Mesu 2018.

Study characteristics
Methods	Study design: randomized controlled trial Study dates: recruitment between October 2012 and November 2016 Length of follow‐up: up to 24 months Subgroup analyses ‐ post hoc: treatment failure at 18 months for those with 1) presence or absence of trypanosomes in CSF at entry; 2) ≥ 100 or < 100 WBC/μL and ≥ 400 or < 400 WBC/μL in CSF at entry; or 3) ≥ 12 or < 12 and ≥ 10 or < 10 score on clinical signs and symptoms score at entry
Participants	Participants: n = 394 randomized Age (mean): fexinidazole: 34.5 (SD 12.6) years; NECT: 35.3 (SD 13.2) years Sex: fexinidazole: 161 (61.0%) male; NECT: 80 (61.5%) male Weight: mean bodyweight was 50.6 kg (IQR 45 to 56), mean BMI was 19.2 kg/m2, with 75% of participants having a BMI lower than 20.7 kg/m2 Diagnosis: parasitologically confirmed late‐stage g‐HAT infection: 1) parasites in at least one body fluid (blood, lymph node fluid, or CSF), and 2) CSF > 20 WBC/μL or trypanosomes in the CSF. Symptoms: most commonly reported clinical signs and symptoms of g‐HAT included headache (281 (71%)), pruritus (228 (57%)), sleepiness (218 (55%)), weight loss (217 (55%)), and asthenia (216 (55%)) Comorbidities:  nervous system disorders: fexinidazole: 67 (25%), NECT: 34 (26%)  Inclusion criteria: people aged 15 years or older with parasitologically confirmed late‐stage g‐HAT infection Exclusion criteria: clinically significant laboratory test abnormalities, pregnancy, unstable abnormalities on electrocardiogram (ECG), QT interval corrected using Fridericia’s formula (QTcF) of at least 450 ms (on automatic reading on two successive ECGs in resting position, done 10 min to 20 min apart), and people not tested for malaria or not having received appropriate treatment for malaria or for soil‐transmitted helminthiasis.
Interventions	Intervention characteristics Experimental drug: fexinidazole (N randomized = 264) Treatment regimen: oral fexinidazole once a day with food (1800 mg, 3 × 600 mg tablets) on days 1 to 4, followed by 1200 mg (2 × 600 mg tablets) once a day on days 5 to 10 Active Comparator: NECT (N randomized = 130) Treatment regimen: nifurtimox tablets three times a day at a dose of 15 mg/kg per day for 10 days (days 1 to 10) with eflornithine given twice a day as a 2‐h intravenous infusion at a total dose of 400 mg/kg for 7 days (days 1 to 7) Co‐intervention for both groups: participants who tested positive for malaria received antimalarial treatment and had a recovery period of at least 3 days before starting study treatment for g‐HAT. All participants received treatment for soil‐transmitted helminthiasis.
Outcomes	Mortality (overall mortality, death during treatment), treatment success, treatment failure, withdrawals, relapse, adverse events, serious adverse events. Time points: end of treatment, 18 months, 24 months
Identification	Funding: Drugs for Neglected Diseases initiative (DNDi) Setting and Country: inpatients in the Central African Republic (Batangafo), and in The Democratic Republic of the Congo (Bagata Hospital, Bagata, Bandundu; Masi Manimba Hospital, Masi Manimba, Bandundu; Vanga Hospital, Vanga, Bandundu; HGR (General Reference Hospital )Mushie Hospital, Mushie, Bandundu; CRT (Centre de Réference et de Traitement) Dipumba, Dipumba General Hospital, Mbuji Mayi, East Kasai; HS Katanda hospital, Katanda, Kasaï Oriental; HGR Isangi Hospital, Isangi, Province Orientale; HGR Bandundu, Bandundu; Dingila  Hospital, Province Bas Uelé, Democratic Republic of Congo). Study IDs: NCT01685827, DNDiFEX004
Notes	We used published and unpublished data from this study in this review
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomly assigned (2:1) on day 1 to receive either fexinidazole or nifurtimox eflornithine combination therapy according to a predefined randomisation list stratified by site."
Allocation concealment (selection bias)	Low risk	Quote: "Randomisation was centralised to avoid selection bias and occurred in blocks of six patients."
Blinding of participants and personnel (performance bias)	High risk	There was a high risk of performance bias due to participants and personnel not being blind, as this was an open‐label study. The route of administration and dosing regimens differed between treatment groups, so a double‐dummy study was not feasible and would have required placebo infusions.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	‘All‐cause mortality’ and ‘death during treatment’ are outcomes not involving judgement.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Although the funder, data management personnel, and statisticians were masked to treatment until the final analysis at 18 months, ‘Relapse’, ‘adverse events that lead to treatment discontinuation’, ‘death likely to be due to HAT’; ’adherence to treatment’, treatment failure, adverse events and serious adverse events involve some measure of judgement and could be affected by knowledge of intervention receipt.
Incomplete outcome data (attrition bias) All outcomes	Low risk	For all outcomes and all time points missing data is < 10%.
Selective reporting (reporting bias)	Low risk	All outcomes listed in online trial record were reported (clinicaltrials.gov/ct2/show/NCT01685827), and 24 month follow‐up clinical study report was made available
Other bias	Low risk	Quote: "Table 1 shows the baseline characteristics of trial participants. Similar demographic characteristics were noted in the primary analysis population in both treatment groups." Judgement Comment: No other risk of biases were detected. Baseline characteristics were balanced between groups

BMI: body mass index; CSF: cerebrospinal fluid; g‐HAT: gambiense human African trypanosomiasis; IQR: interquartile range; NECT: nifurtimox eflornithine combination therapy; SD: standard deviation; WBC: white blood cell count