Background: The clinical development of a single encounter treatment for uncomplicated malaria has the potential to\nsignificantly improve the effectiveness of antimalarials. Exploratory data suggested that the combination of artefenomel\nand piperaquine phosphate (PQP) has the potential to achieve satisfactory cure rates as a single dose therapy. The\nprimary objective of the study was to determine whether a single dose of artefenomel (800 mg) plus PQP in ascending\ndoses is an efficacious treatment for uncomplicated Plasmodium falciparum malaria in the 'target' population of\nchildren ââ?°Â¤ 5 years of age in Africa as well as Asian patients of all ages.\nMethods: Patients in six African countries and in Vietnam were randomised to treatment with follow-up for 42ââ?¬â??63\ndays. Efficacy, tolerability, safety and pharmacokinetics were assessed. Additional key objectives were to characterise the\nexposureââ?¬â??response relationship for polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological\nresponse at day 28 post-dose (ACPR28) and to further investigate Kelch13 mutations. Patients in Africa (n = 355) and\nVietnam (n = 82) were included, with 85% of the total population being children < 5 years of age. Results: ACPR28 in the per protocol population (95% confidence interval) was 70.8% (61.13ââ?¬â??79.19), 68.4% (59.13ââ?¬â??76.66)\nand 78.6% (70.09ââ?¬â??85.67) for doses of 800 mg artefenomel with 640 mg, 960 mg and 1440 mg of PQP respectively.\nACPR28 was lower in Vietnamese than in African patients (66.2%; 54.55ââ?¬â??76.62 and 74.5%; 68.81ââ?¬â??79.68) respectively.\nWithin the African population, efficacy was lowest in the youngest age group of ââ?°Â¥ 0.5 to ââ?°Â¤ 2 years, 52.7% (38.80ââ?¬â??66.35).\nInitial parasite clearance was twice as long in Vietnam than in Africa. Within Vietnam, the frequency of the Kelch13\nmutation was 70.1% and was clearly associated with parasite clearance half-life (PCt1/2). The most significant tolerability\nfinding was vomiting (28.8%).\nConclusions: In this first clinical trial evaluating a single encounter antimalarial therapy, none of the treatment arms\nreached the target efficacy of > 95% PCR-adjusted ACPR at day 28. Achieving very high efficacy following single dose\ntreatment is challenging, since > 95% of the population must have sufficient concentrations to achieve cure across a\nrange of parasite sensitivities and baseline parasitaemia levels. While challenging, the development of tools suitable for\ndeployment as single encounter curative treatments for adults and children in Africa and to support elimination\nstrategies remains a key development goal.
Loading....