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

BackgroundCryptococcal 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).MethodsAn 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.DiscussionA 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 registrationISRCTN, ISRCTN72509687. Registered on 13 July 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-3026-4) contains supplementary material, which is available to authorized users.

Cryptococcal-related Mortality Despite Fluconazole Preemptive Treatment in a Cryptococcal Antigen Screen-and-Treat Program

“…We found blood CrAg titers of >160 to be predictive of death, consistent with previous studies [5,20,21]. Adjunctive treatment options include flucytosine (shown to be effective for treating cryptococcal meningitis in the Advancing Cryptococcal meningitis Treatment for Africa (ACTA) trial [22]) or a single dose of 10 mg/kg liposomal amphotericin (effective fungicidal activity in CSF [23] and currently in a phase 3 trial for treating cryptococcal meningitis [24]). Both treatments are safe and feasible to administer in outpatient settings; randomized, controlled trials are required to establish if they would reduce mortality in asymptomatic CrAg-positive patients.…”

Treatment of invasive fungal diseases in cancer patients—Revised 2019 Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

“…Alternatively, a combination of L‐AmB plus fluconazole or voriconazole might be used, if flucytosine is not available (BIIt) 224‐226 . Recently, an induction therapy with a single, high‐dose L‐AmB given with high‐dose fluconazole and flucytosine was shown not to be inferior to a standard seven‐day course of D‐AmB plus flucytosine in HIV patients 227 . See Table 6a‐c.…”

Clinical Pharmacokinetics, Pharmacodynamics, Safety and Efficacy of Liposomal Amphotericin B

“…Induction based on short-course LAmB is currently being investigated in an open-label, Phase III, randomized, non-inferiority trial. Here, induction therapy with a single dose of LAmB (10 mg/kg), given with 14 days of fluconazole (1200 mg/day) plus flucytosine (100 mg/kg/day), was compared with the current World Health Organization–recommended treatment regimen of 7 days of amphotericin B deoxycholate (1 mg/kg/day) plus flucytosine (100 mg/kg/day), followed by 7 days of fluconazole (1200 mg/day) [94].…”