YORK New York University Medical Center 530 First Avenue New York, NY 10016 Contact: Therese Powers (212) 263-6485 OPEN 940520. NEW YORK St Luke's-Roosevelt Hospital Center 126 West 60th Street New York, NY 10023 Contact: Diana Mott-Tierno (212) 316-9689 OPEN 940520. NEW YORK Roswell Park Cancer Institute Elm and Carlton Street Buffalo, NY 14263 Contact: Paula Grimes (716) 845-8965 OPEN 940520. PENNSYLVANIA The Tuttleman Center Graduate Hospital 1840 South Street 2nd floor Philadelphia, PA 19146 Contact: Barbara Rensman (215) 893-7541 OPEN 940520. 122 UNIQUE IDENTIFIER FDA/00540 PROTOCOL ID NUMBERS FDA 133A PROTOCOL TITLE Placebo-Controlled Trial of Safety and Efficacy of Thalidomide in Patients With Infections Due to Mycobacterium and/or HIV. VERSION NUMBER & DATE (930720) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To demonstrate, in patients with tubercular or nontubercular mycobacterium infections with or without HIV infection, the safety of thalidomide use as judged by symptoms, physical exam, and studies of microbiologic, immunologic, hematologic, renal, and hepatic status. To demonstrate efficacy of the drug as judged by status of fever, nutrition, tuberculosis lesions, and immune responses. Methodology: Patients are randomized to receive thalidomide or placebo orally at 9 PM the night before beginning anti-tuberculosis chemotherapy and continue nightly for 7 nights. Patients are followed for 28 days. Patients are stratified according to HIV status and stage of HIV infection. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive thalidomide or placebo orally at 9 PM the night before beginning anti-tuberculosis chemotherapy and continue nightly for 7 nights. Patients are followed for 28 days. Patients are stratified according to HIV status and stage of HIV infection. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (910401) DISEASE STUDIED Tuberculosis, Nontuberculous mycobacterial infection, Mycobacterium avium-intracellul DISEASES STATUS Patients have the following symptoms and conditions: 1. Positive AFB smear and/or culture for Mycobacterium tuberculosis, M. avium, or other mycobacterial infection, with or without documented HIV infection. NOTE: HIV positive patients must have CD4 count < 500 cells/mm3 and be on antiretroviral therapy. 2. One of the following manifestations: o Temperature over 38 C on at least two occasions in the week prior to study entry. o Recent weight loss of more than 5 kilograms. o Pulmonary involvement of one or more lobes or involvement of other tissues due to tuberculosis or other mycobacterial infections, or symptomatic infections related to HIV status. o Night sweats on two or more occasions in the week prior to study entry. NOTE: Patients must be hospitalized men aged 18-65 and postmenopausal women to age 65. Anticipated requirement for hospitalization must be at least 10 days. ELIGIBILITY ARC. AIDS. OTHER. OTHER PROTOCOL NUMBERS None given STUDY DESIGN Randomized; Double-Blind; 2-Arm PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 28 days. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Positive AFB smear and/or culture for Mycobacterium tuberculosis, M. avium, or other mycobacterial infection, with or without documented HIV infection. NOTE: HIV positive patients must have CD4 count < 500 cells/mm3 and be on antiretroviral therapy. 2. One of the following manifestations: o Temperature over 38 C on at least two occasions in the week prior to study entry. o Recent weight loss of more than 5 kilograms. o Pulmonary involvement of one or more lobes or involvenment of other tissues due to tuberculosis or other mycobacterial infections, or symptomatic infections related to HIV status. o Night sweats on two or more occasions in the week prior to study entry. NOTE: Patients must be hospitalized men aged 18-65 and postmenopausal women to age 65. Anticipated requirement for hospitalization must be at least 10 days. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. (HIV-positive patients must have CD4 count < 500 cells/mm3.) ( 0 - 100 - 200 - 300 - 400 ). PATIENT AGE AGE: 18 Years - 65 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Postmenopausal or permanent sterility including hysterectomy or bilateral tubal ligation. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required for HIV-positive patients if CD4 count < 500 cells/mm3: Antiretroviral therapy. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 66 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Future reproduction. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Neuropathy or other disorders with risk of neuropathy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0184 Thalidomide MANUFACTURERS Drug 1: Gruenthal GMBH Steinfeldstrase Number 2 Stolberg, GE 5190 Contact: Unspecified. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Administered at 9 PM the night before beginning anti-tuberculosis chemotherapy and continuing nightly for 7 ni SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral OTHER TREATMENT INFO. TREATMENT DURATION: 14 days if TB only; 21 days if HIV positive and TB. SUPPORTING AGENCY Rockefeller University. MESH HEADING AIDS-Related Complex/*COMPLICATIONS/DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS/DRUG THERAPY MESH HEADING Adult MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium Infections/COMPLICATIONS/*DRUG THERAPY MESH HEADING Mycobacterium Infections, Atypical/ COMPLICATIONS/*DRUG THERAPY MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*DRUG THERAPY MESH HEADING Mycobacterium tuberculosis/*DRUG EFFECTS MESH HEADING Opportunistic Infections/COMPLICATIONS/*DRUG THERAPY MESH HEADING Thalidomide/*ADVERSE EFFECTS/THERAPEUTIC USE CAS REGISTRY NUMBER 50-35-1 (Thalidomide) LAST REVISION DATE 910401 ENTRY MONTH 9307 NEW YORK Bellevue Hospital Center 27th Street and 1st Avenue / Room 7N24 New York, NY 10016 Contact: William Rom (212) 263-6479 Contact: (212) 263-7098 OPEN 910401. NEW YORK Rockefeller University 1230 York Avenue / Box 280 New York, NY 10021-6399 Contact: Margaret Burroughs (212) 327-7177 OPEN 910401. 123 UNIQUE IDENTIFIER FDA/00535 PROTOCOL ID NUMBERS FDA 131A PROTOCOL TITLE Phase I Study to Evaluate the Safety and Tolerance of RMP-7 Administered With Amphotericin B to Patients With HIV Infection and Cryptococcal Meningitis. VERSION NUMBER & DATE (930607) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the safety of escalating doses of RMP-7 administered in persons with HIV infection and cryptococcal meningitis and to determine the MTD of the drug. To evaluate the pharmacokinetics, including cerebrospinal fluid (CSF) penetration, of amphotericin B when administered with RMP-7. Methodology: Patients receive intravenous RMP-7 added to conventional therapy with intravenous amphotericin B (with or without flucytosine). Treatment continues for 14 days, with follow-up visits 4 and 12 weeks later. GENERAL DESCRIPTION METHODOLOGY: Patients receive intravenous RMP-7 added to conventional therapy with intravenous amphotericin B (with or without flucytosine). Treatment continues for 14 days, with follow-up visits 4 and 12 weeks later. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (931105) DISEASE STUDIED Cryptococcal meningitis. DISEASES STATUS Patients have the following symptoms and conditions: 1. Documented HIV infection by ELISA confirmed by Western blot. 2. Acute cryptococcal meningitis defined by positive cryptococcal culture from CSF or detection of cryptococcal antigen in CSF. Patients with a first recrudescence are permitted if no abscess is evident on MRI or CT and intracranial pressure is not substantially elevated based on ocular findings and opening pressure during lumbar puncture. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS ALK01-006 STUDY DESIGN Randomized; Double-Blind; Dose Escalating; Drug Combination PROTOCOL DETAILS STUDY INTENT: Maximum tolerated dose (MTD), Drug safety, Pharmacokinetics, Combination drug therapy. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 14 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 11 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Acute cryptococcal meningitis. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7.0 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 7.5 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 7.5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2 x ULN. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 7.5 x ULN. Neutrophils >= 750 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Up to 1 mg/kg amphotericin B for the current episode of cryptococcal meningitis. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of any bleeding disorder. 2. History of active renal or hepatic disease. 3. Myocardial infarction within the previous 3 months. 4. Stroke within the previous 3 months. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Cardiovascular disorders including congestive heart failure, uncontrolled hypertension (seated diastolic blood pressure > 95 mm Hg), or symptomatic ischemic heart disease (angina). 2. Orthostatic hypotension, defined as a decrease in systolic blood pressure of >= 20 mm Hg upon standing. 3. Coma. 4. Other CNS disease (e.g., other intracranial infections) that may interfere with assessment of response. 5. Opening CSF pressure >= 350 mm or papilledema. (For patients with recurrent disease, evidence of mass effect on either MRI or CT excludes.) 6. Any concurrent disease that would preclude participation in the study. SUBSTANCE IDENTIFICATION Drug 1 DRG-0182 RMP-7 SUBSTANCE IDENTIFICATION Drug 2 DRG-0006 Amphotericin B TRADE NAME OF SUBSTANCE Drug 2‰ Fungizone MANUFACTURERS Drug 1: Alkermes Incorporated 64 Sidney Street Cambridge, MA 02139 Contact: Dr William F Graney (617) 494-0171. MANUFACTURERS Drug 2: Bristol-Myers Squibb Company PO Box 4000 Princeton, NJ 08534-4000 Contact: Dr Joe Sonk (609) 252-5710. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous. Drug 2: Intravenous OTHER TREATMENT INFO. TREATMENT DURATION: 14 days. SUPPORTING AGENCY Alkermes Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Amphotericin B/ADVERSE EFFECTS/ *PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Antifungal Agents/*ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Meningitis/*DRUG THERAPY/ETIOLOGY MESH HEADING Middle Age MESH HEADING Opportunistic Infections/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antifungal Agents) CAS REGISTRY NUMBER 1397-89-3 (Amphotericin B) LAST REVISION DATE 931105 ENTRY MONTH 9307 CALIFORNIA Los Angeles County / USC Medical Center 1129 North State Street / Room 2E10 Pediatric Pavilion Los Angeles, CA 90033 Contact: DeAnn Diamond (213) 226-3695 CLOSED 940301. CALIFORNIA University of California / San Diego Treatment Center 2760 5th Avenue / Suite 300 San Diego, CA 92103 Contact: Alanna Fraser (619) 543-8080 OPEN 930301. CALIFORNIA UCI Medical Center 101 City Drive South / Building 53 / Route 81 Orange, CA 92668 Contact: Sheila Fitzgibbons (714) 456-7612 OPEN 930301. KANSAS Univ of Kansas School of Medicine - Wichita / Clinical Rsch 1010 North Kansas Wichita, KS 67214-3199 Contact: Dal Harrison (316) 261-2855 OPEN 931105. NORTH CAROLINA Bowman Gray School of Medicine Medical Center Boulevard Winston-Salem, NC 27157-1042 Contact: Ronald Washburn (910) 716-4218 OPEN 930301. NORTH CAROLINA Duke University Medical Center / Infectious Diseases Clinic Trent Drive/ Room 0201 / South Hospital / Orange Zone Durham, NC 27710 Contact: Laura Stewart (919) 684-8216 OPEN 930301. NORTH CAROLINA East Carolina University School of Medicine Section of Infect Diseases Greenville, NC 27858-4354 Contact: Jean Askew (919) 816-2578 CLOSED 940610. NEW YORK SUNY at Stony Brook Health Sciences Center / Div Infect Dis HSC T 15 Room 080 Stony Brook, NY 11794-8153 Contact: Ruth Ann Burk (516) 444-1658 OPEN 930301. OHIO Case Western Reserve University 10900 Euclid Avenue Cleveland, OH 44106 Contact: Corrine Connor (216) 844-3287 OPEN 940215. PENNSYLVANIA Pennsylvania State University / Hershey Medical Center 500 Univ Drive / PO Box 850 / Biomedical Rsrch Bldg C-6833 Hershey, PA 17033 Contact: Francine Damianos (717) 531-7488 OPEN 930301. 124 UNIQUE IDENTIFIER FDA/00575 PROTOCOL ID NUMBERS FDA 129D PROTOCOL TITLE 3TC (Lamivudine; GR109714X) Open-Label Program. VERSION NUMBER & DATE (931104) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Nationwide Access TRIAL CATEGORY Child GENERAL DESCRIPTION PURPOSE: To make lamivudine (3TC) available to patients with progressive, symptomatic HIV disease who cannot participate in a controlled clinical trial and who are refractory or unable to tolerate other therapies. To collect data pertaining to the safety of 3TC at two dose levels: 4 and 8 mg/kg/day. To evaluate the effect of 3TC on markers of hepatitis B in co-infected patients at five to ten selected sites. Methodology: Patients are randomized to receive one of two doses of 3TC for a duration determined by the patient's physician or until termination of the program. Patients are followed monthly. For selected sites only, serum samples are collected every 3 months from patients identified as HBsAg positive. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive one of two doses of 3TC for a duration determined by the patient's physician or until termination of the program. Patients are followed monthly. For selected sites only, serum samples are collected every 3 months from patients identified as HBsAg positive. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940511) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Progressive, symptomatic HIV disease. 2. Mean CD4 count <= 300 cells/mm3 (two samples collected at least 30 days apart, but within 90 days of enrollment). 3. Unable to participate in a controlled trial. 4. Refractory to or unable to tolerate other therapies. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS NUCA 3004 STUDY DESIGN Open Label; Randomized; Dose Comparison PROTOCOL DETAILS STUDY INTENT: Expanded access, Drug safety, Drug efficacy. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Determined by patient's physician or until study termination. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must: 1. Have progressive, symptomatic HIV disease. 2. Have a mean CD4 count <= 300 cells/mm3. 3. Be unable to participate in a controlled trial. 4. Be refractory to or unable to tolerate other therapies. 5. Be able to attend clinic on a monthly schedule. 6. Have consent of parent or guardian if under the age of consent. NOTE: If a pregnant or breast-feeding woman requests enrollment, her physician should contact Glaxo staff directly to discuss the case. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 300 cells/mm3. ( 0 - 100 - 200 - 300 ). PATIENT AGE AGE: 03 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 02 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Practice of unsafe sex. PATIENT EXCLUSION CRIT. AVAILABILITY: Patients located in countries other than the United States or Canada are not eligible. SUBSTANCE IDENTIFICATION Drug 1 DRG-0126 Lamivudine TRADE NAME OF SUBSTANCE Drug 1‰ 3TC MANUFACTURERS Drug 1: Glaxo Incorporated 5 Moore Drive Research Triangle Park, NC 27709 Contact: Jennifer McMillan (919) 248-2100. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 4 or 8 mg/kg/day SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 4 or 8 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral; 300 mg tablets (adults) or 10 mg/ml syrup (children) OTHER TREATMENT INFO. TREATMENT DURATION: Duration determined by patient's physician or until study termination. SUPPORTING AGENCY Glaxo Incorporated. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Reverse Transcriptase/ANTAGONISTS & INHIB CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER EC 2 LAST REVISION DATE 940511 ENTRY MONTH 9312 NEW JERSEY Kern - McNeill International 159 South Street Morristown, NJ 07960 Contact: Michele McNeill (800) 248-9757 OPEN / USA Accrual 931029. 125 UNIQUE IDENTIFIER FDA/00522 PROTOCOL ID NUMBERS FDA 126A PROTOCOL TITLE Phase I/II Study of the Tolerance and Efficacy of Combined Use of Didanosine (2',3'-Dideoxyinosine; ddI) and Lentinan in HIV-Positive Patients. VERSION NUMBER & DATE (930511) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic PROTOCOL CHAIRS CHAIR Lang W PROTOCOL CHAIRS CO-CHAIR Goodgame J GENERAL DESCRIPTION PURPOSE: To determine the tolerance and side effects of a combination of lentinan and didanosine (ddI) compared with ddI alone. To determine whether the combination of lentinan and ddI produces a significant immunorestorative effect within the study observation period (6-12 months) as measured by an increase in one or more of the following: neutrophil count and activity, T-cell subsets, and a decrease in p24 antigen. Methodology: Patients are randomized to receive either lentinan (40 patients) or placebo (10 patients) in combination with ddI for at least 26 weeks; those tolerating their dose may be offered continuation of therapy for an additional 26 weeks. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either lentinan (40 patients) or placebo (10 patients) in combination with ddI for at least 26 weeks; those tolerating their dose may be offered continuation of therapy for an additional 26 weeks. PROTOCOL PHASE Phase I / Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (920219) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositivity. 2. Absolute CD4 count of 200 - 500 cells/mm3. 3. No active opportunistic infection or Kaposi's sarcoma. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS 91-10-15 STUDY DESIGN Randomized; 2-Arm; Drug Combination; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug tolerance, Drug efficacy, Combination and single drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 50 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 26-52 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV seropositivity. 2. Absolute CD4 count of 200 - 500 cells/mm3. 3. No active opportunistic infection or Kaposi's sarcoma. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: >= 30 percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 10 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 500 cells/mm3. ( 200 - 300 - 400 - 500 ). PATIENT INCLUSION CRIT. SGOT(AST): <= 4 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 4 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: > 60. PATIENT AGE AGE: 18 Years - 60 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior ddI for no longer than 3 months. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. 61 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active drug abuse. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded: Radiotherapy within 1 month prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT TREATMENT: Excluded: Radiotherapy. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 1 month prior to study entry: 1. Antiretroviral agents other than ddI (patients may have received prior ddI for no longer than 3 months total). 2. Steroids. 3. Cytotoxic agents. 4. Immunosuppressive agents. 5. Immunomodulators. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antiretroviral agents other than ddI. 2. Steroids. 3. Cytotoxic agents. 4. Immunosuppressive agents. 5. Immunomodulators. 6. 1-Thyroxine. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Lymphoid malignancy. 2. Pancreatitis. 3. Peripheral neuropathy. 4. Critical illness. PATIENT EXCLUSION CRIT. AVAILABILITY: Must not be currently hospitalized. SUBSTANCE IDENTIFICATION Drug 1 DRG-0171 Lentinan SUBSTANCE IDENTIFICATION Drug 2 DRG-0016 Didanosine TRADE NAME OF SUBSTANCE Drug 2‰ Videx MANUFACTURERS Drug 1: AJI PHARMA USA Inc 500 Frank Burr Boulevard Teaneck, NJ 07666 Contact: Dr Maxwell Gordon (201) 836-1196 Contact: Mario Guralnik (201) 836-1196. MANUFACTURERS Drug 2: Bristol-Myers Squibb Company 2400 West Lloyd Expressway Evansville, IN 47721-0001 Contact: DDI Information (800) 662-7999. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 2 mg (or placebo) weekly for 26 weeks (possibly extendefor an additional 26 weeks). Drug 2: 400 mg BID daily for 26 weeks (possibly extended for anadditional 26 weeks) SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 2: 800 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous. Drug 2: Oral OTHER TREATMENT INFO. TREATMENT DURATION: At least 26 weeks. OTHER TREATMENT INFO. END POINT: Toxicity, drug efficacy. SUPPORTING AGENCY AJI PHARMA USA Inc. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Didanosine/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Lentinan/*ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 37339-90-5 (Lentinan) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) LAST REVISION DATE 920219 ENTRY MONTH 9305 CALIFORNIA ViRx Inc 1375 Sutter Street Suite 407 San Francisco, CA 94102 Contact: Karen Allman (415) 474-4440 OPEN 930511. FLORIDA Dr Goodgame and Hopkins 340 N Maitland Avenue Maitland, FL 32751 Contact: Chuck DeMarzo (407) 647-6000 OPEN 930511. 126 UNIQUE IDENTIFIER FDA/00479 PROTOCOL ID NUMBERS FDA 121A PROTOCOL TITLE A Randomized Phase III Clinical Trial of Daunoxome Versus Combination Chemotherapy With Adriamycin/Bleomycin/Vincristine (ABV) in the Treatment of HIV-Associated Kaposi's Sarcoma. VERSION NUMBER & DATE (920514) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: To compare the toxicity profiles (severity and time to onset from initiation of therapy) between daunorubicin (liposomal) and combination chemotherapy with doxorubicin/bleomycin/vincristine (ABV), with both regimens administered in combination with antiretroviral therapy. To compare the duration of responses, response rates, and times to response. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940510) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. Serological documentation of HIV infection by ELISA and Western blot. 2. Biopsy-proven Kaposi's sarcoma with advanced disease defined by any of the following: presence of 25 or more mucocutaneous lesions; development of 10 or more lesions within 1 month; presence of confluent or symptomatic mucocutaneous involvement in the event of fewer than 25 lesions; symptomatic visceral involvement; or lymphedema. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 103-09 STUDY DESIGN Randomized PROTOCOL DETAILS STUDY INTENT: Comparative drug therapy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 13 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Advanced Kaposi's sarcoma. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 1.5 x ULN g/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1500 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.5 x ULN mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 3 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 50. PATIENT INCLUSION CRIT. OTHER: Cardiac left ventricular ejection fraction >= 45 percent. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior intralesional vinblastine. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Symptomatic AIDS-defining opportunistic infection within 2 weeks of entry. 2. History of malignancy other than Kaposi's sarcoma, basal cell carcinoma, or carcinoma in situ of the cervix. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR TREATMENT: Excluded within 7 days prior to study entry: 1. Radiation. 2. Local therapies (e.g., cryotherapy). PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior systemic chemotherapy. 2. Intralesional therapies within 7 days prior to study entry. 3. Growth factors (G-CSF or GM-CSF), immune modifiers, or investigational agents within 14 days prior to study entry. 4. Interferon preparations (alpha or beta) within 28 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Concurrent ganciclovir. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Acute intercurrent infection other than genital herpes. 2. Uncompensated cardiovascular, hepatic, renal, or pulmonary disease unrelated to Kaposi's sarcoma. 3. Symptomatic peripheral neuropathy. 4. Any condition that compromises ability to give informed consent or complete the study. SUBSTANCE IDENTIFICATION Drug 1 DRG-0155 Daunorubicin (liposomal) SUBSTANCE IDENTIFICATION Drug 2 DRG-0047 Doxorubicin SUBSTANCE IDENTIFICATION Drug 3 DRG-0045 Bleomycin SUBSTANCE IDENTIFICATION Drug 4 DRG-0046 Vincristine TRADE NAME OF SUBSTANCE Drug 1‰ Daunoxome TRADE NAME OF SUBSTANCE Drug 2‰ Adriamycin TRADE NAME OF SUBSTANCE Drug 3‰ Blenoxane TRADE NAME OF SUBSTANCE Drug 4‰ Oncovin MANUFACTURERS Drug 1: Vestar Inc 650 Cliffside Drive San Dimas, CA 91773 Contact: Jeanni Brenning (909) 394-4110. MANUFACTURERS Drug 2: Adria Laboratories Incorporated PO Box 16529 Columbus, OH 43216-6529 Contact: Dr Sunil Gupta (614) 764-8178. MANUFACTURERS Drug 3: Bristol-Myers Squibb Company 345 Park Avenue New York, NY 10154 Contact: Nancy Goldfarb (212) 546-5107. MANUFACTURERS Drug 4: Eli Lilly and Company 307 East McCarty Street Indianapolis, IN 46285 Contact: Medical Department (800) 545-5979. SUPPORTING AGENCY Vestar Inc. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Bleomycins/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Daunorubicin/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Doxorubicin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Carriers MESH HEADING Female MESH HEADING Human MESH HEADING Liposomes MESH HEADING Male MESH HEADING Middle Age MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY MESH HEADING Vincristine/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 0 (Bleomycins) CAS REGISTRY NUMBER 0 (Drug Carriers) CAS REGISTRY NUMBER 0 (Liposomes) CAS REGISTRY NUMBER 20830-81-3 (Daunorubicin) CAS REGISTRY NUMBER 23214-92-8 (Doxorubicin) CAS REGISTRY NUMBER 57-22-7 (Vincristine) LAST REVISION DATE 940510 ENTRY MONTH 9212 ARIZONA University of Arizona / Arizona Cancer Center 1501 N Campbell Avenue Tucson, AZ 85724 Contact: Dr G Gonzalez (602) 626-6372 OPEN 921120. CALIFORNIA Kenneth Norris Jr Cancer Hospital 1441 Eastlake Avenue / Room 162 Los Angeles, CA 90033 Contact: Dr Parkish Gill (213) 342-2448 OPEN 921120. CALIFORNIA The Desert Hospital Comprehensive Cancer Center 1695 N Sunrise Way Palm Springs, CA 92262 Contact: Dr Sanford Kempin (619) 323-6891 OPEN 921120. CALIFORNIA Saint Francis Memorial Hospital 900 Hyde Street San Francisco, CA 94109 Contact: Dr Gifford Leoung (415) 353-6216 OPEN 921120. CALIFORNIA Institute for HIV Research / Davies Med Ctr Castro and Dubose Streets San Francisco, CA 94114 Contact: Dr Ivan Silverberg (415) 861-7530 OPEN 921120. COLORADO Denver General Hospital / Div of Medical Oncology Box 0146 / 777 Bannock Street Denver, CO 80204-4507 Contact: Dr Adam Myers (303) 436-5774 OPEN 931105. DISTRICT OF COLUMBIA George Washington U Med Ctr / Div of Hematology/Oncology 2150 Pennsylvania Avenue NW Washington, DC 20037 Contact: Dr Philip Cohen (202) 994-7716 OPEN 921120. FLORIDA Univ of Miami School of Med / Comprehensive AIDS Program Div of Gen Med R-60A / 1800 NW 10th Avenue Miami, FL 33101 Contact: Margaret A Fischl (305) 547-3847 OPEN 931105. ILLINOIS Northwestern University Medical School 233 East Erie Street / Suite 700 Chicago, IL 60611 Contact: Dr J Hayden von Roenn (312) 908-9412 OPEN 921120. MASSACHUSETTS New England Deaconess Hospital / Dept of Hemat/Oncol 110 Frances Street / 4A Boston, MA 02215 Contact: Dr David Scadden (617) 732-8540 OPEN 921120. NEW YORK New York U Med Ctr / Dept of Medicine / Div of Oncology 550 1st Avenue New York, NY 10016 Contact: Dr James Wernz (212) 263-7227 OPEN 921120. OREGON Northwest Kaiser Permanente Med Ctr / Dept of Hemat/Oncol 3414 N Kaiser Center Drive Portland, OR 97227 Contact: Michael Allison (503) 249-3313 Contact: Dr Mark Rarick (503) 249-3430 OPEN 921120. 