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.
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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  ISRCTN10248064. Date of Registration: 22 January 2014.
authors.affiliation: Department of Family Medicine and Public Health, Faculty of Medicine, University of Botswana, P.O.Box 1357 ABG, Gaborone, Botswana. mooketsimolefi@gmail.com.|Botswana-Upenn Partnership, Gaborone, Botswana. mooketsimolefi@gmail.com.
authors.forename: Mooketsi
authors.initials: M
authors.lastname: Molefi
authors.affiliation: Bugando Medical Centre, Mwanza, Tanzania. awilchofle12@gmail.com.|National Institute for Medical Research, Mwanza Research Centre, Mwanza, Tanzania. awilchofle12@gmail.com.
authors.forename: Awilly A
authors.initials: AA
authors.lastname: Chofle
authors.affiliation: Research Centre for Infection and Immunity, St. George's University of London, London, UK. smolloy@sgul.ac.uk.
authors.forename: Síle F
authors.initials: SF
authors.lastname: Molloy
authors.affiliation: Bugando Medical Centre, Mwanza, Tanzania. samuelkalluvya@yahoo.com.
authors.forename: Samuel
authors.initials: S
authors.lastname: Kalluvya
authors.affiliation: National Institute for Medical Research, Mwanza Research Centre, Mwanza, Tanzania. jchangalucha@yahoo.com.
authors.forename: John M
authors.initials: JM
authors.lastname: Changalucha
authors.affiliation: Department of Family Medicine and Public Health, Faculty of Medicine, University of Botswana, P.O.Box 1357 ABG, Gaborone, Botswana. francescacainelli@yahoo.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cainelli
authors.affiliation: Botswana-Upenn Partnership, Gaborone, Botswana. tbleeme@yahoo.com.
authors.forename: Tshepo
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authors.lastname: Leeme
authors.affiliation: Botswana-Upenn Partnership, Gaborone, Botswana. n72823980@gmail.com.
authors.forename: Nametso
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authors.affiliation: Botswana-Upenn Partnership, Gaborone, Botswana. drewg1080@gmail.com.
authors.forename: Drew W
authors.initials: DW
authors.lastname: Goldberg
authors.affiliation: Botswana-Upenn Partnership, Gaborone, Botswana. haverkamp.bup@gmail.com.|Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. haverkamp.bup@gmail.com.
authors.forename: Miriam
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authors.lastname: Haverkamp
authors.affiliation: Botswana-Upenn Partnership, Gaborone, Botswana. gregbisson@me.com.|Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. gregbisson@me.com.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Bisson
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, USA. john.perfect@dm.duke.edu.
authors.forename: John R
authors.initials: JR
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authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland. emili.letang@unibas.ch.|Ifakara Health Institute, Ifakara, Morogoro, Tanzania. emili.letang@unibas.ch.|ISGLOBAL, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clinic-Universitat de Barcelona, Barcelona, Spain. emili.letang@unibas.ch.
authors.forename: Emili
authors.initials: E
authors.lastname: Letang
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland. lukas.fenner@unibas.ch.
authors.forename: Lukas
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authors.lastname: Fenner
authors.affiliation: Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa. graemein@mweb.co.za.|Department of Medicine, Imperial College London, London, UK. graemein@mweb.co.za.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: Department of Medicine, Khayelitsha Hospital, Khayelitsha, Cape Town, South Africa. rosie@polka.co.za.
authors.forename: Rosie
authors.initials: R
authors.lastname: Burton
authors.affiliation: Ragon Institute of MGH, MIT, Harvard Cambridge, MA, USA. tariro.makadzange@gmail.com.|Department of Medicine, University of Zimbabwe College of Health Sciences, Parirenyatwa Hospital, Harare, Zimbabwe. tariro.makadzange@gmail.com.
authors.forename: Tariro
authors.initials: T
authors.lastname: Makadzange
authors.affiliation: Department of Medicine, University of Zimbabwe College of Health Sciences, Parirenyatwa Hospital, Harare, Zimbabwe. ratizw@gmail.com.
authors.forename: Chiratidzo E
authors.initials: CE
authors.lastname: Ndhlovu
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. William.Hope@liverpool.ac.uk.
authors.forename: William
authors.initials: W
authors.lastname: Hope
authors.affiliation: Research Centre for Infection and Immunity, St. George's University of London, London, UK. tharriso@sgul.ac.uk.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Harrison
authors.affiliation: Botswana-Upenn Partnership, Gaborone, Botswana. drjoejarvis@gmail.com.|Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. drjoejarvis@gmail.com.|Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. drjoejarvis@gmail.com.
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authors.initials: JN
authors.lastname: Jarvis
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001902:Botswana; D002985:Clinical Protocols; D060085:Coinfection; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D015725:Fluconazole / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D016919:Meningitis, Cryptococcal / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D012107:Research Design; D013636:Tanzania; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B; D015725:Fluconazole