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- Title
AMBITION-cm: intermittent high dose AmBisome on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a randomized controlled trial.
- Authors
Molefi, Mooketsi; Chofle, Awilly A; Molloy, Síle F; Kalluvya, Samuel; Changalucha, John M; Cainelli, Francesca; Leeme, Tshepo; Lekwape, Nametso; Goldberg, Drew W; Haverkamp, Miriam; Bisson, Gregory P; Perfect, John R; Letang, Emili; Fenner, Lukas; Meintjes, Graeme; Burton, Rosie; Makadzange, Tariro; Ndhlovu, Chiratidzo E; Hope, William; Harrison, Thomas S
- Abstract
<bold>Background: </bold>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.<bold>Methodology/design: </bold>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.<bold>Trial Registration: </bold>ISRCTN10248064. Date of Registration: 22 January 2014.
- Publication
Trials, 2015, Vol 16, Issue 1, p276
- ISSN
1745-6215
- Publication type
journal article
- DOI
10.1186/s13063-015-0799-6