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. 2018 Nov 23;19(1):649. doi: 10.1186/s13063-018-3026-4.

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.

Keywords: AmBisome; Amphotericin B; Clinical trial; Cryptococcal meningitis; Fluconazole; Flucytosine; HIV.

Publication types

  • Clinical Trial Protocol

MeSH terms

  • Africa South of the Sahara
  • Amphotericin B / administration & dosage*
  • Amphotericin B / adverse effects
  • Amphotericin B / economics
  • Amphotericin B / pharmacokinetics
  • Antifungal Agents / administration & dosage*
  • Antifungal Agents / adverse effects
  • Antifungal Agents / economics
  • Antifungal Agents / pharmacokinetics
  • Clinical Trials, Phase III as Topic
  • Cost-Benefit Analysis
  • Cryptococcus neoformans / drug effects*
  • Cryptococcus neoformans / 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*
  • Meningitis, Cryptococcal / economics
  • Meningitis, Cryptococcal / microbiology
  • Meningitis, Cryptococcal / mortality
  • Multicenter Studies as Topic
  • Time Factors
  • Treatment Outcome

Substances

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