Comparison of Fluconazole and Amphotericin B in the Treatment of Brain Infections in Patients With AIDS

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

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

Phase: Phase 3

Status: Completed

Sponsored by: Pfizer

Official(s) and/or principal investigator(s):
Armstrong D, Study Chair
Dismukes W, Study Chair
Powderly W, Study Chair

To compare the safety and effectiveness of a new drug, fluconazole, with that of the usual therapy, amphotericin B, in the prevention of a relapse of cryptococcal meningitis (CM) in patients with AIDS who have been successfully treated for acute CM in the last 6 months.

Cryptococcal meningitis is a life-threatening infectious complication of AIDS. Because relapse after treatment occurs in over 50 percent of cases, chronic maintenance therapy with intravenous (IV) amphotericin B is usually given. However, amphotericin B is not always effective, has toxic effects, and must be given by the intravenous route. Fluconazole is an antifungal agent that can be given orally and has been shown to be effective against cryptococcal infections in animals and against acute CM in a few AIDS patients. Also, the side effects experienced by over 2000 patients or volunteers given fluconazole have seldom been severe enough to require withdrawal of the drug.

Official title: Comparison of Fluconazole (UK-49,858) and Amphotericin B for Maintenance Treatment of Cryptococcal Meningitis in Patients With Acquired Immunodeficiency Syndrome

Study design: Treatment, Parallel Assignment

Detailed description: Cryptococcal meningitis is a life-threatening infectious complication of AIDS. Because relapse after treatment occurs in over 50 percent of cases, chronic maintenance therapy with intravenous (IV) amphotericin B is usually given. However, amphotericin B is not always effective, has toxic effects, and must be given by the intravenous route. Fluconazole is an antifungal agent that can be given orally and has been shown to be effective against cryptococcal infections in animals and against acute CM in a few AIDS patients. Also, the side effects experienced by over 2000 patients or volunteers given fluconazole have seldom been severe enough to require withdrawal of the drug.

Patients accepted in the trial are randomly assigned to fluconazole or amphotericin B. Fluconazole is given orally once a day and amphotericin B is given intravenously once a week. Dosages depend on body weight. Medications may be given with amphotericin B to prevent or reduce discomfort from associated side effects. Patients are treated for 12 months and may continue to receive antiviral therapy, radiation therapy for mucocutaneous Kaposi's sarcoma, or preventive therapy for Pneumocystis carinii pneumonia (PCP) during the study.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria

- HIV infection documented by antibody (ELISA on two occasions or ELISA with Western

blot confirmation), p24 antigen testing, or recovery of HIV in culture.

Prior Medication:

Required:

- Minimum total dose of 15 mg/kg of amphotericin B (either alone or in combination with

flucytosine) during primary therapy. End of primary therapy within 6 weeks of start of maintenance therapy.

- Allowed:

- Past or present antiviral therapy and prophylaxis for Pneumocystis carinii pneumonia

(PCP).

- Pfizer must be notified if the patient is receiving ganciclovir at entry. Allowed with

amphotericin B to treat or prevent side effects.

- Antipyretics.

- Hydrocortisone.

- Meperidine.

Exclusion Criteria

Co-existing Condition:

Patients with the following are excluded:

- Clinical evidence of acute or chronic meningitis other than cryptococcosis.

- Allergy or intolerance of imidazoles, azoles, or amphotericin B. Unable to take oral

medications reliably.

Patients with the following are excluded:

- Clinical evidence of acute or chronic meningitis other than cryptococcosis.

- Allergy or intolerance of imidazoles, azoles, or amphotericin B.

Prior Medication:

Excluded for more than 7 days after initiation of primary therapy for cryptococcosis:

- Ketoconazole.

- Fluconazole.

- Itraconazole.

- Miconazole.

- Any other systemic imidazole or azole.

- Excluded:

- Intrathecal amphotericin B.

- Coumadin-type anticoagulants.

- Oral hypoglycemics.

- Barbiturates.

- Phenytoin.

- Immunostimulants.

- Investigational drug or approved (licensed) drugs for investigational indications.

Prior Treatment:

Excluded:

- Lymphocyte replacement.

UCLA CARE Ctr, Los Angeles, California 90095, United States

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

Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States

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

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

Johns Hopkins Hosp, Baltimore, Maryland 21287, United States

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

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

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

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

Bellevue Hosp / New York Univ Med Ctr, New York, New York 10016, 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

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

Mem Sloan - Kettering Cancer Ctr, New York, New York 10021, United States

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

Beth Israel Med Ctr / Peter Krueger Clinic, New York, New York 10003, United States

City Hosp Ctr at Elmhurst / Mount Sinai Hosp, Elmhurst, New York 11373, United States

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

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

Duke Univ Med Ctr, Durham, North Carolina 27710, United States

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

Holmes Hosp / Univ of Cincinnati Med Ctr, Cincinnati, Ohio 452670405, United States

Univ Hosp of Cleveland / Case Western Reserve Univ, Cleveland, Ohio 44106, United States

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

Click here for more information about Fluconazole

Click here for more information about Amphotericin B

Related publications:

Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, Thompson SE, Sugar AM, Tuazon CU, Fisher JF, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med. 1992 Jan 9;326(2):83-9.

Powderly WG, Saag MS, Cloud GA, Robinson P, Meyer RD, Jacobson JM, Graybill JR, Sugar AM, McAuliffe VJ, Follansbee SE, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group. N Engl J Med. 1992 Mar 19;326(12):793-8.

Powderly WG, Cloud GA, Dismukes WE, Saag MS. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis. 1994 May;18(5):789-92.

McKinney RE Jr, Maha MA, Connor EM, Feinberg J, Scott GB, Wulfsohn M, McIntosh K, Borkowsky W, Modlin JF, Weintrub P, et al. A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. The Protocol 043 Study Group. N Engl J Med. 1991 Apr 11;324(15):1018-25.

Last updated: June 23, 2005