127 UNIQUE IDENTIFIER FDA/00644 PROTOCOL ID NUMBERS FDA 120 PROTOCOL TITLE An Open Multicenter Trial of Fluconazole Oral Suspension in the Treatment of Esophageal Candidiasis in Immunocompromised Patients. VERSION NUMBER & DATE (940727) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To determine the safety, toleration, and efficacy of fluconazole oral suspension in the treatment of esophageal candidiasis in immunocompromised patients, including those with AIDS. Methodology: Patients receive fluconazole oral suspension for a minimum of 3 weeks and maximum of 8 weeks. Patients are evaluated weekly, and treatment continues for 2 weeks after resolution of symptoms. Endoscopic exams and possibly biopsies are performed at baseline and at the end of treatment. Patients undergo follow-up at 2 weeks post-treatment. GENERAL DESCRIPTION METHODOLOGY: Patients receive fluconazole oral suspension for a minimum of 3 weeks and maximum of 8 weeks. Patients are evaluated weekly, and treatment continues for 2 weeks after resolution of symptoms. Endoscopic exams and possibly biopsies are performed at baseline and at the end of treatment. Patients undergo follow-up at 2 weeks post-treatment. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (920121) DISEASE STUDIED Candidiasis, esophageal. DISEASES STATUS Patients have the following symptoms and conditions: 1. AIDS or other immunocompromising condition (e.g., malignancy, renal transplant). 2. Clinical diagnosis of candidal esophagitis based on symptoms such as dysphagia, odynophagia, or retrosternal pain. ELIGIBILITY AIDS. OTHER - immunocompromised. OTHER PROTOCOL NUMBERS R-0220 STUDY DESIGN Open Label; Multicenter; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance. PROTOCOL DETAILS PROJECTED ACCRUAL: 100 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Up to 10 weeks (including follow-up 2 weeks post-treatment). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS or other immunocompromising condition. 2. Candidal esophagitis. 3. Life expectancy of at least 2 months. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 3 mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 3 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase < 3 x ULN. Prothrombin time <= 5 sec over control (unless correctable by vitamin K). PATIENT AGE AGE: 13 Years - 70 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of allergy to imidazoles or azoles. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. 71 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Active use of illicit or illegal drugs. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Any oral or topical antifungal therapy within the past 3 days. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Concomitant oral or topical antifungal agent. 2. Other experimental medications. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Evidence of non-candidal systemic fungal infection. 2. Abnormalities that may preclude esophagoscopy or endoscopy. 3. Unable to tolerate fluconazole. 4. Unable to give informed consent. 5. Enrollment in other experimental trials of approved or non-approved drugs or systemic compounds (unless approved by the Pfizer Clinical Monitor). 6. Other condition that would make patient unsuitable for enrollment. SUBSTANCE IDENTIFICATION Drug 1 DRG-0005 Fluconazole TRADE NAME OF SUBSTANCE Drug 1‰ Diflucan MANUFACTURERS Drug 1: Pfizer Incorporated / Roerig Division 235 East 42nd Street New York, NY 10017-7851 Contact: Professional Information (212) 573-2187. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Administered for 3 - 8 weeks SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, suspension OTHER TREATMENT INFO. TREATMENT DURATION: 3 - 8 weeks. SUPPORTING AGENCY Pfizer Incorporated / Roerig Division. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Candidiasis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Esophagitis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Fluconazole/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Immunocompromised Host MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 86386-73-4 (Fluconazole) LAST REVISION DATE 920121 ENTRY MONTH 9408 CALIFORNIA Los Angeles - USC Medical Center / GI and Liver Disease 1200 North State Street / Room 12-137 Los Angeles, CA 90033 Contact: Francisco Garcia (213) 226-6939 Contact: Dr Loren Laine (213) 226-7994 Contact: (213) 226-7995 OPEN 940808. 128 UNIQUE IDENTIFIER FDA/00477 PROTOCOL ID NUMBERS FDA 119A PROTOCOL TITLE A Study to Evaluate the Effect of Cimetidine on CD4 Lymphocyte Counts in HIV Infection. VERSION NUMBER & DATE (920403) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To determine the change in CD4 count after 4 and 8 weeks in HIV-infected patients treated with cimetidine compared to placebo. To observe time-associated trends at weeks 4, 8, 12, and 16 in the change of CD4 counts for patients taking cimetidine for the full 16 weeks. To establish a safety record for cimetidine use in HIV-positive patients. OPEN/CLOSED INDICATOR Open: Actively accruing patients (920501) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: HIV positive by antibody testing (including tests performed at anonymous test sites) or presumptive diagnosis of HIV positive status by symptoms and lab data (diagnosis of ARC or AIDS not required, provided other criteria are met). ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS 92-01 STUDY DESIGN Placebo-Controlled PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: HIV positivity. NOTE: Patients on an antiviral or immunomodulating drug must have received it for at least 2 months and have no intention to make clinical or therapeutic changes in the first 8 weeks (such as adding a new agent or discontinuing effective viral suppressive therapy) that may interfere with the study. NOTE: Patients who become pregnant after enrollment will be permitted to continue on study drug but must sign an additional informed consent indicating their awareness of the issues in taking a drug with limited safety data during pregnancy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 2.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. OTHER: Neutrophils > 750 cells/mm3. Alkaline phosphatase < 5 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Antiviral and immunomodulating drugs, provided patient has been on such therapy for at least 2 months prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. All FDA-approved medications, antiretrovirals, and PCP prophylaxis drugs, with the exception of warfarin (Coumadin). 2. Other self-prescribed medications available either over the counter or through buyer's clubs. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 4 weeks prior to study entry: cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nazitidine (Azid). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Warfarin (Coumadin). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known intolerance or hypersensitivity to cimetidine. 2. Evidence of active opportunistic infection or malignancy requiring high-dose systemic chemotherapy. 3. Any symptoms suggestive of concurrent illness that are not attributable to overall impairment by HIV or are not diagnosable based on the available evidence. 4. Inability to swallow tablets (gastric feeding tubes are allowed. 5. Not willing to comply with visit schedule and study procedures. SUBSTANCE IDENTIFICATION Drug 1 DRG-0150 Cimetidine TRADE NAME OF SUBSTANCE Drug 1‰ Tagamet MANUFACTURERS Drug 1: Smith Kline Beecham 1 Franklin Plaza / PO Box 7929 Philadelphia, PA 19101-7929 Contact: Product Information / Med Dept (800) 366-8900 X 5231. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, tablets SUPPORTING AGENCY Community Research Initiative of New England. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Cimetidine/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 51481-61-9 (Cimetidine) LAST REVISION DATE 920501 ENTRY MONTH 9212 MASSACHUSETTS Community Research Initiative of New England 320 Washington Street / 3rd Floor Brookline, MA 02146 Contact: Jeanne Day (617) 566-4004 OPEN 921124. 129 UNIQUE IDENTIFIER FDA/00433 PROTOCOL ID NUMBERS FDA 104B PROTOCOL TITLE A Comparative Trial of 256U87 and Acyclovir for the Suppression of Anogenital Herpes Infections in HIV-Infected Patients. VERSION NUMBER & DATE (911210) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To determine the safety and efficacy of oral 256U87 compared to acyclovir in the treatment of recurrent anogenital herpes in HIV-infected patients with CD4 counts = or > 100 cells/mm3. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940502) DISEASE STUDIED Herpes simplex, anogenital. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection with CD4 count = or > 100 cells/mm3. 2. History of recurrent anogenital herpes simplex virus (HSV). 3. Documented culture for anogenital HSV within the last 5 years. 4. Recurrence of anogenital HSV (with or without culture) within 1 year prior to study entry. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS 07 STUDY DESIGN Drug Comparison PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Comparative drug therapy. PROTOCOL DETAILS ACTUAL ACCRUAL: 713 (940502). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 46 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection with CD4 counts = or > 100 cells/mm3. 2. Documented culture of anogenital herpes simplex virus (HSV) within the last 5 years. 3. History of recurrent anogenital HSV infection, with a recurrence (with or without culture) within 1 year prior to study. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: >= 100 cells/mm3. ( 100 - 200 - 300 - 400 - 500 - 600 - 700 - 800 plus). PATIENT INCLUSION CRIT. SGOT(AST): < 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 35 ml/min. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of hypersensitivity to acyclovir. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Systemic antiherpes medication. 2. Interferon. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: Malabsorption or vomiting that would potentially limit the retention and absorption of oral therapy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0119 Valaciclovir SUBSTANCE IDENTIFICATION Drug 2 DRG-0008 Acyclovir TRADE NAME OF SUBSTANCE Drug 2‰ Zovirax MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUPPORTING AGENCY Burroughs Wellcome Company. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Acyclovir/*THERAPEUTIC USE MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/*THERAPEUTIC USE MESH HEADING Anus Diseases/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Herpes Genitalis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 59277-89-3 (Acyclovir) LAST REVISION DATE 940502 ENTRY MONTH 9207 ALABAMA University of South Alabama Division of Infectious Disease Mobile, AL 36688 Contact: Dr Halim (205) 479-6933 Contact: Judy Miller (205) 479-6933 OPEN 920729. ARIZONA University of Arizona / Section of Infectious Diseases 1501 North Campbell Avenue Tucson, AZ 85724 Contact: Joel Gray (602) 626-2533 OPEN 920729. CALIFORNIA Combat Group 1800 North Highland Suite 610 Los Angeles, CA 90028 Contact: Holly Boyd (213) 469-5888 OPEN 940502. CALIFORNIA USC Medical Center 1175 North Cummings Street / Room 349 Los Angeles, CA 90033 Contact: Irene Teran (213) 343-8288 OPEN 931110. CALIFORNIA UCSD Medical Center 8208 225 Dickinson Street San Diego, CA 92103 Contact: Kathy Nuffer (619) 543-8080 OPEN 920729. CALIFORNIA US Naval Hospital Florida Canyon Drive San Diego, CA 92134-5000 Contact: Elaine Schreiber (619) 532-6131 OPEN 931110. CALIFORNIA UCI Medical Center 101 City Drive South / Building 53 / Route 81 Orange, CA 92668 Contact: Sheila Fitzgibbons (714) 456-7612 OPEN 920729. CALIFORNIA ViRx Incorporated 1375 Sutter Street / Suite 407 San Francisco, CA 94109 Contact: Joyce Amann (415) 474-4440 Contact: Michael Baker (415) 474-4440 OPEN 920729. CALIFORNIA San Francisco General Hospital 995 Portrero Avenue Bldg 80 Ward 84 San Francisco, CA 94110 Contact: Patricia Duff (415) 431-0790 OPEN 920729. CALIFORNIA Marcus Conant M D 1635 Divisadero Street Suite 600 San Francisco, CA 94115 Contact: Steven Ellis (415) 923-0222 OPEN 920729. CALIFORNIA Infectious Disease Medical Gp / Adult Immunology Clinic 3012 Summit Street Sixth Floor Oakland, CA 94609 Contact: Jamie Carroll (510) 420-6014 Contact: Doctors office (510) 834-2800 OPEN 920729. CONNECTICUT HIV Care Program / Veterans Administration Medical Ctr 111-1 950 Campbell Avenue West Haven, CT 06516 Contact: Elizabeth Cooney (203) 932-5711 X 374CLOSED 940502. DISTRICT OF COLUMBIA Georgetown University Medical Center Suite 110 Kober-Cogan Bldg / 3800 Reservoir Road NW Washington, DC 20007 Contact: Catherine O'Leary (202) 687-5378 OPEN 920729. DISTRICT OF COLUMBIA Whitman Walker Clinic 1701 NW 14th Street Washington, DC 20009 Contact: Christiane Jones (202) 745-6151 OPEN 940502. DISTRICT OF COLUMBIA George Washington University Medical Center 2300 I Street NW / Number 202 Washington, DC 20037 Contact: Barbara Lewis (202) 994-2417 OPEN 931110. DISTRICT OF COLUMBIA Washington Regional AIDS Program 50 Irving Street / NW Washington, DC 20422 Contact: Donna Mills (202) 745-8695 OPEN 931110. FLORIDA University of South Florida / Div of Infect and Tropical Dis 5471 4th Street South St Petersburg, FL 33705 Contact: Pat Seeley (813) 974-3163 OPEN 920729. GEORGIA Emory Medical School / Division of Infectious Diseases 69 Butler Street Atlanta, GA 30303 Contact: Kara Barrett (404) 616-2440 OPEN 920729. GEORGIA AIDS Research Consortium of Atlanta 131 Ponce deLeon Avenue / Suite 130 Atlanta, GA 30308 Contact: Betty Mear (404) 876-2317 OPEN 931110. IOWA University of Iowa / Div of Infectious Disease 200 Hawkins Road / SW54 / GH Iowa City, IA 52242 Contact: Julie Katseres (319) 353-8441 OPEN 931110. ILLINOIS Northwestern Memorial Hospital / Section of Infect Disease 250 East Superior Street Chicago, IL 60611 Contact: Patty Nedved (312) 908-7631 OPEN 920729. ILLINOIS Rush Presbyterian - St Lukes Medical Ctr / Sec of Infect Dis 1725 West Harrison Ave Suite 143 Academic Facility Chicago, IL 60612 Contact: Donna Samano (312) 942-5865 OPEN 920729. INDIANA Indiana University Medical School / Division of Infect Dis Emerson Hall Room 435 / 545 Barnhill Drive Indianapolis, IN 46223 Contact: Beth Zwicki (317) 274-8456 Contact: Heather Nixon (317) 274-8456 OPEN 920729. KANSAS Univ of Kansas School of Medicine - Wichita / Clinical Rsch 1010 North Kansas Wichita, KS 67214-3199 Contact: Dal Harrison (316) 261-2855 OPEN 920729. MARYLAND University of Maryland 22 South Greene Street P O Box 243 Baltimore, MD 21201 Contact: Troylynn Maupin (410) 328-3588 OPEN 940502. MINNESOTA HIV Programs / Saint Paul Ramsey Medical Center 640 Jackson St Paul, MN 55101 Contact: Ray Nelson (612) 221-1280 OPEN 920729. MISSOURI St Louis University / Div of Dermatology 1310 South Grand Boulevard St Louis, MO 63104 Contact: Corey Isenberg (314) 268-5215 OPEN 931110. MISSOURI UM KC School of Medicine 2411 Holmes Kansas City, MO 64108 Contact: Larry Simmons (816) 556-3554 CLOSED 940502. MISSISSIPPI Division of Infectious Diseases / UMC 2500 North State Street Jackson, MS 39216 Contact: Harold Henderson (601) 984-5560 OPEN 920729. NEW YORK Beth Israel Medical Center / Department of Infect Diseases 1st Avenue at 16th Street New York, NY 10003 Contact: Peter Berge (212) 420-4519 OPEN 931110. NEW YORK Saint Vincents Hospital and Medical Center 412 Sixth Avenue / Fourth Flr New York, NY 10011 Contact: Noel George (212) 604-8319 OPEN 920729. NEW YORK Mount Sinai Hospital / Clinical Trials Unit One Gustave L Levy Place / Box 1042 New York, NY 10029-6574 Contact: Dr Eileen Chusid (212) 241-8254 OPEN 931110. NEW YORK University of Rochester Medical Center 601 Elmwood Avenue / Box 689 Rochester, NY 14642 Contact: Carol Greisberger (716) 275-0526 OPEN 920729. OREGON Research and Education Group 2701 NW Vaughn Street / Suite 770 Portland, OR 97210-5311 Contact: Norma Martinez (503) 229-8428 Contact: Robin Larson (503) 229-8428 OPEN 920729. PENNSYLVANIA University of Pittsburgh / IDM / Graduate Sch of Public Hlth 130 DeSoto Street / Room A 454 / Crabtree Hall Pittsburgh, PA 15261 Contact: Dr Deborah McMahon (412) 624-7883 CLOSED 940502. PENNSYLVANIA Buckley Braffman Stern Medical Associates PC 822 Pine Street / Suite 3A Philadelphia, PA 19107 Contact: Nancy Pietroski (215) 925-8010 OPEN 931110. RHODE ISLAND Roger Williams Medical Center / Dept of Med / Div of Derm 825 Chalkstone Avenue Providence, RI 02908 Contact: Lisa Crandall (401) 456-6703 CLOSED 940502. 130 UNIQUE IDENTIFIER FDA/00164 PROTOCOL ID NUMBERS FDA 104A PROTOCOL TITLE A Study to Compare the Efficacy and Safety of 256U87 Versus Acyclovir in the Treatment of Recurrent Anogenital Herpes Infections in HIV Infected Patients. TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the safety and efficacy of oral 256U87 vs. acyclovir in the treatment of recurrent anogenital herpes in HIV-infected patients (CD4 = or > 100). Methodology: Efficacy variables include the length of the episode, the time to lesion healing, the duration and severity of pain/discomfort, the duration of viral shedding, the proportion of patients with aborted episodes, the proportion of patients requiring extended therapy. GENERAL DESCRIPTION METHODOLOGY: Efficacy variables include the length of the episode, the time to lesion healing, the duration and severity of pain/discomfort, the duration of viral shedding, the proportion of patients with aborted episodes, the proportion of patients requiring extended therapy. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940502) DISEASE STUDIED Herpes simplex, anogenital. DISEASES STATUS Patients have the following symptoms and conditions: HIV-infected individual (CD4 = or > 100) with a history of recurrent anogenital herpes: 1. Having two or more recurrent episodes within 6 months prior to beginning the study OR 2. Patients previously on chronic, suppressive acyclovir therapy during the past year must experience at least one recurrence after suppressive therapy is discontinued. This recurrence must have occurred within 3 months following the end of suppressive therapy and within 3 months prior to study enrollment. History of HSV infections at genital, perirectal, or closely associated sites (e.g., buttocks). ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS 08 STUDY DESIGN Drug Comparison PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy. PROTOCOL DETAILS ACTUAL ACCRUAL: 579 (940502). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 22 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have the following: HIV-infected individual (CD4 = or > 100) with a history of recurrent anogenital herpes. Signed the consent form or present a signed parental consent form if below 18 years. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CD4/CD8 RATION: >= 100. PATIENT INCLUSION CRIT. SGOT(AST): < 3 x ULN. ULN = upper limit of normal. PATIENT INCLUSION CRIT. SGPT(ALT): < 3 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Abstinence or effective method of birth control / contraception including oral contraceptives during the study. Not breast-feeding. Not pregnant. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following are excluded: Hepatic impairment as evidenced by a three-fold increase from the upper limit of normal in alanine or aspartate transaminase. Impairment of renal function as evidenced by any elevation above the upper limit of normal for serum creatinine. History of hypersensitivity to acyclovir. Malabsorption or vomiting that would, in the investigators opinion, potentially limit the retention and absorption of oral therapy. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Breast-feeding. Pregnant. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Systemic antiherpes or immunomodulatory therapy within 30 days prior to entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following conditions or symptoms are excluded: Hepatic impairments as evidenced by a three-fold increase from the upper limit of normal in alanine or aspartate transaminase. Impairment of renal function as evidenced by any elevation above the upper limit of normal for serum creatinine. History of hypersensitivity to acyclovir. Malabsorption or vomiting that would, in the investigators opinion, potentially limit the retention and absortion of oral therapy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0119 Valaciclovir SUBSTANCE IDENTIFICATION Drug 2 DRG-0008 Acyclovir TRADE NAME OF SUBSTANCE Drug 2‰ Zovirax MANUFACTURERS Drug 1: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. MANUFACTURERS Drug 2: Burroughs Wellcome 3030 Cornwallis Road Research Triangle, NC 27709 Contact: Drug Information (800) 443-6763. SUPPORTING AGENCY Burroughs Wellcome. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Acyclovir/*THERAPEUTIC USE MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antiviral Agents/*THERAPEUTIC USE MESH HEADING Anus Diseases/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Herpes Genitalis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antiviral Agents) CAS REGISTRY NUMBER 59277-89-3 (Acyclovir) LAST REVISION DATE 940502 ENTRY MONTH 9108 ALABAMA Mobile, AL 36688 Contact: Dr Halim (205) 479-6933 CLOSED 940502. CALIFORNIA ViRx Incorporated 1375 Sutter Street / Suite 407 San Francisco, CA 94109 Contact: Joyce Amann (415) 474-4440 Contact: Michael Baker (415) 474-4440 OPEN 910807. CALIFORNIA San Francisco General Hospital 995 Portrero Avenue Bldg 80 Ward 84 San Francisco, CA 94110 Contact: Patricia Duff (415) 431-0790 CLOSED 940502. COLORADO Disease Control Services 605 Bannock Street Denver, CO 80204 Contact: Joan Feil (303) 893-7123 CLOSED 940502. CONNECTICUT Veterans Administration Center / 111-1 950 Campbell Ave West Haven, CT 06516 Contact: Dr Elizabeth Cooney (203) 932-5711 X 374CLOSED 940502. FLORIDA University of South Florida 12901 North Bruce Downs Boulevard Box 19 Tampa, FL 33612 Contact: Vicky Kenyon (813) 974-3163 CLOSED 940502. GEORGIA Emory Medical School / Division of Infectious Diseases 69 Butler Street Atlanta, GA 30303 Contact: Kara Barrett (404) 616-2440 OPEN 920301. ILLINOIS Northwestern Memorial Hospital / Section of Inf Dis 250 East Superior Street Chicago, IL 60611 Contact: Tamara Norman (312) 908-9636 OPEN 920301. ILLINOIS Rush Presbyterian - St Lukes Medical Ctr / Sec of Infect Dis 1725 West Harrison Ave Suite 143 Academic Facility Chicago, IL 60612 Contact: Donna Samano (312) 942-5865 CLOSED 940502. INDIANA Indiana University Medical School 545 Barnhill Drive EM 435 Division of Inf Diseases Indianapolis, IN 46202 Contact: Beth Zwickle (317) 274-8456 Contact: Heather Nixon (317) 274-8456 CLOSED 940502. LOUISIANA Louisianna State University Medical School / Dept of Med 1542 Tulane Avenue HIV Program New Orleans, LA 70112-2822 Contact: Marsha Bennett (504) 568-5304 CLOSED 940502. MISSISSIPPI University of Mississippi Medical Center / Div of Inf Dis 2500 North State Street Jackson, MS 39216 Contact: Dr Harold Henderson (601) 984-5560 CLOSED 940502. NEW MEXICO University of New Mexico / Sch of Medicine / Dept of Med Division of Infectious Disease HSSB 302 Box 608 Albuquerque, NM 87131 Contact: Marianne Butzinger (505) 277-5775 Contact: Marianne Butziner after 5 pm (505) 843-2111 CLOSED 940502. NEW YORK St Vincents Hospital and Medical Center 412 Sixth Ave / 4th Floor New York, NY 10011 Contact: Noel George (212) 604-7625 CLOSED 940502. OHIO University of Cincinnati / Medical Ctr / Div of Infect Dis 231 Bethesda Ave Cincinnati, OH 45267-0560 Contact: Jarlath Black (513) 558-6977 Contact: (513) 558-2245 CLOSED 940502. OREGON Research and Education Group 2701 North West Vaughn Street / Suite 770 Portland, OR 97210 Contact: Norma Martinez (503) 229-8428 CLOSED 940502. RHODE ISLAND Roger Williams Medical Center / Dept of Med / Div of Derm 825 Chalkstone Avenue Providence, RI 02908 Contact: Lisa Crandall (401) 456-6703 CLOSED 940502. 131 UNIQUE IDENTIFIER FDA/00655 PROTOCOL ID NUMBERS FDA 088D PROTOCOL TITLE A Phase I Trial of Tecogalan sodium ( DS-4152 ) Administered as an Infusion Twice Weekly for 21 Days. VERSION NUMBER & DATE (940804) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: To evaluate the safety of different doses and dosing regimens of tecogalan sodium (DS-4152) and to establish the MTD at each of the different dosing schedules. Methodology: Patients receive intravenous DS-4152 by infusion twice weekly for 21 days, followed by 2 weeks of rest; courses may repeat. Patients undergo weekly follow-up. A punch biopsy will be obtained from patients with Kaposi's sarcoma. GENERAL DESCRIPTION METHODOLOGY: Patients receive intravenous DS-4152 by infusion twice weekly for 21 days, followed by 2 weeks of rest; courses may repeat. Patients undergo weekly follow-up. A punch biopsy will be obtained from patients with Kaposi's sarcoma. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (940801) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. EITHER histologically confirmed Kaposi's sarcoma with a minimum of four cutaneous lesions and no symptomatic visceral involvement OR a metastatic solid tumor that does not respond to therapy. 2. HIV positive by ELISA and Western blot (Kaposi's sarcoma patients ONLY). 3. NO symptomatic AIDS-defining opportunistic infection within the past 4 weeks. ELIGIBILITY AIDS. OTHER. OTHER PROTOCOL NUMBERS 4152A-PRT005 STUDY DESIGN Dose Comparison; Dose Escalating; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Maximum tolerated dose (MTD), Drug dosing schedule. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Ongoing. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Kaposi's sarcoma plus HIV infection OR metastatic solid tumor. 2. Life expectancy of at least 12 weeks. 3. NO symptomatic AIDS-defining opportunistic infection within the past 4 weeks. 4. Recovered from toxicity of any prior anticancer therapy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9 g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1200 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.25 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 2.0 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 2.0 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.25 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 60 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 2. (WHO scale). PATIENT INCLUSION CRIT. OTHER: WBC >= 2000 cells/mm3. PT and activated PTT normal. Electrolytes, uric acid, calcium, and phosphorus normal. Blood glucose <= 280 mg/dl. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of acute or chronic gastrointestinal bleeding or inflammatory bowel disease. 2. History of myocardial infarction within past 6 months. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Anticancer therapy within the past 3 weeks (6 weeks for nitrosourea or mitomycin C). 2. Investigational agents within the past 4 weeks. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other anticancer therapy. 2. Other investigational agents. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Leukemia or lymphoma. 2. Current gastrointestinal bleeding by stool guaiac. 3. Extensive bone metastases or significant radiographic osteoporosis in patients with solid tumors. 4. Active heart disease such as uncontrolled angina, uncompensated congestive heart failure, or dysrhythmias requiring antiarrhythmics. 5. Acute intercurrent infection other than genital herpes. 6. Symptomatic or known central nervous system involvement (including brain metastases) unless stable and off therapy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0217 Tecogalan sodium TRADE NAME OF SUBSTANCE Drug 1‰ DS-4152 MANUFACTURERS Drug 1: Daiichi Pharmaceutical Corporation 400 Kelby Street / One Parker Plaza Fort Lee, NJ 07024 Contact: Tom Boersig (201) 944-4333 X 212. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1 infusion twice weekly for 21 days SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Disease progression. 2. Unacceptable toxicity. SUPPORTING AGENCY Daiichi Pharmaceutical Corporation. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Antineoplastic Agents/ADMINISTRATION & DOSAGE/ *ADVERSE EFFECTS MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Neoplasms/*DRUG THERAPY MESH HEADING Polysaccharides, Bacterial/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antineoplastic Agents) CAS REGISTRY NUMBER 134633-29-7 (DS 4152) LAST REVISION DATE 940801 ENTRY MONTH 9409 CALIFORNIA UCSS AIDS Program / San Francisco General Hospital 995 Potereo Ave / Bldg 8 / Ward 84 San Francisco, CA 94110 Contact: Dr James Kahn (415) 476-9296 OPEN 940801. 