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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

Information source: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Meningitis, Cryptococcal; HIV Infections

Intervention: Itraconazole (Drug); Flucytosine (Drug); Fluconazole (Drug); Amphotericin B (Drug)

Phase: N/A

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
van der Horst C, Study Chair
Saag M, Study Chair

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.

Clinical Details

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

Study design: Endpoint Classification: Safety Study, Masking: Double-Blind, Primary Purpose: Treatment

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

Minimum age: 13 Years. Maximum age: N/A. Gender(s): 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.

Locations and Contacts

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

Beth Israel Deaconess Med. Ctr., ACTG CRS, Boston, Massachusetts 02215, United States

Bmc Actg Crs, Boston, Massachusetts 02118, United States

Massachusetts General Hospital ACTG CRS, Boston, Massachusetts 02114, 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

Additional Information

Click here for more information about Fluconazole

Click here for more information about Amphotericin B

Click here for more information about Itraconazole

Related 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.

Powderly WG. Recent advances in the management of cryptococcal meningitis in patients with AIDS. Clin Infect Dis. 1996 May;22 Suppl 2:S119-23. Review.

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)


Last updated: March 29, 2012

Page last updated: August 23, 2015

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