Randomized Comparative Study of Fluconazole Versus Clotrimazole Troches in the Prevention of Serious Fungal Infection in Patients With AIDS or Advanced AIDS-Related Complex. (A Nested Study of ACTG 081)

Condition(s) targeted: Candidiasis; Mycoses; HIV Infections

Intervention: Clotrimazole (Drug); Fluconazole (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Pfizer

Official(s) and/or principal investigator(s):
Bozzettee S, Study Chair
Powderly WG, Study Chair

To study the effectiveness, safety, and tolerance of fluconazole versus clotrimazole troches (lozenges) as prophylaxis (preventive treatment) against fungal infections in patients enrolled in ACTG 081 (a study of prophylaxis against pneumocystosis, toxoplasmosis, and serious bacterial infection). Primarily, to compare the rates of invasive infections by C. neoformans, endemic mycoses, and Candida. To compare the mortality rates due to fungal infections between two antifungal prophylactic treatments. Secondarily, to assess the effect of prophylaxis on the incidence of severe fungal infections, defined as invasive infections and esophageal candidiasis and less severe mucocutaneous infection.

Serious fungal infections are significant complicating and life-threatening occurrences in patients with advanced HIV infection. Oropharyngeal candidiasis is found in almost all such patients, and causes pain, difficulty in swallowing, and loss of appetite. Similarly, esophageal candidiasis causes illness in the population. Cryptococcosis, endemic mycoses, and coccidioidomycosis also cause significant illness and death in AIDS patients. Once established, fungal infections in AIDS patients generally require continuous suppressive therapy because attempts at curing these infections are usually unsuccessful. Fluconazole has a number of characteristics that would make it a logical candidate to examine as a prophylactic agent in patients with advanced HIV infection. Animal studies have shown it to be prophylactic in models of candidiasis, cryptococcosis, histoplasmosis, and coccidioidomycosis. Initial experience in patients with active cryptococcal meningitis appears favorable, and studies of oropharyngeal candidiasis show it to be effective.

Official title: Randomized Comparative Study of Fluconazole Versus Clotrimazole Troches in the Prevention of Serious Fungal Infection in Patients With AIDS or Advanced AIDS-Related Complex. (A Nested Study of ACTG 081)

Study design: Prevention, Placebo Control

Detailed description: Serious fungal infections are significant complicating and life-threatening occurrences in patients with advanced HIV infection. Oropharyngeal candidiasis is found in almost all such patients, and causes pain, difficulty in swallowing, and loss of appetite. Similarly, esophageal candidiasis causes illness in the population. Cryptococcosis, endemic mycoses, and coccidioidomycosis also cause significant illness and death in AIDS patients. Once established, fungal infections in AIDS patients generally require continuous suppressive therapy because attempts at curing these infections are usually unsuccessful. Fluconazole has a number of characteristics that would make it a logical candidate to examine as a prophylactic agent in patients with advanced HIV infection. Animal studies have shown it to be prophylactic in models of candidiasis, cryptococcosis, histoplasmosis, and coccidioidomycosis. Initial experience in patients with active cryptococcal meningitis appears favorable, and studies of oropharyngeal candidiasis show it to be effective.

AMENDED: 11/01/90 Sufficient numbers of patients will be enrolled from all centers starting at week 8 of participation in the parent study to achieve a total of 240 evaluable patients who will remain in the nested study for a maximum duration of 45 months. Enrollment will continue until all eligible and interested 081 patients are enrolled. Fungal prophylaxis will begin at the time of enrollment into the nested study and will continue until an efficacy or safety end point is reached, until withdrawal from the nested study, or until death.

Original design: Patients included are those already enrolled in ACTG 081. Patients are enrolled from all centers at either week 8, 12, 16, 20, 24, 28, or 32 of participation in the parent study. They are randomized to receive either oral fluconazole or clotrimazole troches. Prophylaxis continues until a serious fungal infection develops, the end of the parent study is reached (which is expected to be December 1991), the patient withdraws from either the nested or parent study, or the patient dies. Clinical examination is performed at 2 weeks and then monthly (or more if clinically indicated) for the duration of antifungal prophylaxis; the schedule of evaluation is the same as for the parent study. There is a 1-month postprophylaxis follow-up after discontinuation of prophylaxis for any reason.