132 UNIQUE IDENTIFIER FDA/00654 PROTOCOL ID NUMBERS FDA 088C PROTOCOL TITLE A Phase I Trial of Tecogalan sodium ( DS-4152 ) Administered as an Infusion Twice Weekly for 21 Days. VERSION NUMBER & DATE (940804) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: To evaluate the safety of different doses and dosing regimens of tecogalan sodium (DS-4152) and to establish the MTD at each of the different dosing schedules. Methodology: Patients receive intravenous DS-4152 by infusion twice weekly for 21 days, followed by 2 weeks of rest; courses may repeat. Patients undergo weekly follow-up. A punch biopsy will be obtained from patients with Kaposi's sarcoma. GENERAL DESCRIPTION METHODOLOGY: Patients receive intravenous DS-4152 by infusion twice weekly for 21 days, followed by 2 weeks of rest; courses may repeat. Patients undergo weekly follow-up. A punch biopsy will be obtained from patients with Kaposi's sarcoma. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (930801) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. EITHER histologically confirmed Kaposi's sarcoma with a minimum of four cutaneous lesions and no symptomatic visceral involvement OR a metastatic solid tumor that does not respond to therapy. 2. HIV positive by ELISA and Western blot (Kaposi's sarcoma patients ONLY). 3. NO symptomatic AIDS-defining opportunistic infection within the past 4 weeks. ELIGIBILITY AIDS. OTHER. OTHER PROTOCOL NUMBERS 4152A-PRT004 STUDY DESIGN Dose Comparison; Dose Escalating; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Maximum tolerated dose (MTD), Drug dosing schedule. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Ongoing. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Kaposi's sarcoma plus HIV infection OR metastatic solid tumor. 2. Life expectancy of at least 12 weeks. 3. NO symptomatic AIDS-defining opportunistic infection within the past 4 weeks. 4. Recovered from toxicity of any prior anticancer therapy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9 g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1200 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.25 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 2.0 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 2.0 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.25 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 60 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 2. (WHO scale). PATIENT INCLUSION CRIT. OTHER: WBC >= 2000 cells/mm3. PT and activated PTT normal. Electrolytes, uric acid, calcium, and phosphorus normal. Blood glucose <= 280 mg/dl. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of acute or chronic gastrointestinal bleeding or inflammatory bowel disease. 2. History of myocardial infarction within past 6 months. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Anticancer therapy within the past 3 weeks (6 weeks for nitrosourea or mitomycin C). 2. Investigational agents within the past 4 weeks. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other anticancer therapy. 2. Other investigational agents. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Leukemia or lymphoma. 2. Current gastrointestinal bleeding by stool guaiac. 3. Extensive bone metastases or significant radiographic osteoporosis in patients with solid tumors. 4. Active heart disease such as uncontrolled angina, uncompensated congestive heart failure, or dysrhythmias requiring antiarrhythmics. 5. Acute intercurrent infection other than genital herpes. 6. Symptomatic or known central nervous system involvement (including brain metastases) unless stable and off therapy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0217 Tecogalan sodium TRADE NAME OF SUBSTANCE Drug 1‰ DS-4152 MANUFACTURERS Drug 1: Daiichi Pharmaceutical Corporation 400 Kelby Street / One Parker Plaza Fort Lee, NJ 07024 Contact: Tom Boersig (201) 944-4333 X 212. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1 infusion twice weekly for 21 days, followed by 2 weekof rest SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Disease progression. 2. Unacceptable toxicity. SUPPORTING AGENCY Daiichi Pharmaceutical Corporation. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Antineoplastic Agents/ADMINISTRATION & DOSAGE/ *ADVERSE EFFECTS MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Neoplasms/*DRUG THERAPY MESH HEADING Polysaccharides, Bacterial/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antineoplastic Agents) CAS REGISTRY NUMBER 134633-29-7 (DS 4152) LAST REVISION DATE 930801 ENTRY MONTH 9409 NEW YORK Memorial Sloan Kettering Cancer Center 1275 York Avenue / Room H-804 New York, NY 10021 Contact: Dr Susan Krown (212) 639-7426 OPEN 930801. 133 UNIQUE IDENTIFIER FDA/00653 PROTOCOL ID NUMBERS FDA 088B PROTOCOL TITLE A Phase I Trial of Tecogalan sodium ( DS-4152 ) Administered as an Infusion Weekly x 4. VERSION NUMBER & DATE (940804) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: To evaluate the safety of different doses and dosing regimens of tecogalan sodium (DS-4152) and to establish the MTD at each of the different dosing schedules. Methodology: Patients receive intravenous DS-4152 by infusion weekly for 4 weeks, followed by 2 weeks of rest; courses may repeat. Patients undergo weekly follow-up. A punch biopsy will be obtained from patients with Kaposi's sarcoma. GENERAL DESCRIPTION METHODOLOGY: Patients receive intravenous DS-4152 by infusion weekly for 4 weeks, followed by 2 weeks of rest; courses may repeat. Patients undergo weekly follow-up. A punch biopsy will be obtained from patients with Kaposi's sarcoma. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (930501) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. EITHER histologically confirmed Kaposi's sarcoma with a minimum of four cutaneous lesions and no symptomatic visceral involvement OR a metastatic solid tumor that does not respond to therapy. 2. HIV positive by ELISA and Western blot (Kaposi's sarcoma patients ONLY). 3. NO symptomatic AIDS-defining opportunistic infection within the past 4 weeks. ELIGIBILITY AIDS. OTHER. OTHER PROTOCOL NUMBERS 4152A-PRT002 STUDY DESIGN Dose Comparison; Dose Escalating; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Maximum tolerated dose (MTD), Drug dosing schedule. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Ongoing. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Kaposi's sarcoma plus HIV infection OR metastatic solid tumor. 2. Life expectancy of at least 12 weeks. 3. NO symptomatic AIDS-defining opportunistic infection within the past 4 weeks. 4. Recovered from toxicity of any prior anticancer therapy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9 g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1200 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <=1.25 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 2.0 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 2.0 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.25 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 60 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 2. (WHO scale). PATIENT INCLUSION CRIT. OTHER: WBC >= 2000 cells/mm3. PT and activated PTT normal. Electrolytes, uric acid, calcium, and phosphorus normal. Blood glucose <= 280 mg/dl. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of acute or chronic gastrointestinal bleeding or inflammatory bowel disease. 2. History of myocardial infarction within past 6 months. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Anticancer therapy within the past 3 weeks (6 weeks for nitrosourea or mitomycin C). 2. Investigational agents within the past 4 weeks. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other anticancer therapy. 2. Other investigational agents. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Leukemia or lymphoma. 2. Current gastrointestinal bleeding by stool guaiac. 3. Extensive bone metastases or significant radiographic osteoporosis in patients with solid tumors. 4. Active heart disease such as uncontrolled angina, uncompensated congestive heart failure, or dysrhythmias requiring antiarrhythmics. 5. Acute intercurrent infection other than genital herpes. 6. Symptomatic or known central nervous system involvement (including brain metastases) unless stable and off therapy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0217 Tecogalan sodium TRADE NAME OF SUBSTANCE Drug 1‰ DS-4152 MANUFACTURERS Drug 1: Daiichi Pharmaceutical Corporation 400 Kelby Street / One Parker Plaza Fort Lee, NJ 07024 Contact: Tom Boersig (201) 944-4333 X 212. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1 infusion weekly for 4 weeks, followed by 2 weeks of rest SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Disease progression. 2. Unacceptable toxicity. SUPPORTING AGENCY Daiichi Pharmaceutical Corporation. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Antineoplastic Agents/ADMINISTRATION & DOSAGE/ *ADVERSE EFFECTS MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Neoplasms/*DRUG THERAPY MESH HEADING Polysaccharides, Bacterial/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antineoplastic Agents) CAS REGISTRY NUMBER 134633-29-7 (DS 4152) LAST REVISION DATE 930501 ENTRY MONTH 9409 CALIFORNIA Univ of Southern California / Kenneth Norris Jr Cancer Ctr 1441 Eastlake Avenue / Room 162 Los Angeles, CA 90033 Contact: Dr Anil Tulpule (213) 224-6668 OPEN 930501. 134 UNIQUE IDENTIFIER FDA/00652 PROTOCOL ID NUMBERS FDA 088A PROTOCOL TITLE A Phase I Trial of Tecogalan sodium ( DS-4152 ) Administered as an Infusion Every 21 Days. VERSION NUMBER & DATE (940804) TRIAL CATEGORY AIDS-Related Malignancies GENERAL DESCRIPTION PURPOSE: To evaluate the safety of different doses and dosing regimens of tecogalan sodium (DS-4152) and to establish the MTD at each of the different dosing schedules. Methodology: Patients receive intravenous DS-4152 by infusion once every 21 days; courses may repeat. Patients undergo weekly follow-up. A punch biopsy will be obtained from patients with Kaposi's sarcoma. GENERAL DESCRIPTION METHODOLOGY: Patients receive intravenous DS-4152 by infusion once every 21 days; courses may repeat. Patients undergo weekly follow-up. A punch biopsy will be obtained from patients with Kaposi's sarcoma. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (930401) DISEASE STUDIED Kaposi's sarcoma. DISEASES STATUS Patients have the following symptoms and conditions: 1. EITHER histologically confirmed Kaposi's sarcoma with a minimum of four cutaneous lesions and no symptomatic visceral involvement OR a metastatic solid tumor that does not respond to therapy. 2. HIV positive by ELISA and Western blot (Kaposi's sarcoma patients ONLY). 3. NO symptomatic AIDS-defining opportunistic infection within the past 4 weeks. ELIGIBILITY AIDS. OTHER. OTHER PROTOCOL NUMBERS 4152A-PRT001 STUDY DESIGN Dose Comparison; Dose Escalating; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety, Maximum tolerated dose (MTD), Drug dosing schedule. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Ongoing. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Kaposi's sarcoma plus HIV infection OR metastatic solid tumor. 2. Life expectancy of at least 12 weeks. 3. NO symptomatic AIDS-defining opportunistic infection within the past 4 weeks. 4. Recovered from toxicity of any prior anticancer therapy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9 g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1200 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 100000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 1.25 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 2.0 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 2.0 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.25 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 60 ml/min. (if creatinine value unavailable). PATIENT INCLUSION CRIT. KARNOFSKY: >= 2. (WHO scale). PATIENT INCLUSION CRIT. OTHER: WBC >= 2000 cells/mm3. PT and activated PTT normal. Electrolytes, uric acid, calcium, and phosphorus normal. Blood glucose <= 280 mg/dl. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of acute or chronic gastrointestinal bleeding or inflammatory bowel disease. 2. History of myocardial infarction within past 6 months. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Anticancer therapy within the past 3 weeks (6 weeks for nitrosourea or mitomycin C). 2. Investigational agents within the past 4 weeks. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other anticancer therapy. 2. Other investigational agents. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Leukemia or lymphoma. 2. Current gastrointestinal bleeding by stool guaiac. 3. Extensive bone metastases or significant radiographic osteoporosis in patients with solid tumors. 4. Active heart disease such as uncontrolled angina, uncompensated congestive heart failure, or dysrhythmias requiring antiarrhythmics. 5. Acute intercurrent infection other than genital herpes. 6. Symptomatic or known central nervous system involvement (including brain metastases) unless stable and off therapy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0217 Tecogalan sodium TRADE NAME OF SUBSTANCE Drug 1‰ DS-4152 MANUFACTURERS Drug 1: Daiichi Pharmaceutical Corporation 400 Kelby Street / One Parker Plaza Fort Lee, NJ 07024 Contact: Tom Boersig (201) 944-4333 X 212. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 1 infusion q 21 days SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Disease progression. 2. Unacceptable toxicity. SUPPORTING AGENCY Daiichi Pharmaceutical Corporation. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Antineoplastic Agents/ADMINISTRATION & DOSAGE/ *ADVERSE EFFECTS MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Neoplasms/*DRUG THERAPY MESH HEADING Polysaccharides, Bacterial/ADMINISTRATION & DOSAGE/*ADVERSE EFFECTS MESH HEADING Sarcoma, Kaposi's/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Antineoplastic Agents) CAS REGISTRY NUMBER 134633-29-7 (DS 4152) LAST REVISION DATE 930401 ENTRY MONTH 9409 135 UNIQUE IDENTIFIER FDA/00620 PROTOCOL ID NUMBERS FDA 087A PROTOCOL TITLE A Randomized, Controlled, Multicenter Trial of Filgrastim (Recombinant-methionyl Human Granulocyte Colony Stimulating Factor; G-CSF) for the Prevention of Grade 4 Neutropenia in Patients With HIV Infection. VERSION NUMBER & DATE (940112) TRIAL CATEGORY HIV Infection GENERAL DESCRIPTION PURPOSE: To determine, in HIV-infected patients, the efficacy of filgrastim (recombinant-methionyl human granulocyte-colony stimulating factor; G-CSF) in preventing grade 4 neutropenia, i.e., absolute neutrophil count (ANC) < 500 cells/mm3. Methodology: Patients are randomized to receive subcutaneous G-CSF at one of two different doses or no G-CSF (observation) for 24 weeks. Patients who experience ANC < 500 cells/mm3 on two consecutive occasions at least 24 hours apart prior to completing the 24-week study period will be considered to have reached the primary study endpoint; those in the observation group who reach the primary endpoint prior to week 24 may begin receiving G-CSF for the remainder of the study period. After 24 weeks, patients may continue G-CSF on a compassionate basis at the investigator's discretion. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive subcutaneous G-CSF at one of two different doses or no G-CSF (observation) for 24 weeks. Patients who experience ANC < 500 cells/mm3 on two consecutive occasions at least 24 hours apart prior to completing the 24-week study period will be considered to have reached the primary study endpoint; those in the observation group who reach the primary endpoint prior to week 24 may begin receiving G-CSF for the remainder of the study period. After 24 weeks, patients may continue G-CSF on a compassionate basis at the investigator's discretion. PROTOCOL PHASE Phase II / Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940112) DISEASE STUDIED Neutropenia. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV positive by ELISA confirmed by Western blot OR documented history of AIDS by CDC definition. 2. CD4 count < 200 cells/mm3. 3. ANC (segmental neutrophils plus bands) >= 750 and < 1000 cells/mm3 on one occasion within 7 days prior to study entry. NOTE: Stable Kaposi's sarcoma is permitted provided patient does not require myelosuppressive therapy (other than interferon) within 4 weeks prior to study entry. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS GCSF-930101 STUDY DESIGN Randomized; Controlled; Open Label; Multicenter; Dose Comparison PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug prophylaxis. PROTOCOL DETAILS PROJECTED ACCRUAL: 250 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: At least 24 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 22 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection OR history of AIDS. 2. CD4 count < 200 cells/mm3. 3. ANC (segmental neutrophils plus bands) >= 750 and < 1000 cells/mm3 within 7 days prior to study entry. 4. Life expectancy of at least 6 months. NOTE: Stable Kaposi's sarcoma is permitted provided patient does not require myelosuppressive therapy (other than interferon) within 4 weeks prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: < 200 cells/mm3. ( 0 - 100 ). PATIENT INCLUSION CRIT. KARNOFSKY: >= 50. PATIENT INCLUSION CRIT. OTHER: ANC >= 750 and < 1000 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Prior antiretroviral agents (e.g., AZT, ganciclovir, ddI, ddC), trimethoprim-sulfamethoxazole (Bactrim), interferon, and amphotericin B. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Antiretroviral agents (e.g., AZT, ganciclovir, ddI, ddC), trimethoprim-sulfamethoxazole (Bactrim), interferon, and amphotericin B ONLY IF patient is on the same dose for at least 14 days prior to study entry (patients may not start or stop these agents within 14 days prior to study entry). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Substance abuse the would compromise compliance. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: G-CSF, other hematopoietic growth factors (except for erythropoietin), or investigational agents within 14 days prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Malignancy other than Kaposi's sarcoma and localized basal or squamous cell carcinoma. 2. Psychiatric, addictive, or other disorder that compromises ability to give informed consent. 3. Known hypersensitivity to E. coli-derived products. SUBSTANCE IDENTIFICATION Drug 1 DRG-0086 Granulocyte colony-stimulating factor TRADE NAME OF SUBSTANCE Drug 1‰ Neupogen MANUFACTURERS Drug 1: Amgen Inc Amgen Center Thousand Oaks, CA 91320-1789 Contact: David Kaye (805) 447-6692. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Injected at one of two doses for at least 24 weeks SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Subcutaneous OTHER TREATMENT INFO. TREATMENT DURATION: At least 24 weeks. OTHER TREATMENT INFO. END POINT: Development of neutropenia. SUPPORTING AGENCY Amgen Inc. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Granulocyte Colony-Stimulating Factor/ *ADMINISTRATION & DOSAGE/THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Neutropenia/COMPLICATIONS/*PREVENTION & CONTROL CAS REGISTRY NUMBER 62683-29-8 (Granulocyte Colony-Stimulating Factor) LAST REVISION DATE 940112 ENTRY MONTH 9404 ALABAMA University of Alabama / AIDS Outpatient Clinic 908 South 20th Street Birmingham, AL 35294 Contact: Jill Weingarten (205) 934-3690 Contact: Dr Jill Weingarten (205) 934-1714 OPEN 940112. ARIZONA Maricopa County Medical Center 2601 East Roosevelt Phoenix, AZ 85008 Contact: Emily Cardoza (602) 681-1100 OPEN 940112. CALIFORNIA UCLA / CARE Center 10833 Le Conte Ave Los Angeles, CA 90024 Contact: Susie McCarthy (310) 206-6414 OPEN 940112. CALIFORNIA San Francisco General Hospital 1001 Potrero Avenue Building 80 Ward 84 San Francisco, CA 94110 Contact: Mary Payne (415) 476-4082 X 846OPEN 940112. CALIFORNIA Sunnybrook Health Science Center 2075 Bayview Avenue Toronto, CA M4N 3M5 Contact: Miriam Bast (416)480-4689 OPEN 940112. CALIFORNIA The Toronto Hospital 200 Elizabeth Street / CW Ground 325 Toronto, CA M5G 2C9 Contact: Susan Klys (416)340-4239 OPEN 940112. CALIFORNIA St Michael Hospital 30 Bond Street Toronto, CA M5B 1W8 Contact: Manual Laurel (416)864-5746 OPEN 940112. CALIFORNIA Hotel - Dieu de Montreal 3981 St. Laurent Blvd / Mezz 1 Montreal, CA H2W 1Y5 Contact: Catherine L'Homme 5148432712 OPEN 940112. CALIFORNIA The Wellesley Hospital Toronto, CA M5B 1WB Contact: Barry Milton (416)926-7728 OPEN 940112. COLORADO University Hospital / Univ of Colorado Health Sci Ctr Box B-163 / 4200 East Ninth Avenue Denver, CO 80262 Contact: Graham Ray (303) 270-8551 OPEN 940112 ACTU: 0105. DISTRICT OF COLUMBIA George Washington University / Medical Center / Div Inf Dise 2150 Pennsylvania Ave NW Washington, DC 20037 Contact: Susan LeLacheruri (202) 994-2417 OPEN 940112. FLORIDA Therafirst Medical Center 4011 N Federal Highway Ft Lauderdale, FL 33308 Contact: Denise LaMarca (305) 564-4222 OPEN 940112. ILLINOIS Rush Presbyterian - St Lukes / Northwestern University 303 East Superior Street Rm 823 Chicago, IL 60611 Contact: Baiba L Berzins (312) 908-9636 OPEN 940112 ACTU: 2702. KANSAS University of Kansas / School of Medicine 1010 N Kansas Wichita, KS 67214 Contact: Katherine Thiessen (316) 261-2655 OPEN 940112. LOUISIANA Tulane University Medical School / AIDS Clinical Trials Unit 1430 Tulane Avenue New Orleans, LA 70112-2699 Contact: Russell Strada (504) 584-3605 OPEN 940112. MASSACHUSETTS New England Deaconess Hospital 110 Francis Street Boston, MA 02215 Contact: Judy Tessitore (617) 632-8514 Contact: Dr David Scadden (617) 632-8540 OPEN 940112. NORTH CAROLINA Nalle Clinic 1350 South Kings Drive Charlotte, NC 28287 Contact: Jan Caldwell (704) 342-8100 Contact: Dr Joseph Jemsek (704) 342-8318 OPEN 940112. NEW YORK SUNY at Stony Brook HSC T15 080 Stony Brook, NY 11794 Contact: Christine Wallace (516) 444-3904 OPEN 940112. OHIO University Hospitals of Cleveland/Case Western Reserve Univ 206 Cornell Road Cleveland, OH 44106 Contact: Michael Chance (216) 844-8175 OPEN 940112. OREGON Northwest Kaiser Permanente Med Ctr / Dept of Hemat/Oncol 3414 N Kaiser Center Drive Portland, OR 97227 Contact: Michael Allison (503) 249-3313 Contact: Dr Mark Rarick (503) 249-3430 OPEN 940112. OTHER St Paul Hospital 1061 Burrard Street Vancouver, BC V6Z 1Y6 Contact: Dr Kathy Mandigo 6046822344 x3176 OPEN 940112. 136 UNIQUE IDENTIFIER FDA/00563 PROTOCOL ID NUMBERS FDA 085A PROTOCOL TITLE A Phase I Study of Subcutaneously Administered Recombinant Interleukin-2 (Aldesleukin; Proleukin) in HIV-Infected Patients. VERSION NUMBER & DATE (930811) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To determine the MTD and dose-limiting toxicities of recombinant interleukin-2 (aldesleukin; Proleukin) administered subcutaneously in HIV-seropositive patients. To identify a tolerable subcutaneous regimen that will replicate the immunologic improvement demonstrated in the outpatient polyethylene glycolated IL-2 and high-dose continuous infusion IL-2 studies. To evaluate the incidence and level of anti-IL-2 antibody formation to subcutaneously administered Proleukin in this patient population. Methodology: Patients will receive subcutaneous Proleukin, and the MTD will be determined. GENERAL DESCRIPTION METHODOLOGY: Patients will receive subcutaneous Proleukin, and the MTD will be determined. PROTOCOL PHASE Phase I OPEN/CLOSED INDICATOR Open: Actively accruing patients (941018) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Documented HIV infection by ELISA and Western blot. 2. CD4 count > 200 cells/mm3. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS CS-L293-09. BB-IND 5223 STUDY DESIGN Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Maximum tolerated dose (MTD), Drug safety, Drug tolerance, Immunotherapy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection by ELISA and Western blot. 2. CD4 count > 200 cells/mm3. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 9 g/dl. PATIENT INCLUSION CRIT. GRANULOCYTES: >= 1000 cells/mm3. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: > 200 cells/mm3. ( 200 - 300 - 400 - 500 - 600 - 700 - 800 - plus ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 70. PATIENT INCLUSION CRIT. OTHER: Proteinuria <= 1+. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: FDA-approved antiretroviral therapy for at least 2 months prior to study entry. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. SUBSTANCE IDENTIFICATION Drug 1 DRG-0021 Interleukin-2 TRADE NAME OF SUBSTANCE Drug 1‰ Proleukin MANUFACTURERS Drug 1: Cetus Corporation 1400 Fifty-Third Street Emeryville, CA 94608 Contact: Professional Services (800) 238-8779. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Subcutaneous (SC) SUPPORTING AGENCY Cetus Corporation. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Interleukin-2/*ADVERSE EFFECTS MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Interleukin-2) LAST REVISION DATE 941018 ENTRY MONTH 9310 CALIFORNIA Davies Medical Center / Institute - HIV Research & Treatment Castro and Duboce Streets San Francisco, CA 94114 Contact: Dr Stephen Follansbee (415) 565-6153 Contact: (415) 565-6524 OPEN 930811. 137 UNIQUE IDENTIFIER FDA/00464 PROTOCOL ID NUMBERS FDA 083A PROTOCOL TITLE Treatment of Patients With Human Immunodeficiency Virus (HIV)-Related Chronic Diarrhea With Saccharomyces boulardii or Placebo: A Double Blind Trial. VERSION NUMBER & DATE (940304) TRIAL CATEGORY Opportunistic Infections PROTOCOL CHAIRS CHAIR Surawicz CM GENERAL DESCRIPTION PURPOSE: To assess the efficacy of Saccharomyces boulardii (a nonpathogenic yeast) in producing a significant reduction in diarrheal symptoms in HIV-infected patients with chronic diarrhea PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940304) DISEASE STUDIED Diarrhea. DISEASES STATUS Patients have the following symptoms and conditions: 1. Documented HIV infection. 2. Chronic diarrhea (for at least 1 month) that is either a manifestation or complication of documented HIV infection. 3. Has had a stool culture (Salmonella, Shigella, Campylobacter, and Clostridium difficile) and stool analysis for ova and parasite (O/P X 3) within the past 2 months. 4. Has completed a specific course of antimicrobial treatment for diarrhea, if indicated, but was unresponsive (diarrhea still present), OR no antimicrobials for stool pathogens were administered because stool cultures were negative. Patients who are on antiviral medications for HIV infection must have received such medication for at least 2 weeks and must remain on stable dose for weeks 1 and 2 of study. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS BB-IND 2065 STUDY DESIGN Double-Blind; Placebo-Controlled; Randomized PROTOCOL DETAILS STUDY INTENT: Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 100 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 3 months (2 months on drug and 1 month follow-up). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. Chronic diarrhea (for at least 1 month) that is either a manifestation or complication of documented HIV infection. 3. Had a stool culture (Salmonella, Shigella, Campylobacter, and Clostridium difficile) and stool analysis for ova and parasite (O/P X 3) within the past 2 months. 4. Failed antimicrobial treatment for diarrhea OR received no prior antimicrobials for stool pathogens because stool cultures were negative. Patients who are on antiviral medications for HIV infection must have received such medication for at least 2 weeks and must remain on stable dose for weeks 1 and 2 of study. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: 1. Prior antiviral medication for HIV infection (if on such medication, must have received it for at least 2 weeks). 2. Standard antimicrobial therapy for a documented positive gastrointestinal pathogen. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Antiviral medication for HIV infection. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Gastrointestinal medications that cause diarrhea (e.g., magnesium-containing antacids, lactulose). 2. Maintenance antifungal medication for life-threatening fungal infections (other than fluconazole <= 100 mg/day). PATIENT EXCLUSION CRIT. AVAILABILITY: Patients with no telephone in residence are not eligible. SUBSTANCE IDENTIFICATION Drug 1 DRG-0149 Saccharomyces boulardii MANUFACTURERS Drug 1: Biocodex Inc 1910 Fairview Avenue E / Suite 208 Seattle, WA 98102-3699 Contact: Kris Moyer (206) 322-5602. