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Lawrence, David S., Youssouf, Nabila, Molloy, Síle F, Alanio, Alexandre, Alufandika, Melanie, Boulware, David R., Boyer-Chammard, Timothée, Chen, Tao 
ORCID: https://orcid.org/0000-0002-5489-6450, Dromer, Francoise, Hlupeni, Admire, Hope, William, Hosseinipour, Mina C., Kanyama, Cecilia, Lortholary, Oliver, Loyse, Angela, Meya, David B., Mosepele, Mosepele, Muzoora, Conrad, Mwandumba, Henry C., Ndhlovu, Chiratidzo E., Niessen, Louis ORCID: https://orcid.org/0000-0002-8639-5191, Schutz, Charlotte, Stott, Katharine E., Wang, Duolao ORCID: https://orcid.org/0000-0003-2788-2464, Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200, Meintjes, Graeme, Jaffar, Shabbar ORCID: https://orcid.org/0000-0002-9615-1588, Harrison, Thomas S. and Jarvis, Joseph N.
(2018)
'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'. Trials, Vol 19, Issue 1, e649.
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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
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