Researchers plan to conduct a study examining whether a single high dose of liposomal amphotericin with high-dose fluconazole and flucytosine is noninferior to a 7-day course of amphotericin B deoxycholate plus flucytosine for the treatment of cryptococcal meningitis, according to a study protocol published in Trials.
Currently, cryptococcal meningitis is a major cause of mortality for patients in HIV programs located in Africa.
The open-label, phase 3 randomized controlled noninferiority trial will be conducted in 5 countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda, and Zimbabwe. The study will compare cryptococcal meningitis induction therapy with a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) with 7 days of amphotericin B deoxycholate (1 mg/kg/day) given alongside 7 days of flucytosine (100 mg/kg/day) followed by 7 days of fluconazole (1200 mg/day). The study will enroll 850 participants aged ≥18 years with a first episode of HIV-associated cryptococcal meningitis, with 425 participants randomly assigned to each treatment arm.
The researchers plan to follow the participants for 16 weeks. All participants will receive consolidation therapy with fluconazole 800 mg/day to complete 10 weeks of treatment and then fluconazole maintenance and antiretroviral therapy.
The study’s primary end point is all-cause mortality at 10 weeks, with a noninferiority margin of 10% and 90% power. Its secondary end points will include early fungicidal activity; proportion of grade 3/4 adverse events; pharmacokinetic parameters; pharmacokinetic/pharmacodynamic associations; health services costs; all-cause mortality within the first 2 weeks; all-cause mortality within the first 4 weeks; and all-cause mortality, rates of cryptococcal meningitis relapse, rates of immune reconstitution inflammatory syndrome, and rates of disability at 10 weeks.
“The potential impact of a safe, sustainable regimen of high-dose L-AmB with non-inferior efficacy when compared to 1 week of daily-dosed amphotericin B deoxy-cholate would be to reduce the number of [adverse events] seen in patients treated with amphotericin and shorten the length of hospital admissions,” the researchers wrote.
Lawrence DS, Youssouf N, Molloy SLF, et al. 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;19:649.