Efficacy and safety of praziquantel plus artemisinin-based combinations versus praziquantel in the treatment of Kenyan children with Schistosoma mansoni infection: open-label, randomized, head-to-head, non-inferiority trial.

Abstract

Praziquantel alone is insufficient for the control of schistosomiasis due to poor efficacy against juvenile worms and increasing concerns about the risk of drug resistance. We compared the efficacy and safety of praziquantel combined with four different artemisinin-based combinations to praziquantel alone in treating Schistosoma mansoni infection in Kenyan children. In this randomized, open-label, five-arm, head-to-head, non-inferiority trial, children (aged 9-15 years) with S. mansoni infection according to duplicate Kato Katz thick smears from a stool sample in the Mwea irrigation scheme of central Kenya, were enrolled. Participants were randomly assigned (1:1:1:1:1) via a computer-generated block randomization procedure to receive a single oral dose of praziquantel (PZQ) (40 mg/kg/day) alone or in combination with a 3-day course (4 mg/kg of artesunate) of artesunate plus sulfalene-pyrimethamine (As + SP), artesunate plus amodiaquine (As + AQ), artesunate plus mefloquine (As + MQ) or dihydroartemisinin-piperaquine (DHAP). Laboratory technicians were masked to treatment allocation, but participants, clinicians, and study nurses were not. The primary outcomes were the cure rate and frequency of adverse events, which were assessed 6 weeks after treatment in the available case population using a per-protocol analysis. The non-inferiority margin was set at -10% for the risk difference in cure rates between combination therapy and PZQ alone. Between 12 September 2018 and 11 January 2019, 540 participants were assigned to receive PZQ alone (n = 108), PZQ plus As + SP (n = 108), PZQ plus As + AQ (n = 108), PZQ plus As + MQ (n = 108), or PZQ plus DHAP (n = 108). Primary outcome data were available for 523 (96.9%) participants. The cure rate was 82.5% (85/103) in PZQ alone, 81.7% (85/104) in PZQ plus As + SP, 76.2% (80/105) in PZQ plus As + AQ, 88.7% (94/106) in PZQ plus As + MQ, and 85.7% (90/105) in PZQ plus DHAP arm. Non-inferiority was declared for PZQ plus As + MQ (difference 6.2 [95% confidence interval: -3.3 to 15.6]) and PZQ plus DHAP (3.2 [-6.7 to 13.1]) but not for PZQ plus As + SP (-0.8 [-11.2 to 9.6]) or PZQ plus As + AQ (-6.3 [-17.3 to 4.6]). Adverse events were reported by 26% (138/540) of participants, including abdominal pain, headache, and vomiting. There were no serious adverse events. Alternatives to praziquantel should include praziquantel plus artesunate-mefloquine or praziquantel plus dihydroartemisinin-piperaquine. However, further multicentre trials are needed in different epidemiological settings and population groups to confirm these findings.CLINICAL TRIALSThis study is registered with the Pan-African Clinical Trials Registry under PACTR202001919442161.