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.

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.

• Authors: David S Lawrence, Nabila Youssouf, Síle F Molloy, Alexandre Alanio, Melanie Alufandika, David R Boulware, Timothée Boyer-Chammard, Tao Chen, Francoise Dromer, Admire Hlupeni, William Hope, Mina C Hosseinipour, Cecilia Kanyama, Oliver Lortholary, Angela Loyse, David B Meya, Mosepele Mosepele, Conrad Muzoora, Henry C Mwandumba, Chiratidzo E Ndhlovu, Louis Niessen, Charlotte Schutz, Katharine E Stott, Duolao Wang, David G Lalloo, Graeme Meintjes, Shabbar Jaffar, Thomas S Harrison, Joseph N Jarvis
• Journal: Trials (Trials) Vol. 19 Issue 1 Pg. 649 (Nov 23 2018) ISSN: 1745-6215 [Electronic] England
• PMID: 30470259 (Publication Type: Clinical Trial Protocol, Journal Article)

Chemical References

• Antifungal Agents
• liposomal amphotericin B
• Amphotericin B
• Fluconazole
• Flucytosine

Topics

• Africa South of the Sahara
• Amphotericin B (administration & dosage, adverse effects, economics, pharmacokinetics)
• Antifungal Agents (administration & dosage, adverse effects, economics, pharmacokinetics)
• Clinical Trials, Phase III as Topic
• Cost-Benefit Analysis
• Cryptococcus neoformans (drug effects, pathogenicity)
• Drug Administration Schedule
• Drug Costs
• Drug Therapy, Combination
• Equivalence Trials as Topic
• Fluconazole (administration & dosage)
• Flucytosine (administration & dosage)
• Humans
• Induction Chemotherapy
• Meningitis, Cryptococcal (drug therapy, economics, microbiology, mortality)
• Multicenter Studies as Topic
• Time Factors
• Treatment Outcome