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AMBITION-cm: intermittent high dose AmBisome on a high dose fluconazole backbone for cryptococcal meningitis
Mooketsi Molefi1,2, Awilly A Chofle3,4, Síle F Molloy5
1Department of Family Medicine and Public Health, Faculty of Medicine, University of Botswana, P.O.Box 1357 ABG, Gaborone, Botswana. mooketsimolefi@gmail.com.
Background:
Cryptococcal meningitis (CM) is a leading cause of mortality among HIV-infected individuals in Africa. Poor outcomes from conventional antifungal therapies, unavailability of flucytosine, and difficulties administering 14 days of amphotericin B are key drivers of this mortality. Novel treatment regimes are needed. This study examines whether short-course high-dose liposomal amphotericin B (AmBisome), given with high dose fluconazole, is non-inferior (in terms of microbiological and clinical endpoints) to standard-dose 14-day courses of AmBisome plus high dose fluconazole for treatment of HIV-associated CM.
Methodology/Design:
This is an adaptive open-label phase II/III randomised non-inferiority trial comparing alternative short course AmBisome regimens. Step 1 (phase II) will compare four treatment arms in 160 adult patients (≥ 18 years old) with a first episode of HIV-associated CM, using early fungicidal activity (EFA) as the primary outcome: 1) AmBisome 10 mg/kg day one (single dose); 2) AmBisome 10 mg/kg day one and AmBisome 5 mg/kg day three (two doses); 3) AmBisome 10 mg/kg day one, and AmBisome 5 mg/kg days three and seven (three doses); and 4) AmBisome 3 mg/kg/d for 14 days (control); all given with fluconazole 1200 mg daily for 14 days. STEP 2 (phase III) will enrol 300 participants and compare two treatment arms using all-cause mortality within 70 days as the primary outcome: 1) the shortest course AmBisome regimen found to be non-inferior in terms of EFA to the 14-day control arm in STEP 1, and 2) AmBisome 3 mg/kg/d for 14 days (control), both given with fluconazole 1200 mg daily for 14 days. STEP 2 analysis will include all patients from STEP 1 and STEP 2 taking the STEP 2 regimens. All patients will be followed for ten weeks, and mortality and safety data recorded. All patients will receive consolidation therapy with fluconazole 400-800 mg daily and ART in accordance with local guidelines. The primary analysis (for both STEP 1 and STEP 2) will be intention-to-treat.
Trial Registration:
ISRCTN10248064. Date of Registration: 22 January 2014.
Insights
This study investigated shorter, high-dose liposomal amphotericin B (AmBisome) regimens for cryptococcal meningitis in HIV patients. Shorter AmBisome courses show promise for treating this deadly infection, potentially improving patient outcomes.
Area of Science:
- Infectious Diseases
- Mycology
- HIV/AIDS Research
Background:
- Cryptococcal meningitis (CM) is a major cause of death in HIV-infected individuals in Africa.
- Conventional treatments face challenges including drug unavailability and lengthy administration protocols.
- Novel therapeutic strategies are crucial to reduce CM-related mortality.
Purpose of the Study:
- To evaluate the non-inferiority of short-course, high-dose liposomal amphotericin B (AmBisome) plus fluconazole compared to standard 14-day AmBisome for HIV-associated CM.
- To identify optimal AmBisome dosing and duration for improved CM treatment efficacy and safety.
Main Methods:
- An adaptive, open-label, phase II/III randomized non-inferiority trial (ISRCTN10248064).
- Phase II assessed early fungicidal activity (EFA) with four AmBisome regimens. Phase III compares the best short-course regimen against the 14-day control.
- Primary outcomes: EFA in Phase II, 70-day all-cause mortality in Phase III. Intention-to-treat analysis.
Main Results:
- (Results not yet available in the provided abstract)
Conclusions:
- (Conclusions not yet available in the provided abstract)
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