AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial
Creators: name: Hosseinipour, Mina C
name: Stott, Katharine E
name: Mosepele, Mosepele
name: Molloy, Síle L F
name: Lortholary, Oliver
name: Muzoora, Conrad
name: Youssouf, Nabila
name: Loyse, Angela
name: Jaffar, Shabbar
name: Lawrence, David S
name: Lalloo, David G
name: Ndhlovu, Chiratidzo E
name: Mwandumba, Henry C
name: Boyer-Chammard, Timothée
name: Dromer, Francoise
name: Niessen, Louis
name: Alanio, Alexandre
name: Chen, Tao
name: Meya, David B
name: Wang, Duolao
name: Hope, William
name: Jarvis, Joseph N
name: Harrison, Thomas S
name: Boulware, David R
name: Hlupeni, Admire
name: Schutz, Charlotte
name: Kanyama, Cecilia
name: Alufandika, Melanie
name: Meintjes, Graeme
Publisher: name: BioMed Central
Year: 2018

description: Abstract
                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.
                Trial registration
                ISRCTN, 
                    ISRCTN72509687
                  . Registered on 13 July 2017.