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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.

Publication ,  Journal Article
Molefi, M; Chofle, AA; Molloy, SF; Kalluvya, S; Changalucha, JM; Cainelli, F; Leeme, T; Lekwape, N; Goldberg, DW; Haverkamp, M; Bisson, GP ...
Published in: Trials
June 17, 2015

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.

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Published In

Trials

DOI

EISSN

1745-6215

Publication Date

June 17, 2015

Volume

16

Start / End Page

276

Location

England

Related Subject Headings

  • Treatment Outcome
  • Time Factors
  • Tanzania
  • Research Design
  • Meningitis, Cryptococcal
  • Humans
  • General & Internal Medicine
  • Fluconazole
  • Drug Therapy, Combination
  • Drug Administration Schedule
 

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Molefi, M., Chofle, A. A., Molloy, S. F., Kalluvya, S., Changalucha, J. M., Cainelli, F., … 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, 276. https://doi.org/10.1186/s13063-015-0799-6
Molefi, Mooketsi, Awilly A. Chofle, Síle F. Molloy, Samuel Kalluvya, John M. Changalucha, Francesca Cainelli, Tshepo Leeme, et al. “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 (June 17, 2015): 276. https://doi.org/10.1186/s13063-015-0799-6.
Molefi M, Chofle AA, Molloy SF, Kalluvya S, Changalucha JM, Cainelli F, Leeme T, Lekwape N, Goldberg DW, Haverkamp M, Bisson GP, Perfect JR, Letang E, Fenner L, Meintjes G, Burton R, Makadzange T, Ndhlovu CE, Hope W, Harrison TS, Jarvis JN. 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. 2015 Jun 17;16:276.
Journal cover image

Published In

Trials

DOI

EISSN

1745-6215

Publication Date

June 17, 2015

Volume

16

Start / End Page

276

Location

England

Related Subject Headings

  • Treatment Outcome
  • Time Factors
  • Tanzania
  • Research Design
  • Meningitis, Cryptococcal
  • Humans
  • General & Internal Medicine
  • Fluconazole
  • Drug Therapy, Combination
  • Drug Administration Schedule