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

Criteria:

Inclusion Criteria

Concurrent Medication:

Required:

- Zidovudine (AZT).

- Antipneumocystis prophylaxis.

Allowed:

- Topical suppressive antifungal agents.

Eligibility requirements are:

- Participation in NIAID ACTG 081.

- No history of systemic fungal infection, including esophageal or systemic candidiasis,

cryptococcosis, histoplasmosis, coccidioidomycosis, blastomycosis, sporotrichosis, or aspergillosis.

- Willingness to sign an informed consent.

- Transaminases < 5 x upper limit of normal.

- Noncompliance will not be a reason for withdrawal of a patient from the study, unless

patient refuses further treatment.

Allowed:

- A history of oropharyngeal, vaginal or cutaneous candidiasis.

- Dermatophyte infections (i. e., tinea pedis) at entry but not active candida infection.

Sites of suspected dermatophyte involvement other than the feet should have candida excluded by culture.

Prior Medication:

Allowed:

- Topical suppressive antifungal agents.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or diseases are excluded:

- History of systemic fungal infection, including esophageal or systemic candidiasis,

cryptococcosis, histoplasmosis, coccidioidomycosis, blastomycosis, sporotrichosis, or aspergillosis.

- Active systemic fungal infection at time of enrollment.

- Active superficial fungal infection at time of entry. (Such patients may be treated

with topical antifungal agents and may be randomized if they are in clinical remission 14 days after completion of such therapy.)

Concurrent Medication:

Excluded:

- Amphotericin B.

- Fluconazole.

- Itraconazole.

- SCH 39304.

- Other systemic antifungals.

Patients with the following are excluded:

- Previous or currently active systemic fungal infection.

- History of allergy or intolerance to imidazole or azoles.

- Positive serum cryptococcal antigen titer at any dilution.

- Requiring multi-agent therapy for tuberculosis or for symptomatic Mycobacterium avium

infection.

Univ of California / San Diego Treatment Ctr, San Diego, California 921036325, United States

UCSD Med Ctr / Pediatrics / Clinical Sciences, La Jolla, California 920930672, United States

Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr, Sylmar, California 91342, United States

Stanford at Kaiser / Kaiser Permanente Med Ctr, San Francisco, California 94115, United States

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

Georgetown Univ Med Ctr, Washington, District of Columbia 20007, United States

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

Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States

Johns Hopkins Hosp, Baltimore, Maryland 21287, United States

Beth Israel Deaconess Med Ctr, Boston, Massachusetts 02215, United States

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

Boston Med Ctr, Boston, Massachusetts 02118, United States

Univ of Minnesota, Minneapolis, Minnesota 55455, United States

St Paul Ramsey Med Ctr, St. Paul, Minnesota 55101, United States

Robert Wood Johnson Med School/UMDNJ, New Brunswick, New Jersey 089030019, United States

SUNY / State Univ of New York, Syracuse, New York 13210, United States

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

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

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

Case Western Reserve Univ, Cleveland, Ohio 44106, United States

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

Univ of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States

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

Univ of Washington, Seattle, Washington 981224304, United States

Click here for more information about Fluconazole

Related publications:

Glick ME. CTG studies yield results. AIDS Clinical Trials Group. NIAID AIDS Agenda. 1995 Spring;:8-9. No abstract available.

Hanna L. Treatment for HIV-related fungal infections. BETA. 1995 Jun;:10-7. No abstract available.

Powderly WG. Fungal infections. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7:274

Powderly WG. Prophylaxis of fungal infection in HIV infection. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7:270

Powderly WG, Finkelstein D, Feinberg J, Frame P, He W, van der Horst C, Koletar SL, Eyster ME, Carey J, Waskin H, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med. 1995 Mar 16;332(11):700-5.

Last updated: June 23, 2005