Journal Article

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., Boulware, David R., Meintjes, Graeme, Molloy, Síle F., Chen, Tao, Dromer, Francoise, Hlupeni, Admire, Kanyama, Cecilia, Wang, Duolao, Boyer-Chammard, Timothée, Muzoora, Conrad, Jaffar, Shabbar, Hosseinipour, Mina C., Alanio, Alexandre, Ndhlovu, Chiratidzo E., Mwandumba, Henry C., Lortholary, Oliver, Niessen, Louis, Stott, Katharine E., Alufandika, Melanie, Hope, William, Lalloo, David G., Mosepele, Mosepele, Schutz, Charlotte, Harrison, Thomas S., Jarvis, Joseph N., Loyse, Angela, Youssouf, Nabila, Meya, David B.

2018

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Africa South of the Sahara / AmBisome / Amphotericin B / Amphotericin B - administration & dosage / Amphotericin B - adverse effects / Amphotericin B - economics / Amphotericin B - pharmacokinetics / Analysis / Anemia / Antifungal agents / Antifungal Agents - administration & dosage / Antifungal Agents - adverse effects / Antifungal Agents - economics / Antifungal Agents - pharmacokinetics / Antiretroviral drugs / Biomedicine / Clinical trials / Clinical Trials, Phase III as Topic / Cost-Benefit Analysis / Cryptococcal meningitis / Cryptococcus neoformans - drug effects / Cryptococcus neoformans - pathogenicity / Dosage and administration / Drug Administration Schedule / Drug Costs / Drug dosages / Drug therapy / Drug Therapy, Combination / Equivalence Trials as Topic / Fluconazole / Fluconazole - administration & dosage / Flucytosine / Flucytosine - administration & dosage / Health Sciences / HIV / Human immunodeficiency virus / Humans / Induction Chemotherapy / Induction therapy / Laboratories / Life Sciences / Medicine / Medicine & Public Health / Meningitis / Meningitis, Cryptococcal - drug therapy / Meningitis, Cryptococcal - economics / Meningitis, Cryptococcal - microbiology / Meningitis, Cryptococcal - mortality / Mortality / Multicenter Studies as Topic / Parasitic diseases / Statistics for Life Sciences / Study Protocol / Time Factors / Treatment Outcome / Tropical diseases