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

This study has been completed.
Sponsor:
Collaborator:
Washington University School of Medicine
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00000639
First received: November 2, 1999
Last updated: March 29, 2012
Last verified: March 2012
  Purpose

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

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Estimated Enrollment: 400
Study Completion Date: September 1997
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.

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00000639

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

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00000639     History of Changes
Other Study ID Numbers: ACTG 159, FDA 235A, MSG Study 17, 11134
Study First Received: November 2, 1999
Last Updated: March 29, 2012
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
AIDS-Related Opportunistic Infections
Meningitis
Cryptococcosis
Drug Evaluation
Drug Therapy, Combination
Fluconazole
Flucytosine
Acquired Immunodeficiency Syndrome
Amphotericin B
Brain Diseases

Additional relevant MeSH terms:
Cryptococcosis
Acquired Immunodeficiency Syndrome
HIV Infections
Infection
Meningitis
Meningitis, Cryptococcal
Central Nervous System Diseases
Central Nervous System Fungal Infections
Central Nervous System Infections
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Meningitis, Fungal
Mycoses
Nervous System Diseases
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Amphotericin B
Fluconazole
Flucytosine
Hydroxyitraconazole
Itraconazole
Liposomal amphotericin B
14-alpha Demethylase Inhibitors
Amebicides
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on October 23, 2014