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, capsules SUPPORTING AGENCY Biocodex Inc. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Diarrhea/COMPLICATIONS/*THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Saccharomyces/*PHYSIOLOGY LAST REVISION DATE 940304 ENTRY MONTH 9210 138 UNIQUE IDENTIFIER FDA/00607 PROTOCOL ID NUMBERS FDA 059F PROTOCOL TITLE A Randomized Study Comparing the Safety and Efficacy of Three Doses of Oral Ganciclovir to Intravenous Ganciclovir for the Maintenance Treatment of Cytomegalovirus Retinitis in People With AIDS. VERSION NUMBER & DATE (940316) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To compare the time to progression of Cytomegalovirus (CMV) retinitis among each of three doses of oral ganciclovir (3000, 4500, and 6000 mg daily), as well as to intravenous therapy (5 mg/kg daily), when given as maintenance for 26 weeks. To compare the safety and tolerance among oral doses of ganciclovir at the study doses, as well as to intravenous therapy, when administered as maintenance for 26 weeks. Methodology: Patients who have received anti-CMV therapy with intravenous ganciclovir for at least 4 weeks that resulted in stable retinitis are randomized to receive one of three doses of oral ganciclovir or intravenous ganciclovir for 26 weeks of maintenance. GENERAL DESCRIPTION METHODOLOGY: Patients who have received anti-CMV therapy with intravenous ganciclovir for at least 4 weeks that resulted in stable retinitis are randomized to receive one of three doses of oral ganciclovir or intravenous ganciclovir for 26 weeks of maintenance. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940613) DISEASE STUDIED Cytomegalovirus retinitis ( CMV retinitis ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV positive by antibody test, p24 antigen assay, or HIV culture, or diagnosis of AIDS by CDC criteria. 2. No more than two episodes of CMV retinitis progression (relapse resulting in reinduction with intravenous anti-CMV therapy) since the original retinitis diagnosis. 3. Currently stable retinitis, defined as inactive CMV retinal lesions or as progression that has halted following at least 4 weeks of intravenous ganciclovir therapy immediately prior to study entry. (If retinal lesions are not inactive, stability of the retinitis must have been confirmed based on the last two ophthalmologic exams.) ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS GANs2226 STUDY DESIGN Randomized; Dose Comparison; Comparative administration route; Drug Tolerance; Parallel-Group; Multicenter PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Administration route comparison. PROTOCOL DETAILS PROJECTED ACCRUAL: 280 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 26 weeks. PROTOCOL DETAILS ACTUAL ACCRUAL: 8/280 (940218). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 36 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV positive. 2. No more than two episodes of CMV retinitis progression (relapse resulting in reinduction with intravenous anti-CMV therapy) since the original retinitis diagnosis. 3. Currently stable retinitis. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: >= 25000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 500 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Foscarnet prior to the 4 weeks of intravenous induction therapy. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Topical and ophthalmic nucleoside analogs. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of hypersensitivity to acyclovir or ganciclovir. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. More than three induction regimens with intravenous anti-CMV therapy. 2. Any prior oral ganciclovir. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Acyclovir sodium (Zovirax) by any route other than topical. 2. Valaciclovir. 3. Brovavir. 4. Vidarabine. 5. Amantadine hydrochloride. 6. Cytarabine. 7. Idoxuridine. 8. Ribavirin. 9. Interferon. 10. Foscarnet (non-nucleoside pyrophosphate analog). 11. CMV hyperimmune globulin. 12. Soluble CD4. 13. Trichosanthin (Compound Q). 14. Imipenem-cilastatin. 15. Isoprinosine. 16. Levamisole. 17. Other investigational drugs. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Persistent or clinically significant diarrhea, nausea, or abdominal pain. 2. Severe odynophagia. 3. Other gastrointestinal (GI) symptoms or uncontrolled GI disease. 4. Active CMV disease of the GI tract (e.g., CMV colitis, CMV esophagitis). 5. Ocular media opacities (corneal, lenticular, or vitreal) that prevent ophthalmologic retinal assessments. 6. Dementia, decreased mentation, or other encephalopathic signs and symptoms that would preclude informed consent or study compliance. SUBSTANCE IDENTIFICATION Drug 1 DRG-0018 Ganciclovir TRADE NAME OF SUBSTANCE Drug 1‰ Cytovene MANUFACTURERS Drug 1: Syntex Research 3401 Hillview Avenue / PO Box 10850 / Mail Stop A4-HPRA Palo Alto, CA 94303 Contact: Bonnie Charpentier (415) 354-2344. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Oral dose: 1000, 1500, or 2000 mg TID for 26 weeks. Intravenous dose: 5 mg/kg daily for 26 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: Oral: 3000, 4500, or 6000 mg. Intravenous: 5 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral or intravenous (IV) OTHER TREATMENT INFO. TREATMENT DURATION: 26 weeks. SUPPORTING AGENCY Syntex Research. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Cytomegalovirus Infections/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Female MESH HEADING Ganciclovir/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Retinitis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 82410-32-0 (Ganciclovir) LAST REVISION DATE 940613 ENTRY MONTH 9403 ALABAMA University of Alabama / AIDS Outpatient Clinic 908 South 20th Street Birmingham, AL 35294 Contact: Jill Weingarten (205) 934-3690 Contact: Dr Jill Weingarten (205) 934-1714 OPEN 940218. ARIZONA McDowell Clinic 1314 East McDowell Phoenix, AZ 85006 Contact: Mary Mulrow (602) 267-5011 OPEN 940218. ARIZONA Dr Ken Fisher 1444 West Betharmy Home Road Phoenix, AZ 85013 Contact: Ken Reed (602) 433-7712 OPEN 940218. ARIZONA University of Arizona / Section of Infectious Diseases 1501 North Campbell Avenue Tucson, AZ 85724 Contact: Joel Gray (602) 626-2533 OPEN 940218. CALIFORNIA UCLA AIDS Clinical Research Center / BH-412 CHS 10833 Le Conte Avenue / BH - 412 / CHS Los Angeles, CA 90024-1793 Contact: Suzette Chafey (310) 206-6414 Contact: Dr David Hardy (310) 206-3474 OPEN 940218. CALIFORNIA University of California San Diego Medical Center / Dept Ped H - 814 - H / 225 Dickenson San Diego, CA 92103 Contact: Linda Meixner (619) 534-7170 OPEN 940218. CALIFORNIA Davies Medical Center / Institute for HIV Treatment and Rsch Castro and Duboce Streets San Francisco, CA 94114 Contact: Sue Kelly (415) 565-6153 OPEN 940218. CALIFORNIA Mt Zion Hospital and Medical Center / Dep of Clinical Micro 1600 Divisadero / Second Floor San Francisco, CA 94115 Contact: Craig James (415) 476-6356 OPEN 940218. CALIFORNIA San Francisco Veterans' Administration Medical Center 4150 Clement Street #111W San Francisco, CA 94121 Contact: Manon Marovich (415) 221-4810 X 394Contact: Sandra Charles (415) 221-4810 X 394OPEN 940218 ACTU: 0807. CALIFORNIA East Bay AIDS Clinic 3031 Telegraph Avenue Berkeley, CA 94705 Contact: Nancy Orcutt (510) 204-1870 OPEN 940218. DISTRICT OF COLUMBIA George Washington Medical Center / Division Infectious Disea Room 5-408 / 2150 Pennsylvania Avenue Washington, DC 20037 Contact: Dr David Parenti (202) 994-3949 OPEN 940218. FLORIDA Community Research Initiative 1506 San Ignacio Avenue / Suite 200 Coral Gables, FL 33146 Contact: Lexi East (305) 667-9296 OPEN 940218. GEORGIA AIDS Research Consortium of Atlanta 131 Ponce de Leon / Suite 130 Atlanta, GA 30308 Contact: Lisa Ferrigno (404) 876-2317 OPEN 940218. HAWAII Margo Heath-Chiozzi 3675 Kilauea Avenue / Young Bldg / Room 16E Honolulu, HI 96816 Contact: Sue Congdon (808) 737-0036 OPEN 940218. MARYLAND University of Maryland School of Medicine / Research Service 10 North Green Street Baltimore, MD 21201 Contact: Dr Susan Keay (410) 605-7000 X 645OPEN 940218. MISSOURI AIDS Clinical Trials Unit 4511 Forest Park / Suite 304 St Louis, MO 63108 Contact: Janet Voorhese (314) 454-0058 OPEN 940218. NORTH CAROLINA University of North Carolina at Chapel Hill / UNC CTU 516 Burnett Womack / CB# 7215 Chapel Hill, NC 27599-7215 Contact: Barbara Longmire (919) 966-7883 OPEN 940218. NORTH CAROLINA Nalle Clinic 1350 South Kings Drive Charlotte, NC 28207-2198 Contact: Angela Chouffani (704) 344-2280 OPEN 940218. NEW MEXICO University of New Mexico / Department of Medicine HSSB - 302 Albuquerque, NM 87131 Contact: Maria Fernando-Fletcher (505) 277-8207 OPEN 940218. NEW MEXICO AIDS Wellness Clinic 811 St Michaels Drive / Suite P Sante Fe, NM 87501 Contact: Patty Dally (505) 983-1822 OPEN 940218. NEVADA AIDS Outpatient Services / University Medical Center 1800 West Charleston Blvd Las Vegas, NV 89102 Contact: Ann Occhl (702) 383-7075 OPEN 940218. NEW YORK Dr Dorothy Friedberg 310 Lexington Avenue New York, NY 10016 Contact: Kathleen Farrell (212) 263-6485 Contact: Dr Dorothy Friedberg (212) 263-8473 OPEN 940218. NEW YORK St Lukes - Roosevelt Hospital / AIDS Clinical Trials Program 432 West 58th Street New York, NY 10019 Contact: Brenda Kolatch (212) 523-6743 OPEN 940218. NEW YORK The New York Hospital / Cornell Medical Center 525 East 68th Street / Baker 24 New York, NY 10021 Contact: Sandi Slertz (212) 748-4177 OPEN 940218. OHIO Ohio State University School of Medicine 456 West Tenth Avenue / Room 4725 Columbus, OH 43210-1228 Contact: Judith Neidig (614) 293-8112 Contact: (614) 293-5282 OPEN 940218. OHIO Case Western Reserve University / ACTG 2061 Cornell Road Room 120 Cleveland, OH 44106-4984 Contact: Michael Chance (216) 844-8051 OPEN 940218 ACTU: 2501. OKLAHOMA Associates in Medical and Mental Health 1560 East 21st Street / Suite 210 Tulsa, OK 74114-1325 Contact: Virginia Butler (918) 743-1000 OPEN 940218. OREGON Veterans Administration Portland Medical Center Dept of Research & Education / 2701 NW Vaughn / Suite 770 Portland, OR 97210 Contact: Dr James H Sampson (503) 229-8428 OPEN 940218. OTHER St Paul's Hospital Room C - 371 / 1061 Burrard Street Vancouver, BC V6Z 1Y6 Contact: Ginna Bell 8046822344 OPEN 940218. PENNSYLVANIA Buckley Braffman Stern Medical Associates PC 822 Pine Street / Suite 3A Philadelphia, PA 19107 Contact: Nancy Pietroski (215) 925-8010 OPEN 940218. 139 UNIQUE IDENTIFIER FDA/00486 PROTOCOL ID NUMBERS FDA 058J PROTOCOL TITLE Oral/Intravenous Azithromycin in the Treatment of Cryptosporidiosis in Patients Whose Disease Has Not Been Controlled by Conventional Therapy. VERSION NUMBER & DATE (940311) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Child GENERAL DESCRIPTION PURPOSE: To provide azithromycin for the treatment of individual patients with proven cryptosporidiosis whose disease has persisted or progressed despite prior therapies. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940505) DISEASE STUDIED Cryptosporidiosis / diarrhea. DISEASES STATUS Patients have the following symptoms and conditions: 1. Cryptosporidiosis infection proven by stool examination on at least two occasions, one within 4 weeks prior to study entry, or verified by endoscopic biopsy. Other treatable causes of diarrhea must have been excluded. 2. Must have failed or been intolerant to prior therapy with standard antidiarrheal or antibiotic or other therapies for cryptosporidiosis. Patients with documented favorable response to azithromycin under Pfizer protocol 066-143 may receive maintenance therapy under this protocol. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 066-167S PROTOCOL DETAILS STUDY INTENT: Drug therapy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 49 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Cryptosporidiosis infection. 2. Life expectancy of at least 1 week. 3. Must have failed or been intolerant to prior therapy with standard antidiarrheal or antibiotic or other therapies for cryptosporidiosis. 4. Consent of parent or guardian for patients under the legal age of consent. Patients with documented favorable response to azithromycin under Pfizer protocol 066-143 may receive maintenance therapy under this protocol. Patients with persistent diarrhea requiring intravenous (IV) fluid therapy to maintain hydration may receive IV azithromycin after approval by the clinical monitor. Patients whose disease worsens despite a minimum of 2 weeks of oral therapy or patients whose disease shows no improvement after 4 weeks of oral therapy will also be considered for a trial period of intravenous azithromycin. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 01 Days - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Must have failed or been intolerant to prior therapy with standard antidiarrheal or antibiotic therapies for cryptosporidiosis. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known hypersensitivity or significant intolerance to macrolide antibiotics. 2. Eligibility and current treatment at a medical center performing study 066-143, another study of azithromycin for treatment of cryptosporidiosis in AIDS patients. SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin TRADE NAME OF SUBSTANCE Drug 1‰ CP-62,933 MANUFACTURERS Drug 1: Pfizer Incorporated Eastern Point Road / Central Research Groton, CT 06340 Contact: Robert Myers (203) 441-3817. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, intravenous SUPPORTING AGENCY Pfizer Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Antidiarrheals/THERAPEUTIC USE MESH HEADING Azithromycin/*THERAPEUTIC USE MESH HEADING Child MESH HEADING Cryptosporidiosis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Diarrhea/COMPLICATIONS/DRUG THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 0 (Antidiarrheals) CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 940505 ENTRY MONTH 9301 ALASKA Dr Frank Domurat 1200 Airport Heights Drive Suite 300 Anchorage, AK 99508 Contact: Dr Frank Domurat (907) 278-3155 OPEN 940627. ARIZONA Cigna 755 East McDowell Road Phoenix, AZ 85006 Contact: Dr Dean Martin (602) 271-3762 OPEN 930111. ARIZONA Dr David Payne 1050 East University Mesa, AZ 85203 Contact: Dr David Payne (602) 834-6632 OPEN 931112. CALIFORNIA Keith Medical Group 6200 Wilshire Boulevard Los Angeles, CA 90048 Contact: Dr Erik Flelschman (213) 964-1440 OPEN 940210. CALIFORNIA Century City Medical Group 2080 Century Park East Suite 710 Century City, CA 90067 Contact: Dr Barry Chadsey (310) 201-0900 OPEN 940627. CALIFORNIA Dr Richard Kuritzkes 2701 West Alameda Avenue / Suite 308 Burbank, CA 91505 Contact: Dr Richard Kuritzkes (818) 845-3773 OPEN 940210. CALIFORNIA University of California / San Diego Treatment Center 2760 Fifth Avenue / Suite 300 San Diego, CA 92103 Contact: Cathy Nuffer (619) 543-8080 Contact: Dr Diane Havir (619) 543-8080 OPEN 930111. CALIFORNIA Westside Neighborhood Medical Clinic 628 West Micheltorena Santa Barbara, CA 93101 Contact: Dr Jeffrey Syme OPEN 930111. CALIFORNIA Dr William Koonce 219 Nogales Drive Santa Barbara, CA 93105 Contact: Dr William Koonce (805) 682-7200 OPEN 940210. CALIFORNIA San Francisco General Hospital 1001 Porero Avenue San Francisco, CA 94110 Contact: Dr Donald Abrams (415) 476-4082 OPEN 940627. CALIFORNIA Kaiser Permanente 2200 O'Farrell Street San Francisco, CA 94115 Contact: Dr Stanley Hill (415) 202-2220 OPEN 940210. CALIFORNIA Dr Robert Scott 368 28th Street Oakland, CA 94609 Contact: Dr Robert Scott (510) 834-1950 OPEN 940811. CALIFORNIA East Bay AIDS Center 3031 Telegraph Avenue / Suite 235 Berkeley, CA 94705 Contact: Sherry Lyman (510) 204-1870 Contact: Dr Carol Brosgart (510) 204-1201 OPEN 930111. CALIFORNIA Joaquin County General Hospital 500 West Hospital Road French Camp, CA 95231 Contact: Dr Rod Felber (209) 468-6026 OPEN 940210. COLORADO Childrens Hospital / Division of Pediatrics B-055 1056 East 19th Avenue Denver, CO 80218 Contact: Dr Betsy McFarland (303) 861-6981 OPEN 930111. DISTRICT OF COLUMBIA Dr Larry Lyle 801 Pennsylvania Avenue Southeast Washington, DC 20003 Contact: Dr Larry Lyle (202) 546-0796 OPEN 940627. DISTRICT OF COLUMBIA Dr Douglas Ward 1737 20th Street Northwest Washington, DC 20009 Contact: Dr Douglas Ward (202) 745-0201 OPEN 940627. FLORIDA Dr Goodgame and Hopkins 340 N Maitland Avenue Maitland, FL 32751 Contact: Chuck DeMarzo (407) 647-6000 OPEN 931112. FLORIDA Dr Rita Poblete 901 NW Seventeenth Street / Suite D Miami, FL 33136 Contact: Dr Rita Poblete (305) 548-4598 OPEN 940505. FLORIDA University of Miami School of Medicine 1550 Northwest Tenth Avenue Room 201 Miami, FL 33136 Contact: Dr Della Rivera (305) 547-6676 OPEN 940627. FLORIDA Dr Larry Wardzala 1301 East Broward Boulevard / Suite 303 Ft Lauderdale, FL 33301 Contact: Dr Larry Wardzala (305) 463-4602 OPEN 940210. FLORIDA Dr Tom Wazny 2885 Tamiami Trail Port Charlotte, FL 33952 Contact: Dr Tom Wazny (813) 624-7230 OPEN 930111. GEORGIA Medical College of Georgia Infectious Diseases Building AF-2013 Augusta, GA 30912 Contact: John Fisher (706) 721-2236 OPEN 940505. ILLINOIS Dr Richard MacDonald 990 West Fullerton / Suite 495 Chicago, IL 60614 Contact: Dr Richard MacDonald (312) 525-7171 OPEN 930111. ILLINOIS Dr David Blatt 906 West Belmont Chicago, IL 60657 Contact: Dr David Blatt (312) 929-0808 OPEN 930111. ILLINOIS Dr Daniel Berger 2835 North Sheffield / Suite 104 Chicago, IL 60657 Contact: Dr Daniel Berger (312) 296-2400 OPEN 940210. LOUISIANA Browne - Mchardy Clinic 4315 Houma Boulevard Metairle, LA 70006 Contact: Dr Frank Rabito (504) 889-5367 OPEN 940404. MASSACHUSETTS Beth Israel Hospital 330 Brookline Avenue Boston, MA 02215 Contact: Dr Judith Currier OPEN 930111. MASSACHUSETTS Harvard Community Health One Fenway Plaza Boston, MA 02215 Contact: Dr Calvin Cohen (617) 421-5846 OPEN 940811. MARYLAND Dr Michael Levin 4000 Old Court Rd / Suite 301 Pikeville, MD 21208 Contact: Dr Michael Levin (410) 486-5991 OPEN 940404. MISSISSIPPI University of Mississippi / Department of Medicine 2500 North State Street Jackson, MS 39216 Contact: Dr Rathel Nolan (601) 984-5556 OPEN 940210. NEBRASKA University of Nebraska Medical Center 6000 South 42nd Street Omaha, NE 68198-5130 Contact: Dr Susan Swindells (402) 559-8201 OPEN 940210. NEW HAMPSHIRE Manchester Veterans Administration Medical Center 718 Smyth Road Manchester, NH 03104 Contact: Dr Donald Bernard (603) 624-4366 OPEN 931112. NEW JERSEY Dr Nina Regevik 530 New Brunswick Avenue Perth Amboy, NJ 08861 Contact: Dr Nina Regevik (908) 324-5022 OPEN 940627. NEVADA Dr Kathryn Crooks 2810 West Charleston Boulevard / Quall Park IV / Bldg F-54 Las Vegas, NV 89102 Contact: Dr Kathryn Crooks (702) 870-0808 OPEN 940210. NEVADA University Medical Center 1800 West Charleston Las Vegas, NV 89102 Contact: Dr Jerry Cade (702) 877-8600 OPEN 940811. NEW YORK Dr Howard A Grossman 285 West 11th Street / Suite 1-W New York, NY 10014 Contact: George Theodore (212) 929-2629 OPEN 940210. NEW YORK Dr Jeffrey Green 345 East 37th Street / Suite 208 New York, NY 10016 Contact: Dr Jeffrey Green (212) 682-2844 OPEN 940210. NEW YORK The New York Hospital / Cornell Med Ctr / Dept of Medicine 1300 New York Avenue / Room A-421 New York, NY 10021 Contact: Dr Rosemary Soave (212) 746-6320 OPEN 930111. NEW YORK New York Med College / Pediatric Dept Munger Pavilion Valhalla, NY 10595 Contact: Dr Oya Tugal (914) 285-7997 OPEN 930111. NEW YORK State U of New York / Hlth Science Center / Dept of Peds 450 Clarkson Avenue / Box 49 Brooklyn, NY 11203 Contact: Dr Margaret Hammerschlag (718) 245-4074 OPEN 930111. NEW YORK City Hospital Center 79-01 Broadway Elmhurst, NY 11373 Contact: Dr George Alonso (718) 334-3969 OPEN 940505. OKLAHOMA Associates in Medical and Mental Health 1560 East 21st Street / Suite 210 Tulsa, OK 74114-1325 Contact: Virginia Butler (918) 743-1000 OPEN 940210. PENNSYLVANIA Childrens Hospital of Philadelphia / Division of General Ped 34th Street and Civic Center Boulevard / 2nd Floor Room 2015 Philadelphia, PA 19104 Contact: Dr Richard Rutstein (215) 590-1466 OPEN 940404. 140 UNIQUE IDENTIFIER FDA/00474 PROTOCOL ID NUMBERS FDA 058I PROTOCOL TITLE A Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study of Azithromycin as Prophylaxis Against the Development of Mycobacterium avium Complex Disease in HIV-Infected People. VERSION NUMBER & DATE (920903) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the efficacy and safety of azithromycin administered once a week in the prevention of disseminated Mycobacterium avium Complex (MAC) in severely immunocompromised HIV-infected patients with a CD4 count < 100 cells/mm3. OPEN/CLOSED INDICATOR Open: Actively accruing patients (920821) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection confirmed by ELISA with Western blot or polymerase chain reaction (PCR). 2. CD4 count < 100 cells/mm3. 3. No MAC positive blood cultures within 1 month prior to study entry (patients with stool cultures positive for MAC may enter the study provided at least two blood cultures are negative). 4. Absence of symptoms suggestive of disseminated MAC infection (including unexplained diarrhea, fever, and night sweats) within 1 month of study entry. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS 066-155 STUDY DESIGN Double-Blind; Placebo-Controlled; Multicenter; Parallel-Group PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug prophylaxis. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 3 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. CD4 count < 100 cells/mm3. 3. No MAC positive blood cultures within 1 month prior to study entry. 4. No symptoms suggestive of disseminated MAC infection (including unexplained diarrhea, fever, and night sweats) within 1 month of study entry. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 8 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: < 100 cells/mm3. ( 0 ). PATIENT INCLUSION CRIT. BILIRUBIN: < 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 2.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: Neutrophils > 1000 cells/mm3. BUN < 30 mg/dl. Alkaline phosphatase <= 5 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: Anti-pneumocystis prophylactic therapy (dihydropteroate synthetase inhibitors with or without dihydrofolate reductase inhibitors, pentamidine). Allowed: Concomitant anti-HIV therapy (AZT, ddI, ddC) or antifungal therapy (including azoles). PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of MAC or Mycobacterium tuberculosis (MTb) infection. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within the past 4 weeks: Any putative anti-MAC therapies including rifampin, rifabutin, clofazimine, ethambutol, cycloserine, ethionamide, amikacin, and ciprofloxacin or other quinolones thought to be active against MAC. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other investigational new drugs (except for foscarnet or ddC) unless prior agreement has been reached between the investigator and the Pfizer project physician. 2. Concomitant putative immunostimulants. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Positive PPD within 3 months prior to study entry (negative PPD defined as < 5 mm induration). 2. Chest x-ray suggestive of any active disease, in particular tuberculosis. 3. Known hypersensitivity to macrolide antibiotics. 4. Any other acute clinical condition likely to interfere with completion of the protocol. 5. Inability to care for self without considerable assistance and medical care. SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin MANUFACTURERS Drug 1: Pfizer Incorporated Eastern Point Road / Central Research Groton, CT 06340 Contact: Robert Myers (203) 441-3817. SUPPORTING AGENCY Pfizer Incorporated. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Azithromycin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*PREVENTION & CONTROL CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 920821 ENTRY MONTH 9211 CALIFORNIA Naval Hospital Infectious Diseases Division San Diego, CA 92134-5000 Contact: Dr Edward Oldfield III (619) 532-7475 OPEN 921117. NORTH CAROLINA Womack Army Medical Center Medical Clinic Fort Bragg, NC 28307-5000 Contact: Dr Richard Williams (910) 432-6028 OPEN 921117. 141 UNIQUE IDENTIFIER FDA/00473 PROTOCOL ID NUMBERS FDA 058H PROTOCOL TITLE An Open, Multicenter, Randomized, Dose-Ranging Study of Azithromycin in the Treatment of Disseminated Mycobacterium avium-intracellulare Complex Infection (MAC) in Patients with Acquired Immune Deficiency Syndrome (AIDS). VERSION NUMBER & DATE (920901) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the efficacy and safety of two doses of azithromycin given chronically for the treatment of Mycobacterium avium bacteremia in AIDS patients. OPEN/CLOSED INDICATOR Open: Actively accruing patients (920821) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by ELISA and confirmed by Western blot. 2. Disseminated Mycobacterium avium Complex infection defined by a positive blood culture for MAC within 1 month prior to study entry. 3. Fever (> 100 degrees F) that cannot be attributed to another active infection, and at least one other constitutional symptom (such as fatigue, malaise, anorexia). ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 066-148 STUDY DESIGN Open Label; Multicenter; Randomized; Dose Ranging PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 6 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Disseminated Mycobacterium avium Complex. 3. Fever (> 100 degrees F) that cannot be attributed to another active infection, and at least one other constitutional symptom (such as fatigue, malaise, anorexia). 4. Life expectancy of at least the duration of the study. 5. Consent of parent or guardian if below the legal age of consent. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: > 7 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 3.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: < 1.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: Neutrophils > 500 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Abstinence or effective method of birth control / contraception during the study and for 90 days after. OTHER PATIENT INCL. CH. WEIGHT: >= 40 kg OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Medications allowed under a Treatment IND program. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. WEIGHT: < 40 kg PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Not expected to comply with the requirements of the protocol, in the opinion of the investigator. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Treatment with an immunostimulant or immunomodulator compound such as alpha-interferon, gamma-interferon, or any interleukin within 7 days prior to study entry. 2. Any other antibiotic with known activity against M. avium within 7 days prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Known hypersensitivity or significant intolerance to macrolide antibiotics. 2. Inability to take oral medications or a current condition likely to interfere with drug absorption (e.g., gastrectomy). SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin MANUFACTURERS Drug 1: Pfizer Incorporated Eastern Point Road / Central Research Groton, CT 06340 Contact: Robert Myers (203) 441-3817. SUPPORTING AGENCY Pfizer Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Azithromycin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 920821 ENTRY MONTH 9211 MASSACHUSETTS Beth Israel Hospital 330 Brookline Avenue / LY-124 Boston, MA 02215 Contact: Dr Judith Currier (617) 735-4700 OPEN 921105. NEW YORK Bronx Veterans Affairs Medical Center / Div Infec Diseases 130 West Kingsbridge Road Bronx, NY 10468 Contact: Dr Jeffrey Jacobson (718) 584-9000 X 116OPEN 921105. NEW YORK SUNY / Upstate Medical Center 750 East Adams Street Syracuse, NY 13210 Contact: Dr Michael Cynamon (315) 464-5533 OPEN 921105. OHIO Ohio State University Hospitals N-1135 Doan Hall 410 West 10th Avenue Columbus, OH 43210 Contact: Dr Susan Koletar (614) 293-8745 OPEN 921105. 