Safety and efficacy of praziquantel 40 mg/kg versus 80 mg/kg in preschool-aged children with intestinal schistosomiasis in Uganda: a 2 × 2 factorial, double-blind, placebo-controlled, phase 2 randomised trial

Background

Optimal dosing of praziquantel for schistosomiasis for children younger than 5 years is not established and some studies suggest this age group might need a higher dosing per kilogram. Our aim was to assess the safety and efficacy of a split dose of 80 mg/kg of praziquantel tablets given in a single day to preschool children versus the recommended single dose of 40 mg/kg for treatment of Schistosoma mansoni.

Methods

We did a 2 × 2 factorial design, placebo-controlled, phase 2 randomised trial in Uganda. Children aged 12–47 months infected with Schistosoma mansoni were randomly assigned in a 1:1:1:1 ratio to receive crushed praziquantel tablets at single standard (40 mg/kg) versus double standard dosing (80 mg/kg delivered as two 40 mg/kg doses 3 hours apart) and same dose or placebo at 6 months. Coprimary outcomes were parasitological cure and egg reduction rate at 4 weeks. Secondary outcomes included antigenic cure at 4 weeks, adverse events and clinical toxicity 12 h after treatment, and key morbidity markers at 6 months and 12 months. This trial is registered with ClinicalTrials.gov (NCT03640377).

Findings

Between Feb 18 and Dec 14, 2021, 354 children were randomly assigned to either praziquantel 40 mg/kg at baseline and placebo at 6 months (n=88); 40 mg/kg at baseline and 40 mg/kg at 6 months (n=86); 80 mg/kg at baseline and placebo at 6 months (m=89); or 80 mg/kg at baseline and 80 mg/kg at 6 months (n=91). 181 (51%) of 354 participants were boys. The median age was 36 months (28–42). Cure rate at 4 weeks was 67% in the 40 mg/kg group and 90% in the 80 mg/kg group (absolute difference 23% [95% CI 14–31]; p<0·001); for egg reduction rate the difference was 2% (95% CI 1–3; p<0·001) based on geometric mean and 22% (5–59; p<0·001) based on arithmetic mean. There were no differences in adverse event rates between the trial groups. At 12 months, biannual versus annual treatment reduced prevalence of faecal occult blood and 80 mg/kg dose reduced prevalence of faecal calprotectin. No severe adverse events related to the study drug were reported.

Interpretation

Two 40 mg/kg doses given 3 hours apart are safe, well tolerated, and more effective in achieving parasitic cure than the current proposed single 40 mg/kg dose. Until a paediatric formulation of praziquantel is available in endemic areas, the use of crushed tablets with this dosing strategy can be recommended for young children living in S mansoni endemic areas. In addition, twice-a-year treatment compared with once-a-year treatment affected some intestinal morbidity markers.