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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00000639

Collaborator

Washington University School of Medicine (Other)

400

Enrollment

Locations

16.7

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Meningitis, Cryptococcal HIV Infections	Drug: Itraconazole Drug: Flucytosine Drug: Fluconazole Drug: Amphotericin B	N/A

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 Design

Study Type:

Interventional

Masking:

Double

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

Actual Study Completion Date :

Sep 1, 1997

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

13 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

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