142 UNIQUE IDENTIFIER FDA/00429 PROTOCOL ID NUMBERS FDA 058F PROTOCOL TITLE Azithromycin in the Treatment of Cryptosporidiosis in Patients With Acquired Immune Deficiency Syndrome (AIDS): A Randomized, Multi-Center, Placebo-Controlled, Double-Blind Study. VERSION NUMBER & DATE (910712) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the safety and efficacy of azithromycin in the treatment of intestinal cryptosporidial infection in AIDS patients. OPEN/CLOSED INDICATOR Open: Actively accruing patients (920706) DISEASE STUDIED Cryptosporidiosis / diarrhea. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection. 2. Intestinal cryptosporidiosis proven by stool microscopy on at least two occasions prior to study enrollment. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 066-143 STUDY DESIGN Randomized; Multicenter; Placebo-Controlled; Double-Blind PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 4 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. Intestinal cryptosporidiosis proven by stool microscopy on at least two occasions prior to study enrollment. 3. Life expectancy of at least 2 weeks by clinical assessment. In states where the legal age of consent for medical procedures is 21 years, patients below the age of 21 must have consent of parent or guardian. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 7 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. SGOT(AST): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 40 ml/min. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 5 x ULN. Absolute neutrophil count (mature PMNs and Bands only) >= 500 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception during the study and for 30 days after. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Zidovudine. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Zidovudine. 2. Antidiarrheal medication with immodium or paragoric only. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 30 days after. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Not expected to comply with the requirements of the protocol, in the opinion of the investigator. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Another investigational drug within 7 days prior to study enrollment (investigational medications available through a treatment IND will be allowed with the approval of the sponsor, the treatment IND sponsor, and the Pfizer clinical monitor). 2. Immunostimulant or lymphocyte replacement therapy. 3. Cancer chemotherapy (including therapy for Kaposi's sarcoma). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Cancer chemotherapy (including therapy for Kaposi's sarcoma). 2. Any drug or biologic preparation (e.g., bovine colostrum, paromomycin, spiramycin, somatostatin) with possible anticryptosporidial activity. 3. Immunostimulant or lymphocyte replacement therapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Known hypersensitivity or significant intolerance to macrolide antibiotics. 2. Marked abnormalities of liver or renal function. 3. Causes for diarrhea other than, or in addition to, cryptosporidiosis. 4. Inability to receive oral medication. SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin TRADE NAME OF SUBSTANCE Drug 1‰ CP-62,933 MANUFACTURERS Drug 1: Pfizer Incorporated Eastern Point Road / Central Research Groton, CT 06340 Contact: Robert Myers (203) 441-3817. SUPPORTING AGENCY Pfizer Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Azithromycin/*THERAPEUTIC USE MESH HEADING Cryptosporidiosis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 920706 ENTRY MONTH 9207 CALIFORNIA University of California at San Diego Medical Center 225 Dickenson Street Suite 8208 San Diego, CA 92103 Contact: Dr Diane Havlir (619) 792-7675 OPEN 920706. CALIFORNIA Infectious Disease Medical Group 350 30th Street / Suite 511 Oakland, CA 94609 Contact: Dr Patrick Joseph (510) 273-8200 Contact: Bruce Ross (510) 273-8200 OPEN 920706. NEW YORK Cornell University Medical Center 525 East 68th Street / Room 2434 New York, NY 10021 Contact: Brenda Greenhill (212) 746-4177 OPEN 920706 ACTU: 2201. 143 UNIQUE IDENTIFIER FDA/00438 PROTOCOL ID NUMBERS FDA 058D PROTOCOL TITLE A Study to Evaluate the Safety and Efficacy of Azithromycin in Individual Patients With Serious Nontuberculous Mycobacterial Disease Who Are Failing or Intolerant of Other Available Therapy. VERSION NUMBER & DATE 2 (910927) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Child TRIAL CATEGORY Nationwide Access GENERAL DESCRIPTION PURPOSE: To evaluate the efficacy and safety of azithromycin given chronically for the treatment of serious nontuberculous mycobacterial infection in patients failing or intolerant of other available therapy. OPEN/CLOSED INDICATOR Open: Actively accruing patients (920821) DISEASE STUDIED Nontuberculous mycobacterial infection, Mycobacterium avium-intracellulare infection DISEASES STATUS Patients have the following symptoms and conditions: 1. Serious nontuberculous mycobacterial disease defined as disabling or life-threatening infection that may be localized or disseminated. 2. Mycobacterial species has been identified as sensitive to azithromycin, either in vitro or by known in vivo animal or human data. 3. Has been treated for at least 6 weeks and has not responded to more conventional therapy for this infection, OR initially responded and has experienced recurrence or worsening of infection on therapy, OR cannot tolerate continued conventional therapy. ELIGIBILITY AIDS. OTHER. OTHER PROTOCOL NUMBERS 066-169 PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Compassionate use. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 2 units. INPATIENT/OUTPATIENT ST. Inpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Serious nontuberculous mycobacterial infection. 2. Approval of eligibility from Pfizer Clinical Monitor. Patients below the legal age of consent must have consent of parent or guardian. NOTE: Pregnant women, women of childbearing potential, and children will not be specifically excluded from participation. However, patients and physicians should be aware that the safety of azithromycin during pregnancy and in long-term use in children and adults has not been established. The risks and benefits of azithromycin use in these patients will be considered in consultation with the physician and the Pfizer Clinical Monitor. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 3.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT AGE AGE: 01 Days - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Other antimicrobial drugs as long as documented on Case Report Form. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of hypersensitivity or intolerance to azithromycin. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Disseminated Mycobacterium avium complex (MAC) who are eligible for treatment with azithromycin under protocol 066-162. 2. Known hypersensitivity or intolerance to macrolide antibiotics. SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin TRADE NAME OF SUBSTANCE Drug 1‰ CP-62,993 MANUFACTURERS Drug 1: Pfizer Incorporated Eastern Point Road / Central Research Groton, CT 06340 Contact: Robert Myers (203) 441-3817. SUPPORTING AGENCY Pfizer Central Research. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Azithromycin/*THERAPEUTIC USE MESH HEADING Child MESH HEADING Female MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium Infections, Atypical/ COMPLICATIONS/*DRUG THERAPY MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 920821 ENTRY MONTH 9209 CONNECTICUT Pfizer Central Research / USA Accrual Eastern Point Rd Groton, CT 06340 Contact: Dr Debra Williams (203) 441-5463 OPEN 921001. MARYLAND NIH / NCI / Metabolism Branch Room 4N-115 / Building 10 / 9000 Rockville Pike Bethesda, MD 20892 Contact: Dr David Nelson (301) 496-3024 CLOSED 940915. 144 UNIQUE IDENTIFIER FDA/00472 PROTOCOL ID NUMBERS FDA 058C PROTOCOL TITLE An Open-Label Study of the Use of Azithromycin in Patients With Symptomatic Disseminated Mycobacterium avium-intracellulare Complex (MAC) Infection Failing Current Therapy. VERSION NUMBER & DATE 2 (910927) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Child GENERAL DESCRIPTION PURPOSE: To evaluate the efficacy and safety of azithromycin given chronically for the treatment of Mycobacterium avium (MAC) bacteremia in patients failing or intolerant of current available MAC therapy. OPEN/CLOSED INDICATOR Open: Actively accruing patients (920822) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Disseminated MAC as defined by current (within the last month) positive blood, bone marrow, or liver biopsy culture for MAC, and considered symptomatic (fever, night sweats, anorexia, weight loss, fatigue, or malaise). 2. At least 2 months of prior treatment with available combination MAC therapy or less than 2 months of such accompanied by unacceptable adverse effects. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 066-162 STUDY DESIGN Open Label PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 44 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Disseminated MAC as defined by current (within the last month) positive blood, bone marrow, or liver biopsy culture for MAC, and considered symptomatic (fever, night sweats, anorexia, weight loss, fatigue, or malaise). 2. At least 2 months of prior treatment with available combination MAC therapy or less than 2 months of such accompanied by unacceptable adverse effects. 3. Life expectancy of more than 2 weeks. 4. Approval of eligibility from Pfizer Clinical Monitor. 5. Consent of parent or guardian if under legal age of consent. NOTE: Patients who have completed acute treatment with azithromycin for MAC in protocol 066-131 or 066-148 will be exempt from inclusion criteria 1 and 2 and can continue therapy through this protocol if their physician feels they have benefitted from prior azithromycin therapy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 3.0 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT AGE AGE: 01 Days - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of hypersensitivity or intolerance to azithromycin. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Other investigational drugs within 7 days of enrollment, with the exception of Treatment IND drugs (such as ddC). PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other MAC therapy instituted during the first 2 months of the study. 2. Other investigational drugs, with the exception of those available through a Treatment IND program. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms and conditions are excluded: 1. Known hypersensitivity or intolerance to macrolide antibiotics. 2. Inability to take oral medications or current condition that is likely to interfere with absorption (e.g., gastrectomy). SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin MANUFACTURERS Drug 1: Pfizer Incorporated Eastern Point Road / Central Research Groton, CT 06340 Contact: Robert Myers (203) 441-3817. SUPPORTING AGENCY Pfizer Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Azithromycin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Child MESH HEADING Female MESH HEADING Human MESH HEADING Infant MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 920822 ENTRY MONTH 9211 ALABAMA Dr John Dunkel 101-A Bob Wallace Avenue Huntsville, AL 35801 Contact: Dr John Dunkel (205) 533-6558 OPEN 921105. ARIZONA University of Arizona 1609 North Warren Street / Room 121 Tucson, AZ 85719 Contact: Dr Kevin Carmichael (602) 626-6967 OPEN 921105. CALIFORNIA University of California San Diego / Medical Center 225 Dickenson Street / Mail Code 8451 San Diego, CA 92103 Contact: Dr Wayne Danker (619) 543-2744 OPEN 921105. CALIFORNIA Fountain Valley Regional Hospital and Medical Center 17150 Euclid Avenue / Suite 322 Fountain Valley, CA 92708 Contact: Dr Douglas Cable (714) 432-0422 OPEN 921105. CALIFORNIA Devlin Peterson Clinic 513 West Columbus / Suite A Bakersfield, CA 93303-2824 Contact: Patrick Nemechek (805) 633-1242 OPEN 921105. CALIFORNIA Dr David Leece 1235 Osos Street San Luis Obispo, CA 93401 Contact: Dr David Leece (805) 546-5630 OPEN 921105. CALIFORNIA District Health Center No 1 3850 17th Street San Francisco, CA 94114 Contact: Fred Strauss (415) 554-9750 OPEN 921105. CALIFORNIA Davies Medical Center 45 Castro Street / Suite 402 San Francisco, CA 94114 Contact: Dr William Owen (415) 861-2400 OPEN 921105. CALIFORNIA Dr Jacob Lalezari 2300 Sutter Street / Suite 202 San Francisco, CA 94115 Contact: Dr Jacob Lalezari (415) 476-6356 OPEN 921105. CALIFORNIA Kuzell Institute / Division of Infectious Diseases 2200 Webster Street San Francisco, CA 94115-1896 Contact: Dr Lowell Young (415) 923-3262 OPEN 921105. CALIFORNIA Infectious Disease Medical Group 350 30th Street / Suite 511 Oakland, CA 94609 Contact: Dr Patrick Joseph (510) 834-2800 OPEN 921105. CALIFORNIA East Bay AIDS Center 3031 Telegraph Avenue / Suite 235 Berkeley, CA 94705 Contact: Sherry Lyman (510) 204-1870 Contact: Dr Carol Brosgart (510) 204-1201 OPEN 921105. CALIFORNIA Medical Group of Watsonville 850 Freedom Boulevard Watsonville, CA 95076 Contact: Dr Thomas Deetz (408) 724-2211 OPEN 921105. COLORADO Fitzsimmons Army Medical Center / Infectious Diseases Clinic P O Box 6295 Aurora, CO 80045 Contact: Dr William Byrne OPEN 921105. COLORADO Infectious Disease 2045 Franklin Street Denver, CO 80205-5494 Contact: Dr Miguel Mogyoros (303) 861-3652 OPEN 921105. CONNECTICUT Danbury Newton Road Newton, CT 06470 Contact: Dr Donald Evans (203) 426-5626 OPEN 921105. CONNECTICUT Yale University School of Med / Department of Internal Med P O Box 3333 New Haven, CT 06510-8056 Contact: Unspecified (203) 737-4040 OPEN 921105. FLORIDA Wuestoff Hospital 110 Longwood Avenue Rockledge, FL 32956-5002 Contact: Dr Mary Ulrich (407) 636-2211 OPEN 921105. GEORGIA Dr Richard Hudson 155 North Avenue Atlanta, GA 30308 Contact: Dr Richard Hudson OPEN 921105. GEORGIA Geogia Baptist Hospital / Atlanta Medical Associates 100 10th Street Northwest Atlanta, GA 30309 Contact: Dr Dennis Melton (404) 897-6836 OPEN 921105. INDIANA Dr Karen Isreal 1633 North Capitol Avenue / Suite 550 Indianapolis, IN 46202 Contact: Dr Karen Isreal (317) 929-2424 OPEN 921105. INDIANA Wishard Memorial Hospital OPW430 1001 West 10th Street Indianapolis, IN 46202-2879 Contact: Dr L Joseph Wheat (317) 630-6262 OPEN 921105. LOUISIANA Tulane Medical Center / Infectious Diseases 150 South Liberty St / Columbia Bldg / Third Floor New Orleans, LA 70112 Contact: Dr David Mushat (504) 587-7316 OPEN 921105. MASSACHUSETTS University of Massachussetts Medical Center 55 Lake Avenue North Worcester, MA 01655 Contact: Dr Patrick Fairchild (508) 856-4261 CLOSED 930604. MASSACHUSETTS Boston City Hospital / Department of Pediatrics Boston, MA 02118 Contact: Dr Jo-Ann Harris (617) 534-5802 OPEN 921105. MASSACHUSETTS Beth Israel Hospital LY-124 330 Brookline Avenue Boston, MA 02215 Contact: Dr Judith Currier (617) 735-4700 OPEN 921105. MARYLAND Dr Michael Levin 4000 Old Court Road / Suite 301 Pikesville, MD 21208 Contact: Dr Michael Levin (410) 486-5991 OPEN 921105. MARYLAND Dr Raymond Altieri 314 German HIll Road Dundalk, MD 21222 Contact: Dr Raymond Altieri (410) 323-2500 OPEN 921105. NEW HAMPSHIRE Dartmouth-Hitchcock Medical Center / Sect of Infect Diseases Lebanon, NH 03756 Contact: Dr Charles Von Reyn OPEN 921105. NEW JERSEY Dr Jeffrey Kocher 130 Broad Avenue Leonia, NJ 07631 Contact: Dr Jeffrey Kocher OPEN 921105 ACTU: 000F. NEW YORK Cabrini Medical Center 227 East 19th Street New York, NY 10003 Contact: Dr John Montana (212) 505-7730 OPEN 921105. NEW YORK Bellevue Hospital Center AIDS Program First Avenue at 27th Street / Room 12 East 12 New York, NY 10016 Contact: Dr Mary Vogler (212) 561-3906 Contact: (212) 561-4038 OPEN 921105. NEW YORK Department of Veterans Affairs / Division of Infectious Dis 130 West Kingsbridge Road Bronx, NY 10468 Contact: Dr Jeffrey Jacobson (718) 584-9000 OPEN 921105. NEW YORK Office of Dr Thomas Rush 141 North State Road Briarcliff Manor, NY 10510 Contact: Dr Thomas Rush (914) 762-2276 OPEN 921105. NEW YORK State University of New York Health Science Center 750 East Adams Street Syracuse, NY 13210 Contact: Dr Michael Cynamon (315) 464-5533 OPEN 921105. NEW YORK United Health Services Binghamton, NY 13903 Contact: Dr Barbara Chaffee (607) 722-9081 OPEN 921105. NEW YORK University of Rochester / Department of Infect Dis Bos 689 Rochester, NY 14642 Contact: Dr Amy Portmore OPEN 921105. OHIO Ohio State University Hospitals N-1135 Doan Hall / 410 West Tenth Avenue Columbus, OH 43210 Contact: Dr Susan Koletar (614) 293-8745 OPEN 921105. OHIO Doan Hall N-1144 410 West Tenth Avenue Columbus, OH 43210-1228 Contact: Dr Robert Fass (614) 293-8732 OPEN 921105. OHIO Principal Health Care of Ohio 4885 Olentangy River Road Columbus, OH 43214 Contact: Dr Vincent Spagna (614) 451-1551 OPEN 921105. 145 UNIQUE IDENTIFIER FDA/00148 PROTOCOL ID NUMBERS FDA 058A PROTOCOL TITLE Study of Azithromycin in the Treatment of Toxoplasmic Encephalitis in AIDS Patients Who Cannot be Treated with Conventional Therapy. VERSION NUMBER & DATE (901204) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: The primary purpose of this protocol is to provide azithromycin for the treatment of individual patients who require therapy for toxoplasmic encephalitis and who cannot receive conventional therapies due to prior clinical failure or significant intolerance. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940210) DISEASE STUDIED Toxoplasmic encephalitis. DISEASES STATUS Patients have the following symptoms and conditions: 1. A diagnosis of toxoplasmic encephalitis in patients with AIDS established by: a) Demonstration of the organism in cerebrospinal fluid or material obtained at brain biopsy or aspiration of a brain abscess. OR b) Lesions detected by computed tomography or by nuclear magnetic resonance studies characteristic of those described associated with toxoplasmic encephalitis in patients with AIDS but in whom: 1) The decision has been made that the lesions are that make surgical intervention inadvisable or surgical intervention is refused by the patient or is inadvisable for reasons of the patients clinical status or other circumstance. AND 2) Prior specific antitoxoplasmic therapy must have shown some favorable clinical response in cases where the diagnosis of toxoplasmic encephalitis is presumptive (has not been proven by identification of the organism from brain tissue). 2. A minimum life expectancy of one week. 3. Must have failed or been intolerant to prior therapy with sulfa drugs or pyrimethamine. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 066-133 PROTOCOL DETAILS STUDY INTENT: Drug therapy, Compassionate use. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 23 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have the following: o A diagnosis of toxoplasmic encephalitis in patients with AIDS. o Baseline history, physical examination, and clinical laboratory tests. o Given written informed consent prior to his/her inclusion in the study. NOTE: Patients below the age of legal consent will have, in addition to the above consent, written permission and informed consent from a parent or guardian. The final judgement of patient acceptability for inclusion lies with the Pfizer Clinical Monitor. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Therapeutic failure with or intolerance to prior therapy with sulfa drugs or pyrimethamine. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following are excluded: Known sensitivity to macrolide antibiotics. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following conditions or symptoms are excluded: Known sensitivity to macrolide antibiotics. SUBSTANCE IDENTIFICATION Drug 1 DRG-0104 Azithromycin TRADE NAME OF SUBSTANCE Drug 1‰ Azithromycin MANUFACTURERS Drug 1: Pfizer Incorporated Eastern Point Road / Central Research Groton, CT 06340 Contact: Robert Myers (203) 441-3817. SUPPORTING AGENCY Pfizer, Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Azithromycin/*THERAPEUTIC USE MESH HEADING Drug Evaluation MESH HEADING Encephalitis/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Toxoplasmosis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 83905-01-5 (Azithromycin) LAST REVISION DATE 940210 ENTRY MONTH 9102 CALIFORNIA University of California Medical Center 225 Dickinson Street / Owen Clinic H-881 San Diego, CA 92103-1990 Contact: Dr Christopher Matthews (619) 294-3767 OPEN. CALIFORNIA Kern Medical Center 1830 Flower Street Bakersfield, CA 93305 Contact: Patrick Nemechek D O (805) 326-3000 OPEN 911021. CALIFORNIA The Permanente Medical Group Inc 2200 O'Farrell Street San Francisco, CA 94115-3394 Contact: Dr Jeffrey Fessell (415) 929-4848 OPEN. CALIFORNIA Pacific Presbyterian Medical Center PO Box 7999 Clay at Buchanan Street San Francisco, CA 94120 Contact: Dr Lory Wiviott (415) 563-4321 OPEN. CALIFORNIA Scott Eberle M D 2403 Professional Drive / Suite 104 Santa Rosa, CA 95401 Contact: Dr Scott Eberle (707) 544-3340 OPEN 911021. CALIFORNIA University of California Davis / School of Medicine Med Ctr 2221 Stockton Boulevard Sacramento, CA 95817 Contact: Dr Neil Flynn (916) 734-2011 OPEN. FLORIDA South Miami Hospital 7000 Southwest 62nd Avenue Suite 650 Miami, FL 33143 Contact: Dr Paula Sparti (305) 661-1150 OPEN. ILLINOIS Saint Anthony's Medical Center 5666 East State Avenue Rockford, IL 61108-2472 Contact: Dr Scott Homan (815) 226-2000 OPEN. INDIANA Infectious Disease of Indianapolis PSC 1633 North Capitol Suite 700 Indianapolis, IN 46202 Contact: Dr John Black (317) 929-2700 OPEN. LOUISIANA Irwin Trestman M D 4224 Houma Boulevard / Suite 360 Metairie, LA 70006 Contact: Dr Irwin Trestman (504) 456-5144 OPEN 911021. MICHIGAN Dr Paul Benson 2327 Coolidge Berkley, MI 48072 Contact: David Rock (810) 544-9300 OPEN 940210. MICHIGAN Hutzel Hospital 4707 St Antoine Boulevard Detroit, MI 48201 Contact: Theodore Benjamin Jones (313) 745-7269 OPEN ACTU: 1701. NEW JERSEY Leonia Medical Associates P A 130 Broad Avenue Leonia, NJ 07605 Contact: Dr Jeffrey Kocher (201) 944-6612 OPEN 911021. NEW YORK Cabrini Medical Center 227 East 19th Street New York, NY 10003 Contact: Dr Michael Mullen (212) 725-7305 Contact: (212) 979-8929 OPEN. NEW YORK Bellevue Hospital First Avenue and 27th Street New York, NY 10016 Contact: Dr Mindell Seidlin (212) 561-3906 OPEN. NEW YORK Barry Hartman M D 407 East 70th Street New York, NY 10021 Contact: Dr Barry Hartman (212) 746-6320 OPEN. NEW YORK New York Hospital / Cornell Med Ctr / Ctr Special Studies 525 East 68th Street / Baker 24 New York, NY 10021 Contact: Unspecified (212) 748-4190 OPEN. NEW YORK Mount Sinai Medical Center One Gustave Levy Place New York, NY 10029 Contact: Dr Henry Sacks (212) 241-7856 OPEN. NEW YORK Columbia University 630 West 168th Street New York, NY 10032 Contact: Harold Neu (212) 305-3395 OPEN. NEW YORK Hamilton Medical Specialists P C 150 Broad Street Hamilton, NY 13346 Contact: Dr Shelley Gilroy (315) 824-0181 OPEN 911021. OHIO Ohio State University Hospital 410 West Tenth Ave / N 1135 Doan Hall Columbus, OH 43210 Contact: Dr Joseph Plouffe (614) 293-8732 OPEN 940811. OREGON Oregon Health Sciences University 3181 Southwest Sam Jackson Road Portland, OR 97201 Contact: Mark Loveless (503) 295-0950 OPEN. OREGON Good Samaritan Hospital and Medical Center 1015 Northwest 22nd Avenue Portland, OR 97210 Contact: Dr James Sampson (503) 229-8428 OPEN. 146 UNIQUE IDENTIFIER FDA/00656 PROTOCOL ID NUMBERS FDA 048E PROTOCOL TITLE An Open-Label Randomized Pharmacokinetic/Pharmacodynamic Study of Mycobutin ( Rifabutin ) or Rifabutin in Combination With Myambutol ( Ethambutol ) for Prophylaxis of Mycobacterium avium Complex ( MAC ) Bacteremia in AIDS Patients With CD4 Counts <= 100 Cells/mm3. VERSION NUMBER & DATE (940811) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To optimize Mycobacterium avium Complex (MAC) prophylaxis in AIDS patients by measuring serum rifabutin levels and adjusting the dose accordingly. To combine rifabutin with ethambutol to examine the effect of combination therapy in preventing or delaying the incidence of MAC bacteremia in this patient population. Methodology: Patients are randomized to receive oral rifabutin alone or rifabutin/ethambutol daily for 12 months, with possible continuation of medicine lifelong. Doses will be adjusted to maintain minimum blood levels of the drugs. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive oral rifabutin alone or rifabutin/ethambutol daily for 12 months, with possible continuation of medicine lifelong. Doses will be adjusted to maintain minimum blood levels of the drugs. PROTOCOL PHASE Phase IV OPEN/CLOSED INDICATOR Open: Actively accruing patients (940810) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. AIDS. 2. CD4 count <= 100 cells/mm3. 3. NO prior or current MAC infection, and no evidence of disseminated MAC disease on blood culture. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS CS 087287-000 STUDY DESIGN Open Label; Randomized; Prospective; 2-Arm; Drug Combination; Pharmacokinetic PROTOCOL DETAILS STUDY INTENT: Drug prophylaxis, Combination and single pharmacokinetics, Pharmacodynamics, Combination drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 200 patients. (100 patients on each of two treatment arms) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: At least 12 months. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS. 2. CD4 count <= 100 cells/mm3. 3. NO prior or current MAC infection. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMATOCRIT: >= 25 percent. PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 8 g/dl. PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 100 cells/mm3. ( 0 - 100 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2.5 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): < 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): < 5 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 1.5 mg/dl. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase < 3 x ULN. Absolute neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or agree to use barrier methods of birth control / contraception during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Antipneumocystis prophylaxis for at least 4 weeks prior to study entry. Allowed: 1. Prior rifabutin. 2. Prior ethambutol. 3. Prior clarithromycin. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: 1. AZT, d4T, ddI, or ddC. 2. Antipneumocystis prophylaxis. Allowed: Short course (< 14 days) of ciprofloxacin for acute infections. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: Known hypersensitivity to rifabutin, rifampin, or other rifamycins and/or ethambutol. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use barrier methods of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 4 weeks prior to study entry: 1. Rifampin. 2. Isoniazid. 3. Clofazimine. 4. Cycloserine. 5. Ethionamide. 6. Amikacin. 7. Ciprofloxacin. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Other antiretrovirals not specifically allowed. 2. All investigational drugs. 3. Other antimycobacterial therapy, such as clarithromycin, azithromycin, rifampin, clofazimine, amikacin, streptomycin, isoniazid, cycloserine, ethionamide, and ciprofloxacin (>= 14 days). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Positive tuberculin skin test (PPD > 5 mm). 2. Active M. tuberculosis. 3. Perceived as unreliable or unavailable for frequent monitoring. SUBSTANCE IDENTIFICATION Drug 1 DRG-0085 Rifabutin SUBSTANCE IDENTIFICATION Drug 2 DRG-0111 Ethambutol TRADE NAME OF SUBSTANCE Drug 1‰ LM 427 TRADE NAME OF SUBSTANCE Drug 2‰ Myambutol MANUFACTURERS Drug 1: Pharmacia Inc PO Box 16529 Columbus, OH 43216-6529 Contact: Dr James Heusner (614) 764-8129. MANUFACTURERS Drug 2: Lederle Laboratories North Middletown Road Pearl River, NY 10965 Contact: Dr Amy Baim (914) 732-2147 Contact: Dr John Riefler (914) 732-2035. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 300 mg daily (starting dose), with adjustment to maintaa minimum blood level of 0.6 mcg/ml rifabutin. Drug 2: 800 mg daily (starting dose), with adjustment to maintaminimum blood level of 3-5 mcg/ml ethambutol SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 300 mg. Drug 2: 800 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Oral OTHER TREATMENT INFO. TREATMENT DURATION: At least 12 months. SUPPORTING AGENCY Pharmacia Inc. