Efficacy and safety of tribendimidine against Opisthorchis viverrini : two randomised, parallel-group, single-blind, dose-ranging, phase 2 trials

Treatment of the liver fluke infection Opisthorchis viverrini relies exclusively on praziquantel. Tribendimidine could be an alternative treatment option. We aimed to assess the efficacy and safety of ascending single, oral doses of tribendimidine in patients with O viverrini infection.; We did two randomised, parallel-group, single-blind, dose-ranging, phase 2 trials in children (aged 8-14 years) and adults and adolescents (≥15 years) in three O viverrini endemic villages in Champasack province, southern Laos. Patients with O viverrini infection were randomly assigned, via a computer-generated central block-randomisation procedure, with block sizes of three (study 1) and four, eight, and 12 (study 2), to receive oral tribendimidine at doses of 200 mg, 400 mg, or 600 mg in a 1:1:1 ratio (adults and adolescents in study 1); 25 mg, 50 mg, 100 mg, or 200 mg (four 50 mg tablets) in a 1:1:1:1 ratio (adults and adolescents in study 2); or 100 mg, 200 mg, or 400 mg in a 1:1:1 ratio (children in study 1). One non-randomised group of children received tribendimidine 50 mg (study 2). Participants, investigators, and laboratory technicians doing the diagnostic assessments were masked to group assignment, but the investigator administering treatment could have recognised the treatment group based on the number of tablets. The primary objective was to estimate the dose-response relation in terms of cure rate and egg reduction rate. We did available-case analysis of all patients with primary endpoint data. We predicted dose-response associations with Emax models. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN96948551.; Between Oct 25, 2012, and Nov 5, 2013, 318 adolescents and adults were randomly assigned to seven tribendimidine dose groups: 200 mg (n=51), 400 mg (n=49), or 600 mg (n=47) in study 1, and 25 mg (n=39), 50 mg (n=47), 100 mg (n=44), or 200 mg (four 50 mg tablets; n=41) in study 2. 128 children were randomly assigned to receive tribendimidine 100 mg (n=44), 200 mg (n=40), or 400 mg (n=44) in study 1; 39 children were enrolled and received tribendimidine 50 mg in study 2. In adolescents and adults, the number of patients cured increased with increasing tribendimidine doses up to 100 mg: ten of 39 patients (25·6%, 95% CI 13·0-42·1) were cured in the 25 mg group, 20 of 47 patients (42·6%, 28·3-57·8) were cured in the 50 mg group, and 34 of 44 patients (77·3%, 62·2-88·5) were cured in the 100 mg group; geometric mean egg reduction rates were 86·9% (95% CI 74·8-93·4), 95·9% (92·7-97·7), and 99·1% (98·2-99·7), respectively. The 200 mg dose resulted in cure in 40 of 47 (83·0%, 69·2-92·5) adolescents and adults given the 200 mg tablet and 25 of 41 (61·0%, 95% CI 44·5-75·8) of those given four 50 mg tablets; the 400 mg dose resulted in cure in 43 of 47 patients (91·5%, 79·6-97·6) and the 600 mg dose resulted in cure in 36 of 45 patients (80·0%, 65·4-90·4). Corresponding egg reduction rates were 99·8% (95% CI 99·7-100·0) with one 200 mg tablet, 97·9% (95·9-99·2) with four 50 mg tablets, 99·9% (99·8-100·0) with 400 mg, and 99·8% (99·6-99·9) with 600 mg. The Emax model predicted an egg reduction rate of 99·0% (95% CI 95·7-99·8) at 111 mg in adolescents and adults. 50 mg tribendimidine had moderate efficacy in children, with cure recorded in 16 of 39 patients (41·0%, 95% CI 25·6-57·9). The 100 mg dose resulted in cure in 40 of 44 children (98·9%, 95% CI 78·3-97·5) and an egg reduction rate of 99·7% (95% CI 99·0-100·0), with no increased efficacy at higher doses. The Emax model predicted an egg reduction rate of 99·0% (95% CI 92·2-99·9) at 215 mg. Few adverse events were reported and were mostly mild, with few moderate and no serious events. The most common adverse events 3 h after treatment in adolescents and adults were vertigo (n=35 [11%]), headache (n=9 [3%]), nausea (n=6 [2%]), and fatigue (n=4 [1%]), and in children were headache (n=3 [2%]), vertigo (n=2 [1%]), and fatigue (n=2 [1%]).; Tribendimidine has excellent efficacy and tolerability at doses of 100 mg and above. Our study included mainly adults and children with low-intensity O viverrini infection; future studies should assess the efficacy of tribendimidine in patients with infections of moderate and high intensity.; Department for International Development, Medical Research Council, Wellcome Trust Joint Global Health Trials Scheme.