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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)
Information obtained from ClinicalTrials.gov on June 20, 2008
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: Washington University School of Medicine

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: Treatment, Double-Blind, Safety Study

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

Univ of Alabama at Birmingham, Birmingham, Alabama 35294, United States

San Francisco Gen Hosp, San Francisco, California 941102859, United States

San Francisco Veterans Administration Med Ctr, San Francisco, California 94121, United States

Univ of Southern California / LA County USC Med Ctr, Los Angeles, California 900331079, United States

Kaiser Permanente Med Ctr, San Francisco, California 94115, United States

Yale Univ / New Haven, New Haven, Connecticut 065102483, United States

George Washington Univ Med Ctr, Washington, District of Columbia 20037, United States

Univ of Miami School of Medicine, Miami, Florida 331361013, United States

Med College of Georgia, Augusta, Georgia 30912, United States

Emory Univ School of Medicine, Atlanta, Georgia 30303, United States

Northwestern Univ Med School, Chicago, Illinois 60611, United States

Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States

Methodist Hosp of Indiana / Life Care Clinic, Indianapolis, Indiana 46202, United States

Charity Hosp / Tulane Univ Med School, New Orleans, Louisiana 70112, United States

Louisiana State Univ Med Ctr / Tulane Med School, New Orleans, Louisiana 70112, United States

Tulane Univ School of Medicine, New Orleans, Louisiana 70112, United States

Johns Hopkins Univ School of Medicine, Baltimore, Maryland 21205, United States

Harvard (Massachusetts Gen Hosp), Boston, Massachusetts 02114, United States

Beth Israel Deaconess - West Campus, Boston, Massachusetts 02215, United States

Boston Med Ctr, Boston, Massachusetts 02118, United States

Baystate Med Ctr of Springfield, Springfield, Massachusetts 01199, United States

Univ of Massachusetts Med Ctr, Worcester, Massachusetts 01655, United States

Ann Arbor Veterans Administration Med Ctr, Ann Arbor, Michigan 48105, United States

Dr Jack D Sobel, Detroit, Michigan 48201, United States

Univ of Mississippi Med Ctr, Jackson, Mississippi 39216, United States

St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis, Missouri 63112, United States

Univ of Missouri at Kansas City School of Medicine, Kansas City, Missouri 64108, United States

Infectious Diseases Association / Research Med Ctr, Kansas City, Missouri 64132, United States

Saint Michael's Med Ctr, Newark, New Jersey 07102, United States

Montefiore Drug Treatment Ctr / Bronx Municipal Hosp, Bronx, New York 10461, United States

Montefiore Family Health Ctr / Bronx Municipal Hosp, Bronx, New York 10461, United States

Samaritan Village Inc / Bronx Municipal Hosp, Bronx, New York 10461, United States

Nassau County Med Ctr, East Meadow, New York 11554, United States

SUNY - Stony Brook, Stony Brook, New York 117948153, United States

Univ of Rochester Medical Center, Rochester, New York 14642, United States

Mount Sinai Med Ctr, New York, New York 10029, United States

Jack Weiler Hosp / Bronx Municipal Hosp, Bronx, New York 10465, United States

Cornell Univ Med Ctr, New York, New York 10021, United States

Saint Luke's - Roosevelt Hosp Ctr, New York, New York 10025, United States

Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx, New York 10461, United States

Montefiore Med Ctr / Bronx Municipal Hosp, Bronx, New York 10467, United States

Bronx Veterans Administration / Mount Sinai Hosp, Bronx, New York 10468, United States

SUNY / Erie County Med Ctr at Buffalo, Buffalo, New York 14215, United States

Beth Israel Med Ctr, New York, New York 10003, United States

Montefiore Med Ctr Adolescent AIDS Program, Bronx, New York 10467, United States

North Central Bronx Hosp / Bronx Municipal Hosp, Bronx, New York 10467, United States

Comprehensive Health Care Ctr / Bronx Municipal Hosp, Bronx, New York 10461, United States

Harlem Hosp Ctr, New York, New York 10037, United States

Univ of North Carolina, Chapel Hill, North Carolina 275997215, United States

Moses H Cone Memorial Hosp, Greensboro, North Carolina 27401, United States

Univ of Cincinnati, Cincinnati, Ohio 452670405, United States

Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, United States

Univ of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States

Univ of Pennsylvania at Philadelphia, Philadelphia, Pennsylvania 19104, United States

Thomas Jefferson Univ Hosp, Philadelphia, Pennsylvania 191075098, United States

Pennsylvania Hosp, Philadelphia, Pennsylvania 19107, United States

Julio Arroyo, West Columbia, South Carolina 29169, United States

Med Univ of South Carolina / UNC, Charleston, South Carolina 29425, United States

Dr Mark A Pierce, Nashville, Tennessee 37232, United States

Univ of Texas Galveston, Galveston, Texas 775550435, United States

Audie L Murphy Veterans Administration Hosp, San Antonio, Texas 78284, United States

Houston Veterans Administration Med Ctr, Houston, Texas 77030, United States

Houston Med Ctr, Houston, Texas 77030, United States

Dr Thomas M Kerkering, Richmond, Virginia 23298, 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: June 23, 2005

Page last updated: June 20, 2008

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