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Drug Therapy, Combination MESH HEADING Ethambutol/*PHARMACOKINETICS/THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*PREVENTION & CONTROL MESH HEADING Rifabutin/*PHARMACOKINETICS/THERAPEUTIC USE CAS REGISTRY NUMBER 72559-06-9 (Rifabutin) CAS REGISTRY NUMBER 74-55-5 (Ethambutol) LAST REVISION DATE 940810 ENTRY MONTH 9409 CALIFORNIA University of California / Davis Medical Center 2221 Stockton Blvd Sacramento, CA 95817 Contact: Dr Neil Flynn (916) 734-3793 OPEN 940810. 147 UNIQUE IDENTIFIER FDA/00534 PROTOCOL ID NUMBERS FDA 048D PROTOCOL TITLE A Three-Arm Comparative Trial for the Treatment of MAC Bacteremia in AIDS: A Clarithromycin / Ethambutol Regimen Containing Rifabutin (450 mg) or Rifabutin (300 mg) or Placebo. VERSION NUMBER & DATE 2 (940419) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To compare the efficacy of clarithromycin/ethambutol with placebo or with rifabutin at two different doses in reducing colony-forming units (CFUs) by 2 or more logarithms in patients with Mycobacterium avium Complex bacteremia and maintaining this response until 16 weeks post-randomization. To assess survival and comparative tolerability among the three treatment regimens. Methodology: Patients are randomized to receive clarithromycin and ethambutol plus either placebo or rifabutin at one of two doses. Treatment continues indefinitely. PER 04/19/94 AMENDMENT: Doses of rifabutin have been changed from 600 and 900 mg daily to 300 and 450 mg daily. Patients enrolled prior to the start of the amendment and randomized to either the original 600 or 900 mg dose of rifabutin will begin receiving the 300 mg dose. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive clarithromycin and ethambutol plus either placebo or rifabutin at one of two doses. Treatment continues indefinitely. PER 04/19/94 AMENDMENT: Doses of rifabutin have been changed from 600 and 900 mg daily to 300 and 450 mg daily. Patients enrolled prior to the start of the amendment and randomized to either the original 600 or 900 mg dose of rifabutin will begin receiving the 300 mg dose. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (930510) DISEASE STUDIED Mycobacterium avium-intracellulare infection ( MAI ) ( MAC ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Documented HIV infection. 2. Evidence of MAC infection as defined by at least one blood culture positive for MAI or AFB within 14 days prior to study entry, plus a minimum of two MAC-associated symptoms defined as fever OR grade 2 or worse night sweats, fatigue, diarrhea, or abdominal pain within 14 days prior to study entry OR a 5 percent or greater decrease in body weight during the 60 days prior to study entry. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS CS 087250-999 STUDY DESIGN Double-Blind; Randomized; Multicenter; 3-Arm; Drug Combination PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug tolerance, Combination drug therapy. PROTOCOL DETAILS PROJECTED ACCRUAL: 450 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Lifelong. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 44 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. HIV infection. 2. MAC infection. 3. Life expectancy of at least 16 weeks. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: > 50000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: < 3.0 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): < 10 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): < 10 x ULN. PATIENT INCLUSION CRIT. CREATININE: >= 3.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: >= 50. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 500 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Negative pregnancy test. Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Isoniazid for TB prophylaxis ONLY. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of hypersensitivity to rifabutin, rifampin, erythromycin, clarithromycin, azithromycin, or ethambutol. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Positive pregnancy test. Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded within 7 days prior to study entry: 1. Rifabutin. 2. Rifampin. 3. Ethionamide. 4. Cycloserine. 5. Clofazimine. 6. Ethambutol. 7. Amikacin. 8. Ciprofloxacin. 9. Ofloxacin. 10. Sparfloxacin. 11. Azithromycin. 12. Clarithromycin. 13. Pyrazinamide. Excluded within 14 days prior to study entry: 1. Carbamazepine. 2. Terfenadine. 3. Theophylline. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antimycobacterial drugs other than the study drugs. 2. Carbamazepine. 3. Terfenadine. 4. Theophylline. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Perceived unreliability or unavailability for frequent monitoring. PATIENT EXCLUSION CRIT. AVAILABILITY: Anticipated unreliability or unavailability for frequent monitoring. SUBSTANCE IDENTIFICATION Drug 1 DRG-0099 Clarithromycin SUBSTANCE IDENTIFICATION Drug 2 DRG-0111 Ethambutol SUBSTANCE IDENTIFICATION Drug 3 DRG-0085 Rifabutin TRADE NAME OF SUBSTANCE Drug 1‰ Biaxin TRADE NAME OF SUBSTANCE Drug 2‰ Myambutol TRADE NAME OF SUBSTANCE Drug 3‰ LM427 MANUFACTURERS Drug 1: Abbott Laboratories One Abbott Park Road Abbott Park, IL 60064 Contact: Dr J Carl Craft (708) 937-8147. MANUFACTURERS Drug 2: Lederle Laboratories North Middletown Road Pearl River, NY 10965 Contact: Dr Amy Baim (914) 732-2147 Contact: Dr John Riefler (914) 732-2035. MANUFACTURERS Drug 3: Adria Laboratories Incorporated PO Box 16529 Columbus, OH 43216-6529 Contact: Beverly Wynne (614) 764-8307. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 500 mg BID. Drug 2: 15 mg/kg daily. Drug 3: 300 or 450 mg (or placebo) daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 1000 mg. Drug 2: 15 mg/kg. Drug 3: 300 or 450 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Oral. Drug 3: Oral OTHER TREATMENT INFO. TREATMENT DURATION: Lifelong. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reasons: 1. Adverse experience. 2. Considered to be treatment failure. SUPPORTING AGENCY Adria Laboratories Incorporated. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Clarithromycin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Ethambutol/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycobacterium avium-intracellulare Infection/ COMPLICATIONS/*DRUG THERAPY MESH HEADING Rifabutin/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 72559-06-9 (Rifabutin) CAS REGISTRY NUMBER 74-55-5 (Ethambutol) CAS REGISTRY NUMBER 81103-11-9 (Clarithromycin) LAST REVISION DATE 930510 ENTRY MONTH 9307 ARIZONA McDowell Clinic 1314 East McDowell Road Phoenix, AZ 85006 Contact: Mary Coburn (602) 257-0606 OPEN 931026. ARIZONA Maricopa Medical Research Foundation / Department of Medicin 2601 East Roosevelt Phoenix, AZ 85008 Contact: Dr John Post (602) 267-5611 OPEN 940419. CALIFORNIA Combat Group 1800 North Highland Suite 610 Los Angeles, CA 90028 Contact: Holly Boyd (213) 469-5888 OPEN 931026. CALIFORNIA Cedars Sinai Medical Center / Division of Infectious Disease 8700 Beverley Boulevard Los Angeles, CA 90048 Contact: Dr Paula Gaut (310) 855-5000 OPEN 940419. CALIFORNIA Bay Harbor Hospital 1403 W Loma Blvd / Suite 201 Harbor City, CA 90710 Contact: Dr Michael Nakata (310) 530-9211 OPEN 930510. CALIFORNIA HIV Research Group 458 26th Street San Diego, CA 92102 Contact: Karen Sova (619) 544-0482 Contact: Dr Daniel Pearce (619) 544-0482 OPEN 931026. CALIFORNIA UCSD / Center for Special Immunology 2918 Fifth Ave / Suite 300 San Diego, CA 92103 Contact: Dr Scott Loss (619) 543-8080 OPEN 940419. CALIFORNIA Center for Special Immunology 100 Pacifica Suite 100 Irvine, CA 92718 Contact: Dr Paul Cimoch (714) 753-0670 OPEN 940419. CALIFORNIA Sunnyvale Medical Clinic 301 Old San Francisco Road Sunnyvale, CA 94086 Contact: Sandy Odenheimer (408) 524-5091 OPEN 931026. CALIFORNIA Saint Francis Memorial Hospital 900 Hyde Street San Francisco, CA 94109 Contact: Dr Gifford Leoung (415) 353-6216 OPEN 940419. CALIFORNIA General Hospital / AIDS Clinical Trials Unit 995 Potrero Avenue / Bldg 80 / Ward 84 San Francisco, CA 94110 Contact: David Gary (415) 476-9296 X 846OPEN 931026 ACTU: 0808. CALIFORNIA Veterans Administration Medical Center 4150 Clement Street #111W San Francisco, CA 94121 Contact: Manon Marovick RN (415) 221-4810 X 338OPEN 931026. DISTRICT OF COLUMBIA George Washington University Ross Hall / Room 202 / 2300 I Street NW Washington, DC 20037 Contact: Dr David Parenti (202) 994-2417 Contact: Jane Courtless (202) 994-2417 OPEN 931026. DISTRICT OF COLUMBIA Veterans Administration Medical Center 50 Irving Street N W Washington, DC 20422 Contact: Dr Fred Gordon (202) 745-8695 Contact: Patricia Ackerson (202) 745-8695 OPEN 931026. FLORIDA Infectious Disease Consultants / Dr Carlos Ruiz 685 Palm Springs Drive / Suite 2A Altamonte Springs, FL 32701 Contact: Laura Hoffman (407) 830-5577 OPEN 931202. FLORIDA Dr Nelson Zide 4700 / K / Sheridan Street Hollywood, FL 33021 Contact: Sherry Balber (305) 962-0040 Contact: Diana Bryan (305) 962-0040 Contact: Dr Nelson Zide (305) 962-0040 OPEN 931026. FLORIDA Center for Special Immunology 400 Arthur Godfrey Road / Suite 504 Miami Beach, FL 33140 Contact: Dr Robert Keller (305) 538-1400 OPEN 940419. FLORIDA Therafirst Medical Center 4011 North Federal Hwy Ft Lauderdale, FL 33308 Contact: Denise LaMarca (305) 564-4222 Contact: Warren Westervelt (305) 564-4222 Contact: Dr Anthony LaMarca (305) 564-4222 OPEN 931026. FLORIDA Dr Gary Richmond 315 Southeast 14th Street Fort Lauderdale, FL 33316 Contact: Dr Gary Richmond (305) 524-2250 OPEN 940419. FLORIDA Dr Frank Tornaka 1625 Southeast 3rd Avenue Ft Lauderdale, FL 33316 Contact: Dr. Frank Tornaka OPEN 940419. FLORIDA Bay Area AIDS Consortium 2901 Swann Avenue / Suite 107 Tampa, FL 33609 Contact: Clinical Trials Director (813) 877-5696 OPEN 931026. FLORIDA Dr Bary Rodwick 960 Main Street Safety Harbor, FL 34695 Contact: Dr Barry Rodwick (813) 725-9931 OPEN 940419. GEORGIA Infectious Disease Research Consortium of Georgia 1758 Century Blvd Suite A Atlanta, GA 30345 Contact: Dr Winkler Weinberg (404) 325-4677 OPEN 931026. ILLINOIS Dr Daniel Berger 2835 North Sheffield / Suite 104 Chicago, IL 60657 Contact: Dr Daniel Berger (312) 296-2400 OPEN 940419. KANSAS University of Kansas / School of Medicine 1010 N Kansas Wichita, KS 67214 Contact: Dr Donna Sweet (316) 261-2855 OPEN 940419. LOUISIANA Tulane University Medical School / AIDS Clinical Trials Unit 1430 Tulane Avenue New Orleans, LA 70112-2699 Contact: Russell Strada (504) 584-3605 OPEN 931026. MICHIGAN Dr Arnold Markowitz 2112 Cass Lake Road Keego Harbor, MI 48320 Contact: Dr Arnold Markowitz (810) 681-0360 OPEN 940419. NORTH CAROLINA Nalle Clinic 1350 South Kings Drive Charlotte, NC 28287 Contact: Jan Caldwell (704) 342-8100 Contact: Dr Joseph Jemsek (704) 342-8318 OPEN 931026. NEBRASKA University of Nebraska Medical Center / HIV Clinic 600 South 42nd Street Omaha, NE 68198-5130 Contact: Colleen R Kelly (402) 559-8163 OPEN 931203. NEW JERSEY Veterans Administration Hospital 385 Tremont Avenue East Orange, NJ 07019 Contact: Dr Robert Eng (201) 676-1000 X 168OPEN 931026. NEW JERSEY Community Research Initiative of North Jersey 393 Central Avenue Newark, NJ 07102 Contact: William Orr (201) 648-0350 Contact: Vicki Taylor Contact: Dr George Perez OPEN 931026. NEW YORK Chelsea Village Medical Center / St Vincent's Hospital 314 W 14th St / 5th Flr New York, NY 10014 Contact: Dr David Kaufman (212) 620-0144 OPEN 931026. NEW YORK Long Island Jewish Medical Center 269-11 76th Avenue / Division of Hematological Oncology New Hyde Park, NY 11042 Contact: Eileen Fusco (718) 470-7698 Contact: Dr Frederick Siegal (718) 470-8938 OPEN 940419. NEW YORK Community Health Network 758 South Avenue Rochester, NY 14620 Contact: Judy Takacs (716) 244-9000 Contact: Loraine Newcomb (716) 244-9000 OPEN 931026. PENNSYLVANIA Polyclinic Medical Center 2601 North Third Street Harrisburg, PA 17110 Contact: Alice Boucher (717) 782-2987 OPEN 931026. PENNSYLVANIA Buckley Braffman Stern Medical Associates PC 822 Pine Street / Suite 3A Philadelphia, PA 19107 Contact: Nancy Pietroski (215) 925-8010 OPEN 931026. SOUTH CAROLINA Alfred F Burnside Jr M D 1640 St Julian Place Suite 300 Columbia, SC 29204 Contact: John Windham (803) 256-7282 OPEN 931026. SOUTH CAROLINA Veterans Administration Medical Center 109 Bee Street Charleston, SC 29401-5799 Contact: Dr J. Robert Cantey (803) 577-5011 OPEN 940419. 148 UNIQUE IDENTIFIER FDA/00641 PROTOCOL ID NUMBERS FDA 037C PROTOCOL TITLE An Open-Label Safety Study of Oral Ganciclovir Maintenance Treatment of CMV Retinitis in People With Limited Venous Access. VERSION NUMBER & DATE (940613) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Nationwide Access GENERAL DESCRIPTION PURPOSE: To provide oral ganciclovir to patients who require maintenance for control of cytomegalovirus (CMV) retinitis, but who lack patent permanent central venous access for long-term administration of intravenous drugs. Methodology: Patients receive oral ganciclovir as maintenance. Patients enrolled at time of closure of enrollment will receive 2 months of study drug and undergo follow-up. GENERAL DESCRIPTION METHODOLOGY: Patients receive oral ganciclovir as maintenance. Patients enrolled at time of closure of enrollment will receive 2 months of study drug and undergo follow-up. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940613) DISEASE STUDIED Cytomegalovirus retinitis ( CMV retinitis ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by HIV antibody test, p24 antigen assay, or HIV culture, OR diagnosis of AIDS by CDC criteria. 2. Stable CMV retinitis. 3. Treatment with IV ganciclovir or IV foscarnet for at least 18 of the past 21 days. 4. Currently lack a patent permanent central IV catheter. 5. Had a permanent central IV catheter removed two or more times within the past 6 months due to catheter infection or thrombosis. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS GANS2224 STUDY DESIGN Open Label; Multicenter; Single-arm; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: UNLIMITED patients. (Enrollment is open until 1 month after oral ganciclovir is commercially available) PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Until 1 month after oral ganciclovir becomes commercially available. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS. 2. Stable CMV retinitis. 3. Treatment with IV ganciclovir or IV foscarnet for at least 18 of the past 21 days. 4. No permanent central IV catheter at present. 5. Had a permanent central IV catheter removed two or more times within the past 6 months due to catheter infection or thrombosis. 6. Consent of guardian if less than legal age of consent. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: > 25000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils > 500 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception during the study and for 90 days after. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: History of hypersensitivity to acyclovir or ganciclovir. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Intravitreal anti-CMV treatment. 2. Any other concomitant medications precluded by the protocol. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: Require continuation of concomitant medications precluded by this protocol. SUBSTANCE IDENTIFICATION Drug 1 DRG-0018 Ganciclovir MANUFACTURERS Drug 1: Syntex Research 3401 Hillview Avenue / PO Box 10850 Palo Alto, CA 94303 Contact: Dr Bonnie Charpentier (415) 354-2344. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral SUPPORTING AGENCY Syntex Research. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Administration, Oral MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Ganciclovir/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Retinitis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 82410-32-0 (Ganciclovir) LAST REVISION DATE 940613 ENTRY MONTH 9407 CALIFORNIA Syntex Research 3401 Hillview Avenue / PO Box 10850 Palo Alto, CA 94303 Contact: Study Center (Physicians call) (800) 569-4630 OPEN / USA accrual 940613. 149 UNIQUE IDENTIFIER FDA/00640 PROTOCOL ID NUMBERS FDA 037B PROTOCOL TITLE A Randomized, Controlled Study of the Safety and Preventive Efficacy of Oral Ganciclovir When Used in Conjunction With An Intravitreal Ganciclovir Implant in the Treatment of Cytomegalovirus Retinitis. VERSION NUMBER & DATE (940613) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To demonstrate the efficacy of oral ganciclovir at a dose of 1500 mg TID in preventing new cytomegalovirus (CMV) disease in AIDS patients with unilateral CMV retinitis treated with an intravitreal ganciclovir implant. To compare safety and tolerance, time to progression, quality of life, and survival among patients treated with an intravitreal ganciclovir implant, with and without oral ganciclovir, versus standard intravenous (IV) ganciclovir therapy. Methodology: Patients receive intravitreal ganciclovir implant plus oral ganciclovir, intravitreal implant alone, or IV ganciclovir. GENERAL DESCRIPTION METHODOLOGY: Patients receive intravitreal ganciclovir implant plus oral ganciclovir, intravitreal implant alone, or IV ganciclovir. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940607) DISEASE STUDIED Cytomegalovirus retinitis ( CMV retinitis ). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection by HIV antibody test, p24 antigen assay, or HIV culture, OR diagnosis of AIDS by CDC criteria. 2. Unilateral CMV retinitis diagnosed by funduscopy and confirmed by retinal photographs. Previously diagnosed retinitis must be of no more than 6 months duration and be currently stable following at least 4 weeks of IV ganciclovir. No more than two relapses of retinitis may have occurred since original diagnosis. NOTE: Patients with past or present extraocular CMV disease are not eligible. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS GANS2304 STUDY DESIGN Comparative administration route; Partially Blinded; Randomized; Parallel-Group; Placebo-Controlled; Multicenter PROTOCOL DETAILS STUDY INTENT: Drug safety, Drug efficacy, Administration route comparison. PROTOCOL DETAILS PROJECTED ACCRUAL: 450 patients. PROTOCOL DETAILS ACTUAL ACCRUAL: 1/450 (940607). PROTOCOL DETAILS STUDY DURATION: 52 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 23 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS. 2. Unilateral CMV retinitis. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: >= 25000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 500 cells/mm3. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception during the study and for 90 days after. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Topical drugs and ophthalmics. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. History of previous invasive intraocular surgery of any kind in the involved eye or any condition for which ocular surgery in contraindicated. 2. History of hypersensitivity to acyclovir or ganciclovir. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior oral ganciclovir. 2. Prior intravitreal ganciclovir implant. 3. More than three prior induction dose courses of IV anti-CMV therapy. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Vidarabine. 2. Amantadine hydrochloride. 3. Cytarabine. 4. FIAC or FIAU. 5. Idoxuridine. 6. Ribavirin. 7. Valacyclovir. 8. Foscarnet. 9. CMV hyperimmune globulin. 10. Soluble CD4. 11. Trichosanthin. 12. Imipenem-cilastatin. 13. Isoprenosine. 14. Levamisole. 15. Interferon. 16. Other investigational drugs. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Chronic, clinically significant diarrhea, nausea, abdominal pain,or other symptoms of uncontrolled gastrointestinal disease. 2. Ocular opacities (corneal, aqueous, lens, or vitreous) preventing ophthalmologic retinal assessment of fundus photography. 3. Acute retinal necrosis or any other intraocular condition that might preclude study completion. 4. Ocular condition requiring immediate surgery. 5. Unable to have long-term IV catheter placement. SUBSTANCE IDENTIFICATION Drug 1 DRG-0018 Ganciclovir MANUFACTURERS Drug 1: Syntex Research 3401 Hillview Avenue / PO Box 10850 Palo Alto, CA 94303 Contact: Dr Bonnie Charpentier (415) 354-2344. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Oral: 1500 mg TID SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: Oral: 4500 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral; intravitreal implant; intravenous (IV) SUPPORTING AGENCY Syntex Research. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Administration, Oral MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING Ganciclovir/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Retinitis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 82410-32-0 (Ganciclovir) LAST REVISION DATE 940607 ENTRY MONTH 9407 CALIFORNIA Estelle Doheny Eye Clinic 1355 San Pablo Street Los Angeles, CA 90033 Contact: Laurie Levin (213) 342-6466 OPEN 940613. CALIFORNIA Dr Neil Brourman 8641 Wilshire Blvd Suite 205 Beverly Hills, CA 90211 Contact: Karen Minoda (310) 289-3666 Contact: Susan Bagley (310) 289-3666 OPEN 940613. CALIFORNIA Harbor UCLA Medical Center 1000 W Carson Street Box 9 Torrance, CA 90509 Contact: Sharon (310) 222-5189 OPEN 940613. CALIFORNIA University of California Irvine 19722 MacArthur Blvd Irvine, CA 92715 Contact: Dr Baruch Kupperman (714) 856-6256 Contact: (714) 856-8610 OPEN 940613. CALIFORNIA Dr Robert Avery 515 E Micheltorena Ave Suite C Santa Barbara, CA 93103 Contact: Dr Robert Avery (805) 963-1648 OPEN 940613. CALIFORNIA Pacific Medical Center 2340 Clay Street San Francisco, CA 94115 Contact: Dr Everett Ai (415) 923-3948 OPEN 940613. CALIFORNIA Kaiser Hospital 1600 Divisadero San Francisco, CA 94115 Contact: Anna Dowling (415) 202-3981 OPEN 940613. CALIFORNIA Santa Clara Valley Medical Center 751 S Bascom Avenue San Jose, CA 95128 Contact: Susan Burton (415) 364-6563 OPEN 940613. CALIFORNIA Dr Robert T Wendel 3939 J Street #106 Sacremento, CA 95819 Contact: Dana Haselwood (916) 454-4861 OPEN 940613. DISTRICT OF COLUMBIA Dr Alan Palestine 1145 19th Street NW Suite 500 Washington, DC 20036 Contact: Mary Henegan (202) 833-1668 OPEN 940613. FLORIDA Dr Michael Stewart 1801 Barr Street Suite 715 Jacksonville, FL 32204 Contact: Dr Michael Stewart (904) 388-8446 OPEN 940613. FLORIDA Bascom Palmer 900 NW 17th Street Miami, FL 33136 Contact: Ruth Vandenbrouke (305) 326-6348 OPEN 940613. GEORGIA Emory Eye Clinic 1327 Clifton Road Northeast Atlanta, GA 30322 Contact: Debbie Gibbs (404) 248-4815 OPEN 940613. ILLINOIS Dr David Weinberg 303 E Chicago Ave Ward Bldg 2-186 Chicago, IL 60611 Contact: Kathy Naughton (312) 908-8040 OPEN 940613. KENTUCKY University of Kent Medical Center Kentucky Clinic Rm E303 Lexington, KY 40536 Contact: Dr Harsha Sen (502) 323-5000 OPEN 940613. MASSACHUSETTS New England Medical Center 750 Washington Street Box 450 Boston, MA 02111 Contact: Dr Jay Duker (617) 956-4600 Contact: Stephanie/Sec (617) 956-4604 OPEN 940613. NEW YORK Dr Dorothy Friedberg 310 Lexington Ave New York, NY 10016 Contact: Richard Hutt (212) 561-3906 OPEN 940613. NEW YORK St Clares Prof Office 426 E 52nd Street New York, NY 10019 Contact: Dr Kimball Woodward (914) 359-7272 OPEN 940613. NEW YORK New York Hospital 520 East 70th St Star Pavilion New York, NY 10021 Contact: Sandi Sledz (212) 746-4393 Contact: Susan Wise-Cambell (212) 746-2493 OPEN 940613. NEW YORK Vitreo-Retinal Consultants 944 Park Avenue New York, NY 10028 Contact: Dr Ronni Lieberman (212) 737-7400 OPEN 940613. 150 UNIQUE IDENTIFIER FDA/00602 PROTOCOL ID NUMBERS FDA 031F PROTOCOL TITLE An Open-Label Safety Program for the Use of Dideoxycytidine (ddC) in Pediatric Patients With Symptomatic HIV Infection Who Have Failed or Are Intolerant to AZT Monotherapy, or Who Have Completed Other ddC Protocols, or Are Ineligible for Other Ongoing Clinical Studies. VERSION NUMBER & DATE (940307) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Child TRIAL CATEGORY Nationwide Access GENERAL DESCRIPTION PURPOSE: To allow, on a compassionate use basis, dideoxycytidine (ddC) for pediatric patients with symptomatic HIV disease who have failed treatment or who are intolerant to zidovudine (AZT), or who have completed other ddC protocols, or who are ineligible for ongoing clinical trials. Methodology: Patients receive ddC and are evaluated at study entry and every 3 months thereafter, until 3 months after ddC becomes approved for pediatric patients or the sponsor deems it necessary to terminate the protocol. GENERAL DESCRIPTION METHODOLOGY: Patients receive ddC and are evaluated at study entry and every 3 months thereafter, until 3 months after ddC becomes approved for pediatric patients or the sponsor deems it necessary to terminate the protocol. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940101) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Symptomatic HIV infection. 2. Failed or intolerant to AZT monotherapy OR completed other ddC protocols OR ineligible for other ongoing clinical trials. NOTE: Patients who do not meet the eligibility requirements may discuss their cases with the medical monitor. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS NV14610 STUDY DESIGN Open Label; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Compassionate use, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 600 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: Until 3 months after ddC becomes approved for pediatric patients or study is terminated. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Symptomatic HIV infection. 2. Failure on or intolerance to AZT monotherapy OR completed other ddC protocols OR been ineligible for other ongoing clinical trials. NOTE: Patients who do not meet the eligibility requirements may discuss their cases with the medical monitor. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 03 Months - 11 Years. PATIENT SEX MALE PATIENT SEX FEMALE PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 02 Months. 12 Years - 99 Years. SUBSTANCE IDENTIFICATION Drug 1 DRG-0015 Dideoxycytidine TRADE NAME OF SUBSTANCE Drug 1‰ HIVID MANUFACTURERS Drug 1: Hoffmann-La Roche, Incorporated 340 Kingsland Street Nutley, NJ 07110-1199 Contact: Professional Services (800) 526-6367. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 0.01 or 0.005 mg/kg q 8 hr (at investigator's discretion) SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 0.03 or 0.015 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral, 0.1 mg/ml syrup OTHER TREATMENT INFO. TREATMENT DURATION: Until 3 months after ddC becomes approved for pediatric patients or study is terminated. OTHER TREATMENT INFO. END POINT: Serious adverse experiences. SUPPORTING AGENCY Hoffmann-La Roche, Incorporated. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Acquired Immunodeficiency Syndrome/*DRUG THERAPY MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Female MESH HEADING Human MESH HEADING Male MESH HEADING Zalcitabine/*ADVERSE EFFECTS CAS REGISTRY NUMBER 7481-89-2 (Zalcitabine) LAST REVISION DATE 940101 ENTRY MONTH 9403 NEW JERSEY Hoffmann-La Roche Incorporated 340 Kingsland Street Nutley, NJ 07110 Contact: ddC Coord Center (12-5 pm EST) (800) 332-2144 OPEN / USA accrual 940101. 151 UNIQUE IDENTIFIER FDA/00131 PROTOCOL ID NUMBERS FDA 029G PROTOCOL TITLE An Open Label Evaluation of the Safety and Pharmacokinetics of Ganciclovir in Children. VERSION NUMBER & DATE (900427) TRIAL CATEGORY Child TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To evaluate the pharmacokinetics of intravenous ganciclovir in children (ages 3 months - 12 years). To determine the safety and tolerance of a 2 to 3 week induction course of ganciclovir IV (5mg/kg every 12 hours) in immunocompromised children receiving treatment for life- or sight-threatening cytomegalovirus infections. