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Trials. 2015 Jun 17;16:276. doi: 10.1186/s13063-015-0799-6.

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.

Author information

1
Department of Family Medicine and Public Health, Faculty of Medicine, University of Botswana, P.O.Box 1357 ABG, Gaborone, Botswana. mooketsimolefi@gmail.com.
2
Botswana-Upenn Partnership, Gaborone, Botswana. mooketsimolefi@gmail.com.
3
Bugando Medical Centre, Mwanza, Tanzania. awilchofle12@gmail.com.
4
National Institute for Medical Research, Mwanza Research Centre, Mwanza, Tanzania. awilchofle12@gmail.com.
5
Research Centre for Infection and Immunity, St. George's University of London, London, UK. smolloy@sgul.ac.uk.
6
Bugando Medical Centre, Mwanza, Tanzania. samuelkalluvya@yahoo.com.
7
National Institute for Medical Research, Mwanza Research Centre, Mwanza, Tanzania. jchangalucha@yahoo.com.
8
Department of Family Medicine and Public Health, Faculty of Medicine, University of Botswana, P.O.Box 1357 ABG, Gaborone, Botswana. francescacainelli@yahoo.it.
9
Botswana-Upenn Partnership, Gaborone, Botswana. tbleeme@yahoo.com.
10
Botswana-Upenn Partnership, Gaborone, Botswana. n72823980@gmail.com.
11
Botswana-Upenn Partnership, Gaborone, Botswana. drewg1080@gmail.com.
12
Botswana-Upenn Partnership, Gaborone, Botswana. haverkamp.bup@gmail.com.
13
Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. haverkamp.bup@gmail.com.
14
Botswana-Upenn Partnership, Gaborone, Botswana. gregbisson@me.com.
15
Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. gregbisson@me.com.
16
Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, USA. john.perfect@dm.duke.edu.
17
Swiss Tropical and Public Health Institute, Basel, Switzerland. emili.letang@unibas.ch.
18
Ifakara Health Institute, Ifakara, Morogoro, Tanzania. emili.letang@unibas.ch.
19
ISGLOBAL, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clinic-Universitat de Barcelona, Barcelona, Spain. emili.letang@unibas.ch.
20
Swiss Tropical and Public Health Institute, Basel, Switzerland. lukas.fenner@unibas.ch.
21
Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa. graemein@mweb.co.za.
22
Department of Medicine, Imperial College London, London, UK. graemein@mweb.co.za.
23
Department of Medicine, Khayelitsha Hospital, Khayelitsha, Cape Town, South Africa. rosie@polka.co.za.
24
Ragon Institute of MGH, MIT, Harvard Cambridge, MA, USA. tariro.makadzange@gmail.com.
25
Department of Medicine, University of Zimbabwe College of Health Sciences, Parirenyatwa Hospital, Harare, Zimbabwe. tariro.makadzange@gmail.com.
26
Department of Medicine, University of Zimbabwe College of Health Sciences, Parirenyatwa Hospital, Harare, Zimbabwe. ratizw@gmail.com.
27
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. William.Hope@liverpool.ac.uk.
28
Research Centre for Infection and Immunity, St. George's University of London, London, UK. tharriso@sgul.ac.uk.
29
Botswana-Upenn Partnership, Gaborone, Botswana. drjoejarvis@gmail.com.
30
Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. drjoejarvis@gmail.com.
31
Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. drjoejarvis@gmail.com.

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 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.

PMID:
26081985
PMCID:
PMC4479349
DOI:
10.1186/s13063-015-0799-6
[Indexed for MEDLINE]
Free PMC Article

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