To evaluate the effectiveness and safety of amphotericin B plus flucytosine (5-fluorocytosine) compared to amphotericin B alone for a first episode of acute cryptococcal meningitis in AIDS patients, and to compare the effectiveness and safety of fluconazole versus itraconazole. At least 10 percent of patients with a low CD4 count and HIV infection will develop meningitis due to Cryptococcus neoformans. More effective treatments than the standard therapy need to be explored.

Condition	Treatment or Intervention
Meningitis, Cryptococcal HIV Infections	Drug: Itraconazole  Drug: Flucytosine  Drug: Fluconazole  Drug: Amphotericin B

Further Study Details: 

Expected Total Enrollment:  400

At least 10 percent of patients with a low CD4 count and HIV infection will develop meningitis due to Cryptococcus neoformans. More effective treatments than the standard therapy need to be explored.

Patients are selected by a randomization process to take amphotericin B intravenously (in the vein), for 14 days, and either placebo (ineffective substance) or flucytosine for 14 days. Then patients are again selected by a randomization process to take either (1) fluconazole for a total of 8 weeks plus itraconazole placebo; or (2) itraconazole for a total of 8 weeks plus fluconazole placebo.

Ages Eligible for Study:  13 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria

Concurrent Medication: Allowed:

• Interruption of myelosuppressive therapies and/or administration of erythropoietin, at discretion of investigator, to maintain hemoglobin = or > 7 g/dl.
• Adjunctive corticosteroids may be administered during the triazole phase for patients who develop Pneumocystis carinii pneumonia and meet the prescribed criteria.
• Hydrocortisone, not to exceed 50 mg/day, during the amphotericin phase.
• Aerosolized pentamidine or systemic chemoprophylaxis for Pneumocystis carinii pneumonia should be given to all patients with a CD4 count < 200 cells/mm3.
• Antiretroviral drugs (including zidovudine (AZT), didanosine (ddI), dideoxycytidine (ddC)) after patient has tolerated oral triazole for one week (after 3 weeks of study treatment).
• Maintenance treatment (except for rifamycins) for other opportunistic infections such as cytomegalovirus (CMV) retinitis, cerebral toxoplasmosis or mycobacterial infections, provided that their hematologic and hepatic values are stable and they meet the entry criteria. Concurrent Treatment: Allowed:

Transfusion, at discretion of investigator, to maintain hemoglobin = or > 7 g/dl.

Patients must have:

• HIV infection.
• Primary episode of acute cryptococcal meningitis.
• Willing to participate in the study for a full 10 weeks and either be able to give informed consent or have a family member or guardian able to give informed consent.

Prior Medication: Allowed: Fluconazole prophylaxis, not exceeding 200 mg/day.

Risk Behavior: Allowed:

History of high-risk behavior for HIV infection (bisexual or homosexual men, intravenous drug abusers) and their sexual partners.

Exclusion Criteria

Co-existing Condition: Patients with the following conditions or symptoms are excluded:

• Inability to take oral medication (if necessary, flucytosine and flucytosine placebo may be administered via nasogastric tube during the amphotericin phase).
• History of hypersensitivity to imidazole or triazole compounds.
• Active hepatitis (viral, drug-induced, or other) defined by progressive worsening of hepatic enzymes to grade 3 or 4 toxicity on at least two occasions.
• Comatose.
• Concurrent CNS disease which, in the opinion of the investigator, would interfere with assessment of response.

Concurrent Medication: Excluded:

• Continued treatment with H2 blockers (ranitidine (Zantac), cimetidine (Tagamet), omeprazole (Prilosec), nizatidine (Axid), famotidine (Pepcid)).
• Antacids and didanosine (ddI) within 2 hours of triazole administration.
• Rifampin, rifabutin (Ansamycin), and other rifamycin derivatives, phenytoin (Dilantin), phenobarbital, or carbamazepine (Tegretol).
• Other systemic antifungal agents.

Prior Medication: Excluded:

• Amphotericin, > 1 mg/kg, or fluconazole or ketoconazole, > 1200 mg, as prior treatment for current primary episode of acute cryptococcal meningitis or treatment started for this episode more than 72 hours prior to enrollment into study.
• Phenytoin (Dilantin), carbamazepine (Tegretol), phenobarbital, rifabutin (Ansamycin), rifampin or other rifamycins within the last 15 days.

Patients may not have:

• Inability to take oral medication (if necessary, flucytosine and flucytosine placebo may be administered via nasogastric tube during the amphotericin phase).
• History of hypersensitivity to imidazole or triazole compounds.
• Active hepatitis.
• Patients who are comatose.
• Concurrent CNS disease which, in the opinion of the investigator, would interfere with assessment of response.

