Clinical trial NCT00000676: 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)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Candidiasis
Mycoses
HIV Infections
Keywords: Mycoses
Fluconazole
Clotrimazole
Antifungal Agents
Acquired Immunodeficiency Syndrome
AIDS-Related Complex
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Pfizer
First posted: 2001-08-31
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford CRS
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: New Orleans
country: United States
facility: Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Boston
country: United States
facility: Bmc Actg Crs
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - East Campus A0102 CRS
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Buffalo
country: United States
facility: SUNY - Buffalo, Erie County Medical Ctr.
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Ctr.
state: New York
city: New York
country: United States
facility: Beth Israel Med. Ctr. (Mt. Sinai)
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Pittsburgh
country: United States
facility: Pitt CRS
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: Mbeya
country: Tanzania
facility: Mbeya Med. Research Program, Mbeya Referral Hosp. CRS
Study officials:
name: Bozzettee S
role: STUDY_CHAIR
name: Powderly WG
role: STUDY_CHAIR
References:
citation: Glick ME. CTG studies yield results. AIDS Clinical Trials Group. NIAID AIDS Agenda. 1995 Spring:8-9.
citation: Hanna L. Treatment for HIV-related fungal infections. BETA. 1995 Jun:10-7.
citation: Powderly WG. Fungal infections. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7:274
citation: Powderly WG. Prophylaxis of fungal infection in HIV infection. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7:270
citation: 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. doi: 10.1056/NEJM199503163321102.