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
Public Deposited- Creator
- Lawrence, David S
- Youssouf, Nabila
- Molloy, Síle L F
- Alanio, Alexandre
- Alufandika, Melanie
- Boulware, David R
- Boyer-Chammard, Timothée
- Chen, Tao
- 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
- Schutz, Charlotte
- Stott, Katharine E
- Wang, Duolao
- Lalloo, David G
- Meintjes, Graeme
- Jaffar, Shabbar
- Harrison, Thomas S
- Jarvis, Joseph N
- Abstract
- 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.
- Date of publication
- November 23, 2018
- DOI
- Identifier
- Resource type
- Article
- Rights statement
- In Copyright
- Rights holder
- The Author(s).
- Language
- English
- Bibliographic citation
- Trials. 2018 Nov 23;19(1):649
- Publisher
- BioMed Central
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