Alabama
      Univ of Alabama at Birmingham, Birmingham,  Alabama,  35294,  United States
California
      San Francisco Gen Hosp, San Francisco,  California,  941102859,  United States
      San Francisco Veterans Administration Med Ctr, San Francisco,  California,  94121,  United States
      Univ of Southern California / LA County USC Med Ctr, Los Angeles,  California,  900331079,  United States
      Kaiser Permanente Med Ctr, San Francisco,  California,  94115,  United States
Connecticut
      Yale Univ / New Haven, New Haven,  Connecticut,  065102483,  United States
District of Columbia
      George Washington Univ Med Ctr, Washington,  District of Columbia,  20037,  United States
Florida
      Univ of Miami School of Medicine, Miami,  Florida,  331361013,  United States
Georgia
      Med College of Georgia, Augusta,  Georgia,  30912,  United States
      Emory Univ School of Medicine, Atlanta,  Georgia,  30303,  United States
Illinois
      Northwestern Univ Med School, Chicago,  Illinois,  60611,  United States
Indiana
      Indiana Univ Hosp, Indianapolis,  Indiana,  462025250,  United States
      Methodist Hosp of Indiana / Life Care Clinic, Indianapolis,  Indiana,  46202,  United States
Louisiana
      Charity Hosp / Tulane Univ Med School, New Orleans,  Louisiana,  70112,  United States
      Louisiana State Univ Med Ctr / Tulane Med School, New Orleans,  Louisiana,  70112,  United States
      Tulane Univ School of Medicine, New Orleans,  Louisiana,  70112,  United States
Maryland
      Johns Hopkins Univ School of Medicine, Baltimore,  Maryland,  21205,  United States
Massachusetts
      Harvard (Massachusetts Gen Hosp), Boston,  Massachusetts,  02114,  United States
      Beth Israel Deaconess - West Campus, Boston,  Massachusetts,  02215,  United States
      Boston Med Ctr, Boston,  Massachusetts,  02118,  United States
      Baystate Med Ctr of Springfield, Springfield,  Massachusetts,  01199,  United States
      Univ of Massachusetts Med Ctr, Worcester,  Massachusetts,  01655,  United States
Michigan
      Ann Arbor Veterans Administration Med Ctr, Ann Arbor,  Michigan,  48105,  United States
      Dr Jack D Sobel, Detroit,  Michigan,  48201,  United States
Mississippi
      Univ of Mississippi Med Ctr, Jackson,  Mississippi,  39216,  United States
Missouri
      St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis,  Missouri,  63112,  United States
      Univ of Missouri at Kansas City School of Medicine, Kansas City,  Missouri,  64108,  United States
      Infectious Diseases Association / Research Med Ctr, Kansas City,  Missouri,  64132,  United States
New Jersey
      Saint Michael's Med Ctr, Newark,  New Jersey,  07102,  United States
New York
      Montefiore Drug Treatment Ctr / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States
      Montefiore Family Health Ctr / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States
      Samaritan Village Inc / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States
      Nassau County Med Ctr, East Meadow,  New York,  11554,  United States
      SUNY - Stony Brook, Stony Brook,  New York,  117948153,  United States
      Univ of Rochester Medical Center, Rochester,  New York,  14642,  United States
      Mount Sinai Med Ctr, New York,  New York,  10029,  United States
      Jack Weiler Hosp / Bronx Municipal Hosp, Bronx,  New York,  10465,  United States
      Cornell Univ Med Ctr, New York,  New York,  10021,  United States
      Saint Luke's - Roosevelt Hosp Ctr, New York,  New York,  10025,  United States
      Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx,  New York,  10461,  United States
      Montefiore Med Ctr / Bronx Municipal Hosp, Bronx,  New York,  10467,  United States
      Bronx Veterans Administration / Mount Sinai Hosp, Bronx,  New York,  10468,  United States
      SUNY / Erie County Med Ctr at Buffalo, Buffalo,  New York,  14215,  United States
      Beth Israel Med Ctr, New York,  New York,  10003,  United States
      Montefiore Med Ctr Adolescent AIDS Program, Bronx,  New York,  10467,  United States
      North Central Bronx Hosp / Bronx Municipal Hosp, Bronx,  New York,  10467,  United States
      Comprehensive Health Care Ctr / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States
      Harlem Hosp Ctr, New York,  New York,  10037,  United States
North Carolina
      Univ of North Carolina, Chapel Hill,  North Carolina,  275997215,  United States
      Moses H Cone Memorial Hosp, Greensboro,  North Carolina,  27401,  United States
Ohio
      Univ of Cincinnati, Cincinnati,  Ohio,  452670405,  United States
      Ohio State Univ Hosp Clinic, Columbus,  Ohio,  432101228,  United States
Pennsylvania
      Univ of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States
      Univ of Pennsylvania at Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States
      Thomas Jefferson Univ Hosp, Philadelphia,  Pennsylvania,  191075098,  United States
      Pennsylvania Hosp, Philadelphia,  Pennsylvania,  19107,  United States
South Carolina
      Julio Arroyo, West Columbia,  South Carolina,  29169,  United States
      Med Univ of South Carolina / UNC, Charleston,  South Carolina,  29425,  United States
Tennessee
      Dr Mark A Pierce, Nashville,  Tennessee,  37232,  United States
Texas
      Univ of Texas Galveston, Galveston,  Texas,  775550435,  United States
      Audie L Murphy Veterans Administration Hosp, San Antonio,  Texas,  78284,  United States
      Houston Veterans Administration Med Ctr, Houston,  Texas,  77030,  United States
      Houston Med Ctr, Houston,  Texas,  77030,  United States
Virginia
      Dr Thomas M Kerkering, Richmond,  Virginia,  23298,  United States

Study chairs or principal investigators

van der Horst C,  Study Chair
Saag M,  Study Chair

Study ID Numbers:  ACTG 159; FDA 235A; MSG Study 17
Record last reviewed:  September 1994
Last Updated:  April 7, 2005
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00000639
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08