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940613) DISEASE STUDIED Cytomegalovirus retinitis ( CMV retinitis ). DISEASES STATUS Patients have the following symptoms and conditions: Congenital or acquired immune deficiency including: AIDS. Iatrogenic immunosuppression for transplantation or for autoimmune disorders. Immunosuppression due to cytotoxic chemotherapy. immunodeficiency associated with neoplasia. Congenital immunodeficiency. Eligible to receive ganciclovir for the treatment of life- or sight-threatening Cytomegalovirus (CMV) disease as defined below. o CMV retinitis confirmed by an ophthalmologist. o Life-threatening CMV disease such as pneumonia, gastrointestinal disease, hepatitis, or other organ specific or disseminated disease, or CMV viremia, detection of CMV antigenemia, or CMV viruria which, in the opinion of the investigator, is an indication of life-threatening CMV disease. CMV disease should be confirmed by appropriate diagnostic procedures: (1) Inclusion bodies consistent with CMV, or (2) A positive CMV culture of the specific tissue, or (3) A positive CMV DNA hybridization probe assay of the specific tissue, or (4) An immunochemically specific identification of the CMV antigen. Children are allowed if: 1. Appropriate diagnostic procedures necessary to obtain organ specific virologic confirmation have been undertaken and all available histologic, or immunologic tests and cultures have been requested. 2. The investigator indicates that the disease is immediately life-threatening and delay in treatment while awaiting test results would put the patient at increased risk. 3. There is laboratory evidence of acute CMV infection such as seroconversion, four-fold increase in CMV titer, or viral isolation or positive rapid diagnostic test from another site (viremia, viruria, throat washings, etc.). If cultures, DNA probe, and immunologic testing remain negative and if the patient fails to respond to ganciclovir the drug should be discontinued. If cultures and probe remain negative but the patient appears to respond to theray, clinical judgement may support continuing of ganciclovir treatment. Underlying immunodeficiency is required; infants and children with congenital CMV infection but no immunodeficiency disorder will not be eligible for this study. ELIGIBILITY AIDS. OTHER - immunocompromised. OTHER PROTOCOL NUMBERS ICM 1788 STUDY DESIGN Open Label PROTOCOL DETAILS STUDY INTENT: Pharmacokinetics, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 20 patients. PROTOCOL DETAILS ACTUAL ACCRUAL: 16/20 (940309). PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 8 units. INPATIENT/OUTPATIENT ST. Inpatient or outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have the following: Congenital or acquired immune deficiency. Eligiblity to receive ganciclovir for the treatment of life- or sight-threatening Cytomegalovirus (CMV) disease. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. PLATELET COUNT: >= 25000 platelets/mm3. (with some exceptions). PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophil count (ANC) >= 500 cells/mm3. (with some exceptions). PATIENT AGE AGE: 03 Months - 12 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Negative pregnancy test. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: Topical acyclovir. Consult with the Syntex study monitor for the following: Cytokines. Soluble CD4. Trichosanthin (Compound Q). Imipenem-cilastatin. Other investigational drugs. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following are excluded: o Mild to moderate Cytomegalovirus (CMV) infection that does not meet the clinical severity criteria. o Absolute neutrophil count (ANC) < 500 cells/mm3 or a platelet count < 25000 platelets/mm3. Note: Exceptions may be made for patients with pre-existing neutropenia or thrombocytopenia and immediately life-threatening disease, if the investigator believes that a delay in starting ganciclovir therapy is not advisable. In such patients, the investigator should advise the parents or guardians of the risk of further bone marrow suppression and the increased risk of infection or bleeding. o Receiving excluded medications that it is not possible to discontinue. o Congenital or neonatal CMV infections without documented congenital or acquired immunodeficiency. o Demonstrated hypersensitivity to acyclovir or ganciclovir. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 02 Months. 13 Years - 99 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. Positive pregnancy test. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Other myelosuppressive drugs. Antimetabolites. Alkylating agents. Nucleoside analogues (topical acyclovir is allowed). Interferons. Foscarnet. Consult with the Syntex study monitor for the following: Cytokines. Soluble CD4. Trichosanthin (Compound Q). Imipenem-cilastatin. Other investigational drugs. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following conditions or symptoms are excluded: Mild to moderate Cytomegalovirus infection that does not satisfy the clinical severity criteria. Congenital or neonatal CMV infections without documented congenital or acquired immunodeficiency. SUBSTANCE IDENTIFICATION Drug 1 DRG-0018 Ganciclovir TRADE NAME OF SUBSTANCE Drug 1‰ Cytovene MANUFACTURERS Drug 1: Syntex Research 3401 Hillview Avenue / PO Box 10850 Palo Alto, CA 94303 Contact: Dr Bonnie Charpentier (415) 354-2344. SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: IV SUPPORTING AGENCY Syntex Research. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Child MESH HEADING Child, Preschool MESH HEADING Cytomegalovirus Infections/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Female MESH HEADING Ganciclovir/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Immunocompromised Host MESH HEADING Infant MESH HEADING Male MESH HEADING Retinitis/COMPLICATIONS/DRUG THERAPY CAS REGISTRY NUMBER 82410-32-0 (Ganciclovir) LAST REVISION DATE 940613 ENTRY MONTH 9008 ALABAMA University of Alabama at Birmingham 653 Childrens Hospital Tower UAB Station Birmingham, AL 35294 Contact: Dr Richard Whitley (205) 934-5316 OPEN. CALIFORNIA The Center for the Health Sciences / UCLA 10833 Le Conte Avenue Room 22-442 MDCC Los Angeles, CA 90024 Contact: Dr Yvonne Bryson (310) 825-5235 OPEN. CALIFORNIA Children's Hospital of Los Angeles 4650 Sunset Boulevard Los Angeles, CA 90027 Contact: Dr Carl Lenarsky (213) 669-2546 OPEN. CALIFORNIA Los Angeles County Hospital / USC Medical Ctr / Pediatrics 1200 North State Street Los Angeles, CA 90033 Contact: Dr Andrea Kovacs (213) 226-3834 OPEN. ILLINOIS University of Chicago / Wylers 5841 South Maryland Avenue / Box 286 / Room C-623A Chicago, IL 60637 Contact: Dr Daniel Johnson (312) 702-6176 OPEN. NEBRASKA University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-3280 Contact: Dr Mark Schaefer (402) 559-4000 Contact: Beeper OPEN. NEW YORK University of Rochester Medical Center 601 Elmwood Avenue / Box 690 Rochester, NY 14642 Contact: Dr Lisa M Frenkel (716) 275-5944 OPEN 920409. 152 UNIQUE IDENTIFIER FDA/00679 PROTOCOL ID NUMBERS FDA 025C PROTOCOL TITLE Phase IV Study on the Safety and Efficacy of Megace Oral Suspension in HIV-Positive Females. VERSION NUMBER & DATE (941003) GENERAL DESCRIPTION PURPOSE: To further evaluate the safety of megestrol acetate (Megace) oral suspension in the treatment of anorexia and cachexia in HIV-positive women. To compare the effectiveness of 400 versus 800 mg daily of Megace by measurement of weight gain, appetite grade, and other parameters at 12 and 24 weeks. Methodology: Patients are randomized to receive 400 or 800 mg Megace oral suspension daily for 24 weeks; at 12 weeks, those receiving 400 mg who have not gained 5 pounds over baseline or had appetite improvement to good or excellent are escalated to 800 mg daily. Patients are evaluated at 4 week intervals. Dose may be adjusted to maintain a desired weight. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive 400 or 800 mg Megace oral suspension daily for 24 weeks; at 12 weeks, those receiving 400 mg who have not gained 5 pounds over baseline or had appetite improvement to good or excellent are escalated to 800 mg daily. Patients are evaluated at 4 week intervals. Dose may be adjusted to maintain a desired weight. PROTOCOL PHASE Phase IV OPEN/CLOSED INDICATOR Open: Actively accruing patients (940817) DISEASE STUDIED Anorexia, Cachexia. DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV seropositive. 2. Evidence of HIV wasting syndrome that includes anorexia (appetite fair or poor) and weight loss >= 10 percent of pre-illness body weight. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS MEG169-93.007 STUDY DESIGN Dose Comparison; Randomized; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety. PROTOCOL DETAILS PROJECTED ACCRUAL: 40 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 24 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 4 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patient must have: 1. HIV infection. 2. Evidence of HIV wasting syndrome that includes anorexia (appetite fair or poor) and weight loss >= 10 percent of pre-illness body weight. 3. Perception of weight loss as a detriment. 4. Life expectancy of at least 24 weeks. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Allowed: Megestrol acetate for weight gain at a dose < 400 mg for < 60 days, provided therapy was discontinued at least 3 months prior to study entry. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Hospitalization for or exacerbation of illness associated with weight loss within the past 2 weeks. 2. Participation in other investigational drug studies within the past month. 3. Previous abnormal mammogram (if 35-40 years of age) or abnormal mammogram within the past year (if over 40 years of age). [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. SEX: MALE; FEMALE PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: IV drug abuse not treated for at least 4 months. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. New antiviral therapy within the past 8 weeks. 2. Medications to promote weight gain (e.g., corticosteroid, dronabinol) within the past 2 months. 3. Megestrol acetate within the past 3 months. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Initiation during the study of any therapy to treat HIV or anorexia/cachexia (other than study drug). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Poorly controlled hypertension. 2. Heart failure. 3. Deep vein thrombosis. 4. Uncontrolled severe diarrhea. 5. Treatable active current infection (excluding chronic low-grade opportunistic infections). 6. Unable to intake food. 7. Impaired digestive/absorptive function. SUBSTANCE IDENTIFICATION Drug 1 DRG-0063 Megestrol acetate TRADE NAME OF SUBSTANCE Drug 1‰ Megace MANUFACTURERS Drug 1: Bristol-Myers Squibb 777 Scudders Mill Road Plainsboro, NJ 08536 Contact: Judy Wagner (609) 897-2132. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 400 or 800 mg daily for 24 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 400 or 800 mg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral OTHER TREATMENT INFO. TREATMENT DURATION: 24 weeks. SUPPORTING AGENCY Bristol-Myers Squibb. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Anorexia/COMPLICATIONS/*DRUG THERAPY MESH HEADING Cachexia/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Human MESH HEADING Megestrol/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Middle Age CAS REGISTRY NUMBER 3562-63-8 (Megestrol) LAST REVISION DATE 940817 ENTRY MONTH 9410 CALIFORNIA University of California / Davis Medical Center 2221 Stockton Blvd Sacramento, CA 95817 Contact: Dr Neil Flynn (916) 734-3793 OPEN 940817. CONNECTICUT Yale Medical School / AIDS Program 135 College Street / Suite 323 New Haven, CT 06510-2483 Contact: Dr Gerald Friedland (203) 737-2450 OPEN 940817. DISTRICT OF COLUMBIA Georgetown University Medical Center 3800 Reservoir Road / Kober-Cogan Bldg Suite 110 Washington, DC 20007-2197 Contact: Dr Mary Young (202) 687-3200 OPEN 940817. RHODE ISLAND The Miriam Hospital 164 Summit Avenue Providence, RI 02906 Contact: Dr Maria Mileno (401) 331-8500 X 402OPEN 940817. 153 UNIQUE IDENTIFIER FDA/00687 PROTOCOL ID NUMBERS FDA 020I PROTOCOL TITLE Phase III Multicenter, Open-Label, Randomized Trial of Induction Versus Induction Plus Maintenance Foscarnet ( Foscavir ) Therapy for Gastrointestinal CMV Disease. VERSION NUMBER & DATE (941206) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: PRIMARY: To compare the frequency of and time to relapse of Cytomegalovirus (CMV) gastrointestinal disease following foscarnet induction therapy only versus induction plus maintenance therapy. SECONDARY: To determine frequency of and time to recurrence of gastrointestinal symptoms, response rate of pathological lesions, and incidence of nongastrointestinal CMV disease in this patient population. Methodology: Patients receive intravenous foscarnet either as induction only for 4 weeks or as induction for 4 weeks followed by maintenance for 22 weeks. All patients are followed for 26 weeks or until relapse. GENERAL DESCRIPTION METHODOLOGY: Patients receive intravenous foscarnet either as induction only for 4 weeks or as induction for 4 weeks followed by maintenance for 22 weeks. All patients are followed for 26 weeks or until relapse. PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (941206) DISEASE STUDIED Cytomegalovirus ( CMV ) gastrointestinal disease. DISEASES STATUS Patients have the following symptoms and conditions: 1. AIDS. 2. Symptomatic CMV disease of the upper and/or lower gastrointestinal (GI) tract. 3. CMV GI disease is a first episode OR patient either failed a prior single course of up to 4 weeks of intravenous ganciclovir induction therapy or is intolerant of ganciclovir. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 93-FOS-29 STUDY DESIGN Multicenter; Open Label; Randomized PROTOCOL DETAILS STUDY INTENT: Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 145 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 26 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 16 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. AIDS. 2. CMV GI disease. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 14 days of study entry. Abstinence or effective method of birth control / contraception during the study and for 90 days after. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 14 days of study entry. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Prior foscarnet in extremis. 2. Investigational agents other than 3TC or d4T within 7 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Drugs that may interact with foscarnet. 2. Systemic acyclovir, ganciclovir, or acyclovir prodrug. 3. Drugs known to affect renal function. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Non-GI CMV disease. 2. Ulcerative colitis, inflammatory bowel disease, or other condition that may interfere with study results. 3. Other GI pathogens. SUBSTANCE IDENTIFICATION Drug 1 DRG-0017 Foscarnet sodium TRADE NAME OF SUBSTANCE Drug 1‰ Foscavir MANUFACTURERS Drug 1: Astra USA Inc 50 Otis Street Westborough, MA 01581 Contact: Dr Sarah Martin-Munley (508) 366-1100 X 2309. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: Induction: 90 mg/kg BID for 4 weeks. Maintenance: 120 mg/kg/day for 22 weeks SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: Induction: 180 mg/kg. Maintenance: 120 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV) OTHER TREATMENT INFO. TREATMENT DURATION: Up to 26 weeks. SUPPORTING AGENCY Astra USA Inc. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adult MESH HEADING Aged MESH HEADING Cytomegalovirus Infections/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Female MESH HEADING Foscarnet/*ADMINISTRATION & DOSAGE/ THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age CAS REGISTRY NUMBER 4428-95-9 (Foscarnet) LAST REVISION DATE 941206 ENTRY MONTH 9412 CALIFORNIA Los Angeles - USC Medical Center / GI and Liver Disease 1200 North State Street / Room 12-137 Los Angeles, CA 90033 Contact: Francisco Garcia (213) 226-6939 Contact: Dr Loren Laine (213) 226-7994 Contact: (213) 226-7995 OPEN 941206. CALIFORNIA University of California San Diego 2760 Fifth Avenue / Suite 300 San Diego, CA 92103 Contact: UCSD Treatment Center (619) 543-8080 OPEN 941206. CALIFORNIA San Francisco General Hospital 1001 Potrero Avenue San Francisco, CA 94110 Contact: Ulana Mencinski (415) 206-4746 Contact: Dr Paul Greenberg (415) 206-8824 Contact: Dr John P Cello (415) 206-8822 OPEN 941206. CALIFORNIA East Bay AIDS Center 3031 Telegraph Avenue / Suite 235 Berkeley, CA 94705 Contact: Sherry Lyman (510) 204-1870 Contact: Dr Carol Brosgart (510) 204-1201 OPEN 941206. FLORIDA Miami Veterans Administration Medical Center 1201 NW 16th Street / Special Immunology Unit / Dept 111-I Miami, FL 33125 Contact: Ghislaine Paperwalla RN (305) 324-4455 X 352Contact: Karen Clevens NP Contact: Dr Nancy Klimas (305) 324-4455 X 433OPEN 941206. GEORGIA Emory University School of Medicine / GI Division 69 Butler Street SE Atlanta, GA 30303 Contact: Lorraine Alexander (404) 616-4436 Contact: Dr C Mel Wilcox (404) 616-4435 Contact: Fax (404) 522-0404 OPEN 941206. ILLINOIS Rush Presbyterian - St Lukes Medical Center 600 South Paulina / Suite 143 / Academic Facility Chicago, IL 60612 Contact: Michelle Agnoli (312) 942-5865 Contact: Dr Harold Kessler OPEN 941206. ILLINOIS Rush Presbyterian - St Lukes Medical Center 1725 West Harrison Street / Professional Building Chicago, IL 60612 Contact: Janice Griffin (312) 942-5861 Contact: Dr Michael Brown (312) 942-5861 Contact: Mary Elizabeth Roarke Contact: Ruth Ann Burk OPEN 941206. MICHIGAN Dr Robert Bresalier / Henry Ford Hospital Main Campus / 2799 West Grand Blvd Detroit, MI 48202 Contact: Sandra Wilson (313) 876-9452 OPEN 941206. NEW YORK Dr Douglas Dieterich 345 East 37th Street Suite 204 New York, NY 10016 Contact: Kathleen Farrell (212) 263-6485 Contact: Dr Douglas Dieterich (212) 986-3330 OPEN 941206. NEW YORK Dept of Vet Affairs Med Ctr (632) / Gastroenterology Section 79 Middleville Road Northport, NY 11768 Contact: Mary Garcia (516) 261-4400 X 247OPEN 941206. OHIO Ohio State University Hospital Doan Hall / Room N 1148 / 410 West Tenth Avenue Columbus, OH 43210 Contact: Dr Maybeth Ramundo (614) 293-8112 OPEN 941206. 154 UNIQUE IDENTIFIER FDA/00617 PROTOCOL ID NUMBERS FDA 020H PROTOCOL TITLE A Multicenter Study of Oral Versus Intravenous Hydration in AIDS Patients With CMV Retinitis Treated With Foscavir. VERSION NUMBER & DATE (940329) TRIAL CATEGORY Opportunistic Infections PROTOCOL CHAIRS CHAIR Wool GM GENERAL DESCRIPTION PURPOSE: To assess the relative efficacy of oral versus intravenous hydration during foscarnet sodium (Foscavir) induction therapy (90 mg/kg BID), as determined by changes in creatinine clearance. To estimate the timing and volume of oral fluid hydration required to establish a diuresis before and during intravenous Foscavir therapy. To assess the general tolerance of two hydration regimens by the adverse event profile associated with each. Methodology: Patients are randomized to receive oral hydration versus intravenous hydration therapy during concomitant intermittent intravenous Foscavir therapy for treatment of cytomegalovirus (CMV) retinitis. Treatment continues during 2 or 3 weeks of induction Foscavir therapy. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive oral hydration versus intravenous hydration therapy during concomitant intermittent intravenous Foscavir therapy for treatment of cytomegalovirus (CMV) retinitis. Treatment continues during 2 or 3 weeks of induction Foscavir therapy. PROTOCOL PHASE Phase IV OPEN/CLOSED INDICATOR Open: Actively accruing patients (940301) DISEASE STUDIED Cytomegalovirus retinitis ( CMV retinitis ). DISEASES STATUS Patients have the following symptoms and conditions: 1. Documented HIV infection. 2. Recent diagnosis of CMV retinitis, by ophthalmoscopic appearance, that requires induction therapy. 3. No corneal, lens, or vitreous opacification that precludes examination of the fundi. 4. No evidence of other end organ CMV infection. 5. No evidence of tuberculous, diabetic, or hypertensive retinopathy. ELIGIBILITY AIDS. OTHER PROTOCOL NUMBERS 93-FOS-31 STUDY DESIGN Open Label; Randomized; Comparative administration route; Prospective; Multicenter PROTOCOL DETAILS STUDY INTENT: Administration route comparison. PROTOCOL DETAILS PROJECTED ACCRUAL: 112 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 2-3 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 11 units. INPATIENT/OUTPATIENT ST. Outpatient PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. Recent diagnosis of CMV retinitis, by ophthalmoscopic appearance, that requires induction therapy. 3. No corneal, lens, or vitreous opacification that precludes examination of the fundi. 4. No evidence of other end organ CMV infection. 5. No evidence of tuberculous, diabetic, or hypertensive retinopathy. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: >= 50 ml/min. PATIENT INCLUSION CRIT. KARNOFSKY: >= 60. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 7 days of study entry. Abstinence or effective method of birth control / contraception during the study and for 90 days after. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 7 days of study entry. No abstinence or no agreement to use effective method of birth control during study and for 90 days after. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: 1. Any investigational drug within 28 days prior to study entry. 2. Potentially nephrotoxic drugs (e.g., amphotericin B, aminoglycosides, cisplatin) within 7 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Any investigational drug. 2. Potentially nephrotoxic drugs (e.g., amphotericin B, aminoglycosides, cisplatin). PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Clinically significant cardiac, pulmonary, neurologic, gastrointestinal or renal impairment that would prevent adequate voluntary oral hydration (e.g., intubation, coma, status post-gastrectomy, colon resection, gastrointestinal tumors, malabsorption, chronic diarrhea) OR with which hydration would be hazardous (e.g., congestive heart failure). 2. Known allergy to foscarnet or related compounds. 3. Considered noncompliant or unreliable for study participation. SUBSTANCE IDENTIFICATION Drug 1 DRG-0017 Foscarnet sodium TRADE NAME OF SUBSTANCE Drug 1‰ Foscavir MANUFACTURERS Drug 1: Astra USA Inc 50 Otis Street Westborough, MA 01581 Contact: Dr Sarah Martin-Munley (508) 366-1100 X 2309. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 90 mg/kg BID accompanied by either oral or intravenous hydration SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 180 mg/kg SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Intravenous (IV) OTHER TREATMENT INFO. TREATMENT DURATION: 2-3 weeks. SUPPORTING AGENCY Astra USA Inc. MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Administration, Oral MESH HEADING Adult MESH HEADING Aged MESH HEADING Cytomegalovirus Infections/COMPLICATIONS/ *DRUG THERAPY MESH HEADING Female MESH HEADING Fluid Therapy MESH HEADING Foscarnet/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Infusions, Intravenous MESH HEADING Male MESH HEADING Middle Age MESH HEADING Retinitis/COMPLICATIONS/*DRUG THERAPY CAS REGISTRY NUMBER 4428-95-9 (Foscarnet) LAST REVISION DATE 940301 ENTRY MONTH 9404 CALIFORNIA Dr Milan Fiala 100 UCLA Medical Plaza / Suite 100 Los Angeles, CA 90024-6970 Contact: Dr Milan Fiala (310) 206-6392 OPEN 940301. CALIFORNIA Dr G Michael Wool Century City Plaza / 2080 Century Park East / Suite 1006 Los Angeles, CA 90067 Contact: Andrew Miranda (310) 556-7991 OPEN 940301. CALIFORNIA Dr Ralph Hansen 436 North Bedford Drive / Suite 308 Beverly Hills, CA 90210 Contact: Marilyn Irwin (310) 246-6550 OPEN 940301. CALIFORNIA AIDS Community Research Consortium 1048 El Camino Real Redwood City, CA 94063 Contact: Debbie Harris (415) 364-6563 Contact: Dr Stanley Deresinski OPEN 940301. GEORGIA Dr Joel Rosenstock 35 Collier Road / Suite 245 Atlanta, GA 30309 Contact: Kym Prieto (404) 325-4677 OPEN 940301. INDIANA Dr John Karedes Bank One Tower / 111 Monument Circle / Suite 3010 Indianapolis, IN 46204 Contact: Reba Baker (317) 638-2005 OPEN 940301. MICHIGAN Dr Paul Benson 2327 Coolidge Berkley, MI 48072 Contact: David Rock (810) 544-9300 OPEN 940301. NEW JERSEY Dr Ronald Nahass 411 Courtyard Drive Somerville, NJ 08876 Contact: Debbie Winters (609) 497-1068 OPEN 940301. NEW YORK Dr Ronald J Grossman 345 East 37th Street / Suite 209 New York, NY 10016 Contact: Jeff Silverstein (212) 818-0853 OPEN 940301. NEW YORK Community Health Network 758 South Avenue Rochester, NY 14620 Contact: Judy Takacs (716) 244-9000 Contact: Loraine Newcomb (716) 244-9000 OPEN 940301. 155 UNIQUE IDENTIFIER FDA/00616 PROTOCOL ID NUMBERS FDA 015I PROTOCOL TITLE Double-Blind Study of the Effect of Timunox (Thymopentin) on Lymphoproliferative Responses and Virus Load in HIV-Infected Subjects Receiving Nucleoside Analog Antiretroviral Therapy. VERSION NUMBER & DATE (940420) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To evaluate the mechanism whereby thymopentin appears to retard the progressive immune suppression attributable to HIV infection. Methodology: Patients are randomized to receive subcutaneous thymopentin or placebo thrice weekly for 4 weeks. GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive subcutaneous thymopentin or placebo thrice weekly for 4 weeks. PROTOCOL PHASE Phase II OPEN/CLOSED INDICATOR Open: Actively accruing patients (940401) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Seropositive for HIV-1 antibody by ELISA confirmed by Western blot. 2. CD4 count <= 400 cells/mm3 within 6 weeks prior to study entry. 3. Must have tolerated their current nucleoside analog antiretroviral treatment (zidovudine, didanosine, or dideoxycytidine) for at least 4 weeks prior to study entry. 4. Asymptomatic or minimally symptomatic disease, as defined by ABSENCE of the following: - HIV-associated neurologic abnormalities - Oral hairy leukoplakia - Unintentional weight loss greater than 10 percent of usual body weight - Unexplained temperature above 38 C on five or more consecutive days or 10 days within any 30-day period - Five or more episodes of unexplained drenching night sweats in any 30-day period - Unexplained diarrhea for 7 or more consecutive days in any 30-day period - Vulvovaginal candidiasis that is persistent (poorly responsive to local therapy) or frequent (> three episodes/year). NOTE: Patients may have had NO MORE THAN ONE of the following conditions prior to entry: - Herpes zoster infection within the last 2 years - Confirmed oral candidiasis - Bacillary angiomatosis - Listeriosis. ELIGIBILITY ASYM. ARC. OTHER PROTOCOL NUMBERS 07.32.039-94 STUDY DESIGN Double-Blind; Randomized; Placebo-Controlled; Multicenter PROTOCOL DETAILS STUDY INTENT: Drug efficacy. PROTOCOL DETAILS PROJECTED ACCRUAL: 60 patients. PROTOCOL DETAILS DURATION OF PATIENT ON STUDY: 4 weeks. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 3 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Asymptomatic or minimally symptomatic HIV infection (no evidence of AIDS). 2. CD4 count <= 400 cells/mm3 within 6 weeks prior to study entry. 3. Tolerated the current nucleoside analog antiretroviral treatment for at least 4 weeks prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 11 g/dl. (men); >= 10 g /dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: <= 400 cells/mm3. ( 0 - 100 - 200 - 300 - 400 ). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: 90. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 21 days prior to study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Nucleoside analog antiretroviral treatment for at least 4 weeks prior to study entry. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Required: Current nucleoside analog antiretroviral treatment. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior condition are excluded: Abnormal chest x-ray consistent with active opportunistic infection within 6 weeks prior to study entry. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 21 days prior to study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Significant active alcohol or drug abuse sufficient to prevent study compliance. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Any prior antiretroviral agents other than zidovudine, didanosine, or dideoxycytidine within 30 days prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Any antiretroviral agents other than zidovudine, didanosine, or dideoxycytidine. 