A Randomized Double Blind Protocol Comparing Amphotericin B With Flucytosine to Amphotericin B Alone Followed by a Comparison of Fluconazole and Itraconazole in the Treatment of Acute Cryptococcal Meningitis

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Meningitis, Cryptococcal
• Intervention / Treatment: Drug: Fluconazole; Drug: Itraconazole; Drug: Flucytosine; Drug: Amphotericin B

Detailed Description

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.

• Study Type: Interventional
• Enrollment: 400
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC CRS
    • San Francisco, California, United States, 94110
      • Ucsf Aids Crs
  • Florida
    • Miami, Florida, United States, 33136
      • Univ. of Miami AIDS CRS
  • Hawaii
    • Honolulu, Hawaii, United States
      • Univ. of Hawaii at Manoa, Leahi Hosp.
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
    • Indianapolis, Indiana, United States, 46202
      • Methodist Hosp. of Indiana
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital ACTG CRS
    • Boston, Massachusetts, United States, 02118
      • Bmc Actg Crs
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Med. Ctr., ACTG CRS
  • Missouri
    • Saint Louis, Missouri, United States
      • Washington U CRS
    • Saint Louis, Missouri, United States
      • St. Louis ConnectCare, Infectious Diseases Clinic
  • New York
    • Buffalo, New York, United States, 14215
      • SUNY - Buffalo, Erie County Medical Ctr.
    • New York, New York, United States, 10021
      • Cornell University A2201
    • New York, New York, United States, 10003
      • Beth Israel Med. Ctr. (Mt. Sinai)
    • Rochester, New York, United States, 14642
      • Univ. of Rochester ACTG CRS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Unc Aids Crs
    • Charlotte, North Carolina, United States
      • Carolinas HealthCare System, Carolinas Med. Ctr.
    • Greensboro, North Carolina, United States, 27401
      • Regional Center for Infectious Disease, Wendover Medical Center CRS
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Univ. of Cincinnati CRS
    • Columbus, Ohio, United States, 43210
      • The Ohio State Univ. AIDS CRS
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hosp. of the Univ. of Pennsylvania CRS
    • Pittsburgh, Pennsylvania, United States, 15213
      • Pitt CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: Double

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Washington University School of Medicine
• Investigators: Study Chair: van der Horst C; Study Chair: Saag M

Publications and helpful links

General Publications

• van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, Johnson PC, Tuazon CU, Kerkering T, Moskovitz BL, Powderly WG, Dismukes WE. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997 Jul 3;337(1):15-21. doi: 10.1056/NEJM199707033370103.
• Powderly WG. Recent advances in the management of cryptococcal meningitis in patients with AIDS. Clin Infect Dis. 1996 May;22 Suppl 2:S119-23. doi: 10.1093/clinids/22.supplement_2.s119.
• Powderly WG, Tuazon C, Cloud GA, Saag MS, Van Der Horst C. Serum and CSF cryptococcal antigen in management of cryptococcal meningitis in AIDS. Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:66 (abstract no 6)

Study record dates

Study Major Dates

• Study Start: December 7, 2022
• Primary Completion: December 7, 2022
• Study Completion (Actual): September 1, 1997

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Actual): November 2, 2021
• Last Update Submitted That Met QC Criteria: October 26, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Fluconazole; Meningitis; Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Drug Evaluation; Cryptococcosis; Flucytosine; Amphotericin B; Brain Diseases
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections and Mycoses; Mycoses; Meningitis, Fungal; Central Nervous System Fungal Infections; Cryptococcosis; Meningitis; Meningitis, Cryptococcal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antimetabolites; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Itraconazole; Fluconazole; Flucytosine; Amphotericin B; Liposomal amphotericin B
• Other Study ID Numbers: ACTG 159; FDA 235A; MSG Study 17; 11134 (DAIDS ES Registry Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No