Fexinidazole as a new oral treatment for human African trypanosomiasis due to Trypanosoma brucei rhodesiense: a prospective, open-label, single-arm, phase 2-3, non-randomised study.

BACKGROUND Rhodesiense human African trypanosomiasis is a neglected disease with epidemic potential that can rapidly become lethal if left untreated. The aim of this study was to show that fexinidazole could offer an alternative to existing treatments (melarsoprol for stage 2 and suramin for stage 1 rhodesiense human African trypanosomiasis), using a benchmark study design. METHODS This was a prospective, open-label, single-arm, phase 2-3, non-randomised study done in two centres (Lwala, Uganda and Rumphi, Malawi). Participants were enrolled if they were aged 6 years or older, weighed 20 kg or more, had parasitologically confirmed rhodesiense human African trypanosomiasis, were able to swallow fexinidazole tablets with a meal, and had a Karnofsky score of 40 or more. Pregnant or breastfeeding women were eligible after the first trimester of pregnancy. While admitted to hospital, participants received oral fexinidazole for 10 days at the recommended dosage according to bodyweight and were followed up for 12 months. The fatality and non-response to treatment rates observed with fexinidazole were compared with predefined rates based on literature. The primary endpoint was the fatality rate at end of hospital admission (EoH) in participants with stage 2 rhodesiense human African trypanosomiasis (considering only deaths possibly related to the disease or fexinidazole), to be compared with 8·5%, an approximation of the fatality rate obtained with melarsoprol. This study is registered with ClinicalTrials.gov, NCT03974178. FINDINGS Between Sept 29, 2019, and Oct 12, 2022, 46 participants with rhodesiense human African trypanosomiasis were screened, of whom 45 were included and treated (35 with stage 2 and ten with stage 1 disease). One death occurred during treatment but was considered unrelated to rhodesiense human African trypanosomiasis or fexinidazole and excluded from the efficacy analysis. No other deaths had occurred by EoH in participants with stage 2 rhodesiense human African trypanosomiasis, giving a fatality rate of 0 (0%) of 34 (90% CI 0-8·43), which was lower than the predefined 8·5% rate (p=0·0488). One participant with stage 2 rhodesiense human African trypanosomiasis had a relapse at week 9. No failures were reported in participants with stage 1 rhodesiense human African trypanosomiasis. No unexpected safety signals were identified on the basis of standard assessments and electrocardiograms. INTERPRETATION Fexinidazole is a safe and easy-to-use treatment, and is a better-accepted alternative to existing treatments for rhodesiense human African trypanosomiasis, such as melarsoprol or suramin. FUNDING EDCTP and various donors through the Drugs for Neglected Diseases initiative.