2. HIV vaccines or any investigational or non-FDA approved medication or immunomodulatory or experimental therapy within 30 days prior to study entry. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Known hypersensitivity to thymopentin or any component of the formulation. 2. Significant chronic underlying medical illness that would impede study participation. 3. Grade 2 or higher peripheral neuropathy related to nucleoside analog antiretroviral treatment. SUBSTANCE IDENTIFICATION Drug 1 DRG-0065 Thymopentin TRADE NAME OF SUBSTANCE Drug 1‰ Timunox MANUFACTURERS Drug 1: Immunobiology Research Institute Route 22 East PO Box 999 Annandale, NJ 08801-0999 Contact: Linda Meyerson (908) 730-1750. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 50 mg (or placebo) thrice weekly for 4 weeks SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Subcutaneous OTHER TREATMENT INFO. END POINT: Lymphoproliferative responses, T-cell subsets, apoptosis, and HIV viral RNA levels. SUPPORTING AGENCY Immunobiology Research Institute. MESH HEADING AIDS-Related Complex/*DRUG THERAPY MESH HEADING Adult MESH HEADING Aged MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Thymopentin/*THERAPEUTIC USE CAS REGISTRY NUMBER 69558-55-0 (Thymopentin) LAST REVISION DATE 940401 ENTRY MONTH 9404 CALIFORNIA Dr Jeffrey Galpin 5620 Wilbur Avenue / Suite 322 Tarzana, CA 91356 Contact: Vicki Ramirez (818) 345-2172 OPEN 940401. CALIFORNIA Dr Marcus Conant 1635 Divisadero Street San Francisco, CA 94115 Contact: Tanya Kocian (415) 923-0222 OPEN 940401. PENNSYLVANIA Novum Inc 5900 Penn Avenue Pittsburgh, PA 15206 Contact: Sharon Grace (412) 363-3300 OPEN 940401. 156 UNIQUE IDENTIFIER FDA/00576 PROTOCOL ID NUMBERS FDA 015H PROTOCOL TITLE Double-Blind Study of Timunox (Thymopentin) in Asymptomatic HIV-Infected Patients Receiving Either Mono (AZT or ddI) or Combination (AZT/ddI or AZT/ddC) Anti-Retroviral Therapy. VERSION NUMBER & DATE (940725) TRIAL CATEGORY HIV Infection TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To confirm results from a previous study in which the combination of thymopentin plus zidovudine (AZT), an antiretroviral agent, slowed disease progression in HIV-infected asymptomatic patients. To evaluate the efficacy and safety of thymopentin in HIV-infected asymptomatic patients receiving either monotherapy with AZT, didanosine (ddI), or stavudine (d4T), or combination antiretroviral therapy with AZT/ddI or AZT/dideoxycytidine (ddC). PROTOCOL PHASE Phase III OPEN/CLOSED INDICATOR Open: Actively accruing patients (940511) DISEASE STUDIED Primary HIV infection. DISEASES STATUS Patients have the following symptoms and conditions: 1. Asymptomatic HIV infection. 2. CD4 count 200-400 cells/mm3. 3. No HIV-associated neurologic abnormalities or constitutional symptoms. 4. No oral hairy leukoplakia. 5. At least 6 months of prior AZT or at least 4 weeks of prior d4T or ddI OR prior combination therapy with AZT/ddI or AZT/ddC. ELIGIBILITY ASYM. OTHER PROTOCOL NUMBERS 07.32.033-93 STUDY DESIGN Double-Blind; Randomized; Placebo-Controlled; Multicenter; Drug Tolerance PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Combination drug therapy. PROTOCOL DETAILS ACTUAL ACCRUAL: 337 (940511). PROTOCOL DETAILS STUDY DURATION: 1-2 years. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 40 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Asymptomatic HIV infection. 2. CD4 count 200-400 cells/mm3. 3. No HIV-associated neurologic abnormalities or constitutional symptoms. 4. No oral hairy leukoplakia. 5. At least 6 months of prior AZT or at least 4 weeks of prior d4T or ddI OR prior combination therapy with AZT/ddI or AZT/ddC. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. HEMOGLOBIN: >= 11 g/dl. (men); >= 10 g/dl (women). PATIENT INCLUSION CRIT. PLATELET COUNT: >= 75000 platelets/mm3. PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: 200 - 400 cells/mm3. ( 200 - 300 - 400 ). PATIENT INCLUSION CRIT. SGPT(ALT): <= 5 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. KARNOFSKY: 100. PATIENT INCLUSION CRIT. OTHER: Absolute neutrophils >= 1000 cells/mm3. Total serum or pancreatic amylase <= 2 x ULN. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Not breast-feeding. OTHER PATIENT INCL. CH. PRIOR MEDICATION: Required: Prior AZT (>= 300 mg/day) for at least 6 months OR prior didanosine (minimum 300 mg/day if > 45 kg or 200 mg/day if <= 45 kg) for at least 4 weeks OR d4T (minimum 30 mg/day) for at least 4 weeks. Allowed: Prior ddC (minimum 1.125 mg/day) for at least 4 weeks, if given in combination with AZT. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: 1. Herpes zoster (within the past 2 years). 2. Oral candidiasis (confirmed). 3. Vulvovaginal candidiasis (persistent, frequent, or poorly responsive to therapy). 4. Bacillary angiomatosis. 5. Listeriosis. 6. Idiopathic thrombocytopenia purpura. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Breast-feeding. PATIENT EXCLUSION CRIT. RISK BEHAVIOR: Significant active alcohol or drug abuse. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded at any time prior to study entry: More than one dose of thymopentin. Excluded within 30 days prior to study entry: 1. HIV vaccines. 2. Investigational or non-FDA approved medication. 3. Immunomodulatory therapies. 4. Experimental therapies. 5. Any antiretroviral therapy other than AZT, ddI, ddC, or d4T. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. HIV vaccines. 2. Investigational or non-FDA approved medication. 3. Immunomodulatory therapies. 4. Experimental therapies. 5. Any antiretroviral therapy other than AZT, ddI, ddC, d4T. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Abnormal chest x-ray, consistent with active opportunistic infection. 2. Hypersensitivity to thymopentin. 3. Significant chronic underlying medical illness. 4. Grade 2 or worse peripheral neuropathy. SUBSTANCE IDENTIFICATION Drug 1 DRG-0065 Thymopentin SUBSTANCE IDENTIFICATION Drug 2 DRG-0004 Zidovudine SUBSTANCE IDENTIFICATION Drug 3 DRG-0016 Didanosine SUBSTANCE IDENTIFICATION Drug 4 DRG-0015 Dideoxycytidine SUBSTANCE IDENTIFICATION Drug 5 DRG-0043 Stavudine TRADE NAME OF SUBSTANCE Drug 1‰ Timunox MANUFACTURERS Drug 1: Immunobiology Research Institute Route 22 East PO Box 999 Annandale, NJ 08801-0999 Contact: Linda Meyerson (908) 730-1750. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. MANUFACTURERS Drug 3: Drugs are provided by each participating unit site. MANUFACTURERS Drug 4: Drugs are provided by each participating unit site. MANUFACTURERS Drug 5: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 2: Minimum 300 mg/day. Drug 3: At least 300 mg/day (if > 45 kg) or 200 mg/day (if <= 4Drug 4: At least 1.125 mg/day. Drug 5: Minimum 30 mg/day SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Subcutaneous (SC) OTHER TREATMENT INFO. END POINT: Disease progression, death. SUPPORTING AGENCY Immunobiology Research Institute. MESH HEADING Adult MESH HEADING Aged MESH HEADING Didanosine/*THERAPEUTIC USE MESH HEADING Drug Therapy, Combination MESH HEADING Female MESH HEADING HIV Infections/*DRUG THERAPY MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Stavudine/*THERAPEUTIC USE MESH HEADING Thymopentin/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Zalcitabine/*THERAPEUTIC USE MESH HEADING Zidovudine/*THERAPEUTIC USE CAS REGISTRY NUMBER 30516-87-1 (Zidovudine) CAS REGISTRY NUMBER 3056-17-5 (Stavudine) CAS REGISTRY NUMBER 69558-55-0 (Thymopentin) CAS REGISTRY NUMBER 69655-05-6 (Didanosine) CAS REGISTRY NUMBER 7481-89-2 (Zalcitabine) LAST REVISION DATE 940511 ENTRY MONTH 9312 CALIFORNIA Harbor UCLA Medical Center 1124 West Carson Street / N24 Clinic Torrance, CA 90502 Contact: Dena Duran (310) 222-3848 OPEN 931207. CALIFORNIA Olive View Medical Center / Department of Medicine 14445 Olive View Drive / 2B182 Olive View Medical Center Sylmar, CA 91342 Contact: Betsy Manchester (818) 364-3205 OPEN 931215 ACTU: 0602. CALIFORNIA Pacific Oaks Medical Group 4940 Van Nuys Boulevard 2nd Floor Sherman Oaks, CA 91403 Contact: Neil Albright (818) 906-6279 OPEN 931217. CALIFORNIA HIV Research Group 458 26th Street San Diego, CA 92102 Contact: Karen Sova (619) 544-0482 Contact: Dr Daniel Pearce (619) 544-0482 OPEN 931207. CALIFORNIA ACRC AIDS Community Research Consortium 1048 El Camino Real / Suite A Redwood City, CA 94063 Contact: Deborah Harriss (415) 364-6564 OPEN 931215. CALIFORNIA Conant Medical Group C/O Clinical Research 1635 Divisadero Street / Suite 606 San Francisco, CA 94115 Contact: Tanya Kocian (415) 923-1333 Contact: (415) 661-2613 Contact: (415) 923-0222 OPEN 931215. CALIFORNIA Dr Jeffrey Fessel Kaiser-Permanente 2200 O'Farrell San Francisco, CA 94115 Contact: Gretchen VanRaalte (415) 202-3480 OPEN 940511. CONNECTICUT Dr Gary Blick 25 Valley Drive / Suite 200B Greenwich, CT 06830 Contact: Julie Calo (203) 622-1118 OPEN 931207. DISTRICT OF COLUMBIA Dr Larry Bruni 801 Pennsylvannia Avenue / Suite 201 Washington, DC 20003 Contact: Dr Larry Bruni (202) 546-0796 OPEN 931207. FLORIDA Stratogen 300 Arthur Godrey Road / Suite 200 Miami Beach, FL 33140 Contact: Brenda Haliburton-Jones (305) 538-1400 OPEN 931207. FLORIDA Community Research Initiative 1508 San Ignacio Avenue / Suite 200 Coral Gables, FL 33146 Contact: John Cochrane (305) 661-1150 Contact: Rick Siclari (305) 667-9296 OPEN 931207. FLORIDA Stratogen Health of Ft Lauderdale 800 E Cypress Creek Road Suite 400 Ft Lauderdale, FL 33334 Contact: Dr Gary Morey (305) 938-7000 Contact: Patty Easley (305) 938-7000 OPEN 940511. FLORIDA Dr Bienvenido Yangco 4600 North Habana Avenue / Suite 14 Tampa, FL 33614 Contact: Vicki Kenyon (813) 870-4760 Contact: Dr Bienvenido Yangco (813) 870-4759 OPEN 931207. GEORGIA West Paces Medical Center 3193 Howell Mill Road Suite 306 Atlanta, GA 30327 Contact: Kim Cole (404) 350-5714 Contact: Dr. Steven Marlowe (404) 350-5690 OPEN 940511. ILLINOIS Northwestern University / Dept of Infectious Diseases 303 East Superior / Room 828 Chicago, IL 60611 Contact: Pam Donath (312) 908-0949 OPEN 931207. ILLINOIS Rush-Presbyterian St Luke's Medical Center 600 South Paulina 143 ACFAC Chicago, IL 60612 Contact: Michelle Agnoli (312) 942-5865 OPEN 931207. INDIANA Indiana U School of Medicine / Department of Infectious Dis 545 Barnhill Dr / Emerson Hall / Rm 435 Indianapolis, IN 46202-5124 Contact: Beth Zwickl (317) 274-8456 Contact: Heather Nixon (317) 274-8456 OPEN 931207. KANSAS Univ of Kansas School of Medicine - Wichita / Clinical Rsch 1010 North Kansas Wichita, KS 67214-3199 Contact: Dal Harrison (316) 261-2855 OPEN 931207. MASSACHUSETTS Community Research Initiative of New England 320 Washington Street / 3rd Floor Brookline, MA 02146 Contact: Jeanne Day (617) 566-4004 OPEN 931207. MISSOURI Systemic Mycoses Pathogen Study Group Wash Univ Sch of Med / 4511 Forest Park Pkwy / Suite 304 St Louis, MO 63108 Contact: Michael Klebert (314) 454-0058 Contact: Mike Conklin (314) 454-0058 OPEN 931207. MISSOURI Kansas City AIDS Research Consortium 2411 Holmes Blue IV Kansas City, MO 64108-2792 Contact: Gary R. Johnson (816) 235-5366 Contact: Dr. Lawrence Dall (816) 235-1964 OPEN 940511. NEW YORK Dr David DiPietro 369 8th Avenue New York, NY 10001 Contact: Phyllis Ristau (212) 929-2530 OPEN 931207. NEW YORK Dr Howard A Grossman 285 West 11th Street / Suite 1-W New York, NY 10014 Contact: George Theodore (212) 929-2629 OPEN 931207. NEW YORK Dr Patrick Hennessey 650 First Avenue New York, NY 10016 Contact: Kevin Gehan (212) 683-6470 OPEN 931207. NEW YORK New York Hospital / Cornell Clinical Trials 525 East 68th Street / Baker 24 / Box 566 New York, NY 10021 Contact: Trisha Sarracco (212) 746-4161 Contact: Jim Mahoney (212) 746-4160 OPEN 931216. NEW YORK Van Etten Hospital / Bronx Municipal Hospital Center Pelham Parkway South and Eastchester Roads / Suite 607 Bronx, NY 10461 Contact: Sylvia Perkins (718) 918-3670 OPEN 931207. NEW YORK Long Island Jewish Medical Center 269-11 76th Avenue / Division of Hematological Oncology New Hyde Park, NY 11042 Contact: Eileen Fusco (718) 470-7698 Contact: Dr Frederick Siegal (718) 470-8938 OPEN 931207. NEW YORK SUNY Stony Brook / Division of Infectious Diseases HSC-T15 / Room 080 Stony Brook, NY 11794-8153 Contact: Ruthann Burke (516) 444-1658 OPEN 931207. OHIO Cleveland Clinic / Dept of Rheumatic and Immunologic Dis Desk A-50 / 9500 Euclid Avenue Cleveland, OH 44106 Contact: Carol Tuggle (216) 444-5258 OPEN 931207. OREGON Dr Joel Godbey 220 Northeast Multinomah / Suite 200 Portland, OR 97232 Contact: Joel Godbey (503) 230-8770 CLOSED 940511. OTHER Initiativa Comunitaria de Investigacion PO Box 774 / Old San Juan Station San Juan, PR 00902 Contact: Dr Hermes Garcia (809) 250-8629 Contact: Dr. PENNSYLVANIA Novum Inc 5900 Penn Avenue Pittsburgh, PA 15206 Contact: Sharon Grace (412) 363-3300 OPEN 931207. PENNSYLVANIA Philadelphia FIGHT 201 North Broad Street / 6th Floor Philadelphia, PA 19107 Contact: Carol Graeber (215) 557-8265 OPEN 931207. PENNSYLVANIA Graduate Hospital / Pepper Pavilion 18th and Lombard Streets / Suite 505 Philadelphia, PA 19146 Contact: Shawn Sheeron (215) 893-2714 OPEN 931207. 157 UNIQUE IDENTIFIER FDA/00586 PROTOCOL ID NUMBERS FDA 012R PROTOCOL TITLE A Double-Blind, Placebo-Controlled Study of Fluconazole in the Prevention of Active Coccidioidomycosis and Other Systemic Fungal Infections in HIV-Infected Patients Living in the Coccidioidal Endemic Area. VERSION NUMBER & DATE (940104) TRIAL CATEGORY Opportunistic Infections TRIAL CATEGORY Asymptomatic GENERAL DESCRIPTION PURPOSE: To compare the efficacy of fluconazole (200 mg daily) versus placebo in preventing the development of active coccidioidomycosis and other systemic fungal infections among HIV-infected patients with CD4 lymphocyte counts < 250 cells/mm3 who are living in the coccidioidal endemic area. Methodology: Patients are randomized to receive either fluconazole or placebo daily GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive either fluconazole or placebo daily OPEN/CLOSED INDICATOR Open: Actively accruing patients (940413) DISEASE STUDIED Coccidioidomycosis, Fungal infections (Mycoses). DISEASES STATUS Patients have the following symptoms and conditions: 1. HIV infection documented by ELISA confirmed by Western blot. 2. CD4 count < 250 cells/mm3. 3. No active coccidioidomycosis or other fungal disease requiring systemic antifungal therapy. 4. Residence in area considered to be endemic for Coccidioides immitis. ELIGIBILITY ASYM. ARC. AIDS. OTHER PROTOCOL NUMBERS R-0266 STUDY DESIGN Double-Blind; Placebo-Controlled; Randomized; 2-Arm PROTOCOL DETAILS STUDY INTENT: Drug prophylaxis, Drug efficacy. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 3 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. Documented HIV infection. 2. CD4 count < 250 cells/mm3. 3. No active coccidioidomycosis or other fungal disease requiring systemic antifungal therapy. 4. Residence in area considered to be endemic for Coccidioides immitis. 5. Consent of parent or guardian if under legal age of consent. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: < 250 cells/mm3. ( 0 - 100 - 200 ). PATIENT INCLUSION CRIT. BILIRUBIN: <= 2 x ULN mg/dl. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGOT(AST): <= 7 x ULN. PATIENT INCLUSION CRIT. SGPT(ALT): <= 7 x ULN. PATIENT INCLUSION CRIT. CREATININE: <= 2.0 mg/dl. PATIENT INCLUSION CRIT. CREATININE CLEARENCE: > 65 ml/min. (If creatinine value unavailable). PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 7 x ULN. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test within 2 days of study entry. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: History of hypersensitivity to azole or imidazole compounds. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test within 2 days of study entry. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Systemic antifungal agents within 2 weeks prior to study entry. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: Systemic antifungal therapy. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following symptoms or conditions are excluded: 1. Unable to take oral medication. 2. Positive serum cryptococcal antigen. SUBSTANCE IDENTIFICATION Drug 1 DRG-0005 Fluconazole TRADE NAME OF SUBSTANCE Drug 1‰ Diflucan MANUFACTURERS Drug 1: Pfizer Incorporated / Roerig Division 235 East 42nd Street New York, NY 10017-7851 Contact: Professional Information (212) 573-2187. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 200 mg (or placebo) daily SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 200 mg (or placebo) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral SUPPORTING AGENCY Pfizer Incorporated / Roerig Division. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Coccidioidomycosis/COMPLICATIONS/*PREVENTION & CONTROL MESH HEADING Female MESH HEADING Fluconazole/*THERAPEUTIC USE MESH HEADING HIV Infections/*COMPLICATIONS MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycoses/COMPLICATIONS/*PREVENTION & CONTROL CAS REGISTRY NUMBER 86386-73-4 (Fluconazole) LAST REVISION DATE 940413 ENTRY MONTH 9401 ARIZONA McDowell Clinic 1314 East McDowell Road Phoenix, AZ 85006 Contact: Mary Coburn (602) 257-0606 OPEN 940104. ARIZONA Veterans Administration Medical Center 3601 S Sixth Avenue Tucson, AZ 85723 Contact: Kathy Delgado (602) 792-1450 X 664OPEN 940104. CALIFORNIA Dr Lawrence Cone 3900 Bob Hope Drive / Probst Bldg Rancho Mirage, CA 92270 Contact: Connie Dzekov (619) 346-5688 OPEN 940104. 158 UNIQUE IDENTIFIER FDA/00587 PROTOCOL ID NUMBERS FDA 012Q PROTOCOL TITLE Comparative Randomized Study of the Efficacy, Safety, and Toleration of Fluconazole Oral Suspension or Nystatin Oral Suspension in the Treatment of Patients With Oropharyngeal Candidiasis in Association With the Acquired Immunodeficiency Syndrome. VERSION NUMBER & DATE (940104) TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: To compare the efficacy, safety, and toleration of fluconazole as a single daily oral suspension (100 mg) for 14 days versus nystatin oral suspension (500000 units) four times daily for 14 days in the treatment of oropharyngeal candidiasis in patients with AIDS or HIV infection. Methodology: Patients are randomized to receive 100 mg fluconazole oral suspension once daily (swallowed at approximately the same time every day) for 14 days OR 500000 units nystatin oral suspension used to rinse the mouth four times daily for 14 days. No food or drink is permitted immediately following the administration of the nystatin GENERAL DESCRIPTION METHODOLOGY: Patients are randomized to receive 100 mg fluconazole oral suspension once daily (swallowed at approximately the same time every day) for 14 days OR 500000 units nystatin oral suspension used to rinse the mouth four times daily for 14 days. No food or drink is permitted immediately following the administration of the nystatin OPEN/CLOSED INDICATOR Open: Actively accruing patients (940104) DISEASE STUDIED Candidiasis, oropharyngeal. DISEASES STATUS Patients have the following symptoms and conditions: 1. ARC or AIDS. 2. Signs of oropharyngeal candidiasis (i.e., typical white plaques) with some associated symptoms (at minimum, presence of a sore mouth). 3. Confirmation of diagnosis by presence of pseudohyphae or hyphae forms identified from swab or scraping obtained from a typical oral lesion (culture specimens must be obtained within 48 hours prior to study entry). NOTE: Patients with signs or symptoms of esophagitis (e.g., odynophagia) are not eligible unless esophagoscopy is performed and results are negative. ELIGIBILITY ARC. AIDS. OTHER PROTOCOL NUMBERS R-0223 STUDY DESIGN 2-Arm; Randomized; Comparative; Drug Comparison; Prospective PROTOCOL DETAILS STUDY INTENT: Drug efficacy, Drug safety, Drug tolerance, Comparative drug therapy, Comparative toxicity. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 5 units. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: Patients must have: 1. ARC or AIDS. 2. Signs of oropharyngeal candidiasis (i.e., typical white plaques) with some associated symptoms. 3. Confirmation of diagnosis by microscopic exam and culture of organism. 4. Life expectancy of at least 4 weeks. NOTE: Patients with signs or symptoms of esophagitis (e.g., odynophagia) are not eligible unless esophagoscopy is performed and results are negative. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT INCLUSION CRIT. BILIRUBIN: <= 3 mg/dl. PATIENT INCLUSION CRIT. SGOT(AST): <= 3 x ULN. (ULN = upper limit of normal). PATIENT INCLUSION CRIT. SGPT(ALT): <= 3 x ULN. PATIENT INCLUSION CRIT. OTHER: Alkaline phosphatase <= 3 x ULN. Prothrombin time <= 5 sec over control. PATIENT AGE AGE: 13 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Not pregnant. Negative pregnancy test. Not breast-feeding. Abstinence or effective method of birth control / contraception including oral contraceptives during the study. OTHER PATIENT INCL. CH. CONCURRENT MEDICATION: Allowed: 1. Phenytoin. 2. Oral hypoglycemics. 3. Coumarin-type anticoagulants. 4. Cyclosporine. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: Patients with the following prior conditions are excluded: Known history of intolerance or allergy to imidazoles or triazoles or the polyene components of nystatin. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 12 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Pregnant. Positive pregnancy test. Breast-feeding. No abstinence or no agreement to use effective method of birth control / contraception during the study. PATIENT EXCLUSION CRIT. PRIOR MEDICATION: Excluded: Other antifungal agents within the past 3 days. PATIENT EXCLUSION CRIT. CONCURRENT MEDICATION: Excluded: 1. Antifungal agents other than study drugs. 2. Other experimental medications. PATIENT EXCLUSION CRIT. COMPLICATIONS: Patients with the following conditions are excluded: 1. Unable to tolerate oral medication. 2. Concurrent enrollment on another experimental trial of approved or non-approved drugs or systemic compounds (without approval of Pfizer clinical monitor). PATIENT EXCLUSION CRIT. AVAILABILITY: Unable or unwilling to be followed at the same center for the conduct of this study. SUBSTANCE IDENTIFICATION Drug 1 DRG-0005 Fluconazole SUBSTANCE IDENTIFICATION Drug 2 DRG-0064 Nystatin TRADE NAME OF SUBSTANCE Drug 1‰ Diflucan MANUFACTURERS Drug 1: Pfizer Incorporated / Roerig Division 235 East 42nd Street New York, NY 10017-7851 Contact: Professional Information (212) 573-2187. MANUFACTURERS Drug 2: Drugs are provided by each participating unit site. SUBSTANCE ADMIN. INFO. DOSAGE SCHEDULE: Drug 1: 100 mg in oral suspension swallowed once daily for 14 days (loading dose of 200 mg given on day 1). Daily dose in patwith renal impairment will be 50 and 25 mg for estimated creaticlearance of 21-50 and 11-20 ml/min, respectively. Drug 2: 500000 units (in 5 ml) used to rinse the mouth QID SUBSTANCE ADMIN. INFO. DAILY DOSAGE: Drug 1: 100 mg (50 or 25 mg for patients with renal impairment)Drug 2: 2 million units (in 20 ml) SUBSTANCE ADMIN. INFO. DELIVERY MODE: Drug 1: Oral. Drug 2: Oral rinse OTHER TREATMENT INFO. TREATMENT DURATION: 14 days. OTHER TREATMENT INFO. DISCONTINUE: Patients discontinue treatment for the following reason: Disease progression. SUPPORTING AGENCY Pfizer Incorporated / Roerig Division. MESH HEADING AIDS-Related Complex/*COMPLICATIONS MESH HEADING Acquired Immunodeficiency Syndrome/ *COMPLICATIONS MESH HEADING Adolescence MESH HEADING Adult MESH HEADING Aged MESH HEADING Candidiasis, Oral/COMPLICATIONS/*DRUG THERAPY MESH HEADING Female MESH HEADING Fluconazole/ADVERSE EFFECTS/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Nystatin/ADVERSE EFFECTS/*THERAPEUTIC USE CAS REGISTRY NUMBER 1400-61-9 (Nystatin) CAS REGISTRY NUMBER 86386-73-4 (Fluconazole) LAST REVISION DATE 940104 ENTRY MONTH 9401 CALIFORNIA California Medical Research Group 3636 North First Street Fresno, CA 93726 Contact: Cathy Good (209) 221-1317 OPEN 940104. CALIFORNIA University of California Hospital 521 Parnassus Avenue / Suite C-443 San Francisco, CA 94143 Contact: Jackie Octavio (415) 476-9365 OPEN 940104. MARYLAND The Johns Hopkins School of Medicine 1830 East Monument Street Baltimore, MD 21205 Contact: Karen Grimer (410) 955-1754 OPEN 940104. PENNSYLVANIA Medical College of Pennsylvania 3100 Henry Avenue Philadelphia, PA 19129 Contact: Ken Gebhart (215) 842-7444 OPEN 940104. 159 UNIQUE IDENTIFIER FDA/00072 PROTOCOL ID NUMBERS FDA 012C PROTOCOL TITLE Non-Comparative Study of Fluconazole in Patients With Serious Mycoses and Who Cannot Be Treated With Conventional Antifungal Therapy. TRIAL CATEGORY Nationwide Access TRIAL CATEGORY Opportunistic Infections GENERAL DESCRIPTION PURPOSE: The primary purpose of this protocol is to provide fluconazole for the treatment of individual patients who require therapy for serious or life-threatening systemic fungal infection, who have failed on conventional antifungal therapy or have had unacceptable reactions to conventional antifungal therapy, and who are ineligible for other established fluconazole clinical trial protocols. OPEN/CLOSED INDICATOR Open: Actively accruing patients (940413) DISEASE STUDIED Candidiasis, Fungal infections (Mycoses). DISEASES STATUS Patients with clinically established serious or life-threatening systemic fungal disease such as Candidiasis, cryptococcal infections, histoplasmosis, blastomycosis, coccidiomycosis, or paracoccidiomycosis will be considered if conventional fungal therapy is not an acceptable alternative. Clinically established fungal disease is defined as the presence of infection documented by culture, histologic, or antigen detection methods. Fungi include (but are not limited to) Candida and candida-like organisms, cyptococcus, histoplasmosis, blastomycosis, ccidioidomycosis, and paracoccidioidomycosis. ELIGIBILITY OTHER. ARC. AIDS. OTHER PROTOCOL NUMBERS 056-152 PROTOCOL DETAILS STUDY INTENT: Compassionate use. PROTOCOL DETAILS NUMBER OF PARTICIPATING AGENCIES: 1 unit. PATIENT INCLUSION CRIT. GENERAL INCLUSION CRITERIA: AMENDED: 900207 Open only to unapproved indications and/or age ranges. Original design: Patients with clinically established serious or life-threatening systemic fungal disease will be considered if conventional fungal therapy is not an acceptable alternative. Unacceptability of conventional therapy is defined as: o Failure of conventional therapy to control or eradicate infection after appropriate trial(s) of generally accepted regimen(s). o Serious and unacceptable untoward reaction(s) to conventional antifungal therapy. OR A major contraindication to the use of conventional antifungal therapy. The patient must be ineligible or have no access to other established fluconazole investigational protocols. The final judgment of patient acceptability for inclusion lies with the Pfizer Clinical Monitor. [Refer to Laboratory values for additional requirements.] PATIENT INCLUSION CRIT. CD4 (T4 CELL) COUNT: Unspecified cells/mm3. PATIENT AGE AGE: 18 Years - 99 Years. PATIENT SEX MALE PATIENT SEX FEMALE OTHER PATIENT INCL. CH. REPRODUCTIVE CRITERIA: Unspecified. PATIENT EXCLUSION CRIT. GENERAL EXCLUSION CRITERIA: A patient will be excluded if he/she has previously had an unacceptable adverse effect due to fluconazole. [Refer to Laboratory values for additional requirements.] PATIENT EXCLUSION CRIT. AGE: 01 Days - 17 Years. PATIENT EXCLUSION CRIT. REPRODUCTIVE CRITERIA: Unspecified. PATIENT EXCLUSION CRIT. COMPLICATIONS: A patient will be excluded if he/she has previously had an unacceptable adverse effect due to fluconazole. SUBSTANCE IDENTIFICATION Drug 1 DRG-0005 Fluconazole TRADE NAME OF SUBSTANCE Drug 1‰ Diflucan MANUFACTURERS Drug 1: Pfizer Incorporated, Roerig Division 235 East 42nd Street New York, NY 10017-7851 Contact: Dr Perry Eisman (212) 573-7358. SUPPORTING AGENCY Pfizer, Incorporated. MESH HEADING Adult MESH HEADING Aged MESH HEADING Drugs, Investigational/THERAPEUTIC USE MESH HEADING Female MESH HEADING Fluconazole/*THERAPEUTIC USE MESH HEADING Human MESH HEADING Male MESH HEADING Middle Age MESH HEADING Mycoses/*DRUG THERAPY CAS REGISTRY NUMBER 0 (Drugs, Investigational) CAS REGISTRY NUMBER 86386-73-4 (Fluconazole) LAST REVISION DATE 940413 ENTRY MONTH 8907 CONNECTICUT Pfizer Central Research / USA Accrual Eastern Point Road Groton, CT 06340 Contact: Pat Robinson (203) 441-4812 OPEN 910326. SS 2 /C? USER: