TY - JOUR
T1 - AMBIsome Therapy Induction OptimisatioN (AMBITION)
T2 - High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial 11 Medical and Health Sciences 1103 Clinical Sciences
AU - Lawrence, David S.
AU - Youssouf, Nabila
AU - Molloy, Síle L.F.
AU - Alanio, Alexandre
AU - Alufandika, Melanie
AU - Boulware, David R.
AU - Boyer-Chammard, Timothée
AU - Chen, Tao
AU - Dromer, Francoise
AU - Hlupeni, Admire
AU - Hope, William
AU - Hosseinipour, Mina C.
AU - Kanyama, Cecilia
AU - Lortholary, Oliver
AU - Loyse, Angela
AU - Meya, David B.
AU - Mosepele, Mosepele
AU - Muzoora, Conrad
AU - Mwandumba, Henry C.
AU - Ndhlovu, Chiratidzo E.
AU - Niessen, Louis
AU - Schutz, Charlotte
AU - Stott, Katharine E.
AU - Wang, Duolao
AU - Lalloo, David G.
AU - Meintjes, Graeme
AU - Jaffar, Shabbar
AU - Harrison, Thomas S.
AU - Jarvis, Joseph N.
N1 - Funding Information:
The study is jointly funded through the European and Developing Countries Clinical Trials Partnership (EDCTP), Swedish International Development Cooperation Agency (SIDA) and Wellcome Trust / Medical Research Council (UK) / UKAID Joint Global Health Trials. The AmBisome for the trial has been donated by Gilead. The funders had no role in the design of the trial, nor will they be involved in the collection, analysis and interpretation of data or the preparation of manuscripts. Katharine Stott is a Wellcome Trust Clinical PhD Fellow (203919/Z/16/Z).
Funding Information:
The study is jointly funded through the European and Developing Countries Clinical Trials Partnership (EDCTP), Swedish International Development Cooperation Agency (SIDA) and Wellcome Trust / Medical Research Council (UK) / UKAID Joint Global Health Trials. Recruitment commenced in Botswana in January 2018 and in South Africa in July 2018; recruitment will commence at the other sites pending the requisite ethical and regulatory approvals.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/11/23
Y1 - 2018/11/23
N2 - Background: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). Methods: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. Discussion: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment.
AB - Background: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). Methods: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. Discussion: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment.
KW - AmBisome
KW - Amphotericin B
KW - Clinical trial
KW - Cryptococcal meningitis
KW - Fluconazole
KW - Flucytosine
KW - HIV
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U2 - 10.1186/s13063-018-3026-4
DO - 10.1186/s13063-018-3026-4
M3 - Article
C2 - 30470259
AN - SCOPUS:85057081843
VL - 19
JO - Trials
JF - Trials
SN - 1745-6215
IS - 1
M1 - 649
ER -