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

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

Sponsors

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator: Washington University School of Medicine

Source National Institute of Allergy and Infectious Diseases (NIAID)
Brief Summary

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.

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.

Overall Status Completed
Completion Date September 1997
Phase N/A
Study Type Interventional
Enrollment 400
Condition
Intervention

Intervention Type: Drug

Intervention Name: Itraconazole

Intervention Type: Drug

Intervention Name: Flucytosine

Intervention Type: Drug

Intervention Name: Fluconazole

Intervention Type: Drug

Intervention Name: Amphotericin B

Eligibility

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.

Gender: All

Minimum Age: 13 Years

Maximum Age: N/A

Healthy Volunteers: No

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

United States

Verification Date

March 2012

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Study Design Info

Primary Purpose: Treatment

Masking: Double

Source: ClinicalTrials.gov