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



Lawrence, David S, Youssouf, Nabila, Molloy, Sile LF, Alanio, Alexandre, Alufandika, Melanie, Boulware, David R, Boyer-Chammard, Timothee, Chen, Tao ORCID: 0000-0002-5489-6450, Dromer, Francoise, Hlupeni, Admire
et al (show 19 more authors) (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, 19 (1). 649-.

[thumbnail of AMBITION P3 Manuscript - Trials Publication.pdf] Text
AMBITION P3 Manuscript - Trials Publication.pdf - Published version

Download (1MB)

Abstract

<h4>Background</h4>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).<h4>Methods</h4>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.<h4>Discussion</h4>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.<h4>Trial registration</h4>ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

Item Type: Article
Uncontrolled Keywords: Cryptococcal meningitis, HIV, AmBisome, Amphotericin B, Fluconazole, Flucytosine, Clinical trial
Depositing User: Symplectic Admin
Date Deposited: 03 Dec 2018 10:35
Last Modified: 19 Jan 2023 01:11
DOI: 10.1186/s13063-018-3026-4
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3029225