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

Mooketsi Molefi, Awilly A. Chofle, Síle F. Molloy, Samuel Kalluvya, John M. Changalucha, Francesca Cainelli, Tshepo Leeme, Nametso Lekwape, Drew W. Goldberg, Miriam Haverkamp, Gregory P. Bisson, John R. Perfect, Emili Letang, Lukas Fenner, Graeme Meintjes, Rosie Burton, Tariro Makadzange, Chiratidzo E. Ndhlovu, William Hope, Thomas S. HarrisonJoseph N. Jarvis

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Abstract

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 14days 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 (≥18years old) with a first episode of HIV-associated CM, using early fungicidal activity (EFA) as the primary outcome: 1) AmBisome 10mg/kgday one (single dose); 2) AmBisome 10mg/kgday one and AmBisome 5mg/kgday three (two doses); 3) AmBisome 10mg/kgday one, and AmBisome 5mg/kgdays three and seven (three doses); and 4) AmBisome 3mg/kg/d for 14days (control); all given with fluconazole 1200mg daily for 14days. STEP 2 (phase III) will enrol 300 participants and compare two treatment arms using all-cause mortality within 70days 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 3mg/kg/d for 14days (control), both given with fluconazole 1200mg daily for 14days. 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 400-800mg daily and ART in accordance with local guidelines. The primary analysis (for both STEP 1 and STEP 2) will be intention-to-treat.

Original languageEnglish
Article number276
JournalTrials
Volume16
Issue number1
DOIs
Publication statusPublished - Jun 17 2015

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Keywords

  • AmBisome
  • Amphotericin B
  • Clinical trial
  • Cryptococcal meningitis
  • Fluconazole
  • HIV

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology (medical)

Cite this

Molefi, M., Chofle, A. A., Molloy, S. F., Kalluvya, S., Changalucha, J. M., Cainelli, F., Leeme, T., Lekwape, N., Goldberg, D. W., Haverkamp, M., Bisson, G. P., Perfect, J. R., Letang, E., Fenner, L., Meintjes, G., Burton, R., Makadzange, T., Ndhlovu, C. E., Hope, W., ... Jarvis, J. N. (2015). 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. Trials, 16(1), [276]. https://doi.org/10.1186/s13063-015-0799-6