BACKGROUND: Few therapeutic options are available to treat the late-stage of 
human African trypanosomiasis, a neglected tropical disease, caused by 
Trypanosoma brucei gambiense (g-HAT). The firstline treatment is a combination 
therapy of oral nifurtimox and intravenous eflornithine that needs to be 
administered in a hospital setting by trained personnel, which is not optimal 
given that patients often live in remote areas with few health resources. 
Therefore, we aimed to assess the safety and efficacy of an oral regimen of 
fexinidazole (a 2-substituted 5-nitroimidazole with proven trypanocidal 
activity) versus nifurtimox eflornithine combination therapy in patients with 
late-stage g-HAT.
METHODS: In this randomised, phase 2/3, open-label, non-inferiority trial, we 
recruited patients aged 15 years and older with late-stage g-HAT from g-HAT 
treatment centres in the Democratic Republic of the Congo (n=9) and the Central 
African Republic (n=1). Patients were randomly assigned (2:1) to receive either 
fexinidazole or nifurtimox eflornithine combination therapy according to a 
predefined randomisation list (block size six). The funder, data management 
personnel, and study statisticians were masked to treatment. Oral fexinidazole 
was given once a day (days 1-4: 1800 mg, days 5-10: 1200 mg). Oral nifurtimox 
was given three times a day (days 1-10: 15 mg/kg per day) with eflornithine 
twice a day as 2 h infusions (days 1-7: 400 mg/kg per day). The primary endpoint 
was success at 18 months (ie, deemed as patients being alive, having no evidence 
of trypanosomes in any body fluid, not requiring rescue medication, and having a 
cerebrospinal fluid white blood cell count ≤20 cells per μL). Safety was 
assessed through routine monitoring. Primary efficacy analysis was done in the 
modified intention-to-treat population and safety analyses in the 
intention-to-treat population. The acceptable margin for the difference in 
success rates was defined as 13%. This study has been completed and is 
registered with ClinicalTrials.gov, number NCT01685827.
FINDINGS: Between October, 2012, and November, 2016, 419 patients were 
pre-screened. Of the 409 eligible patients, 14 were not included because they 
did not meet all inclusion criteria (n=12) or for another reason (n=2). 
Therefore, 394 patients were randomly assigned, 264 to receive fexinidazole and 
130 to receive nifurtimox eflornithine combination therapy. Success at 18 months 
was recorded in 239 (91%) patients given fexinidazole and 124 (98%) patients 
given nifurtimox eflornithine combination therapy, within the margin of 
acceptable difference of -6·4% (97·06% CI -11·2 to -1·6; p=0·0029). We noted no 
difference in the proportion of patients who experienced treatment-related 
adverse events (215 [81%] in the fexinidazole group vs 102 [79%] in the 
nifurtimox eflornithine combination therapy group). Treatment discontinuations 
were unrelated to treatment (n=2 [1%] in the fexinidazole group). Temporary 
nifurtimox eflornithine combination therapy interruption occurred in three (2%) 
patients. 11 patients died during the study (nine [3%] in the fexinidazole group 
vs two [2%] in the nifurtimox eflornithine combination therapy group).
INTERPRETATION: Our findings show that oral fexinidazole is effective and safe 
for the treatment of T b gambiense infection compared with nifurtimox 
eflornithine combination therapy in late-stage HAT patients. Fexinidazole could 
be a key asset in the elimination of this fatal neglected disease.
FUNDING: Drugs for Neglected Diseases initiative.