Efficacy and safety of praziquantel plus Artemisinin-based combinations in the treatment of Schistosoma mansoni infection: A randomized, head-to-head, non-inferiority trial

Background: Praziquantel alone is insufficient for the control of schistosomiasis. Unlike praziquantel, artemisinin derivatives are effective for treating juvenile schistosome worms but not adult worms. Few studies have assessed the role of combination therapy, including praziquantel and artemisinin-based combinations, in treating schistosomiasis. Methods: A randomized, open-label, noninferiority trial was conducted in central Kenya to assess the efficacy and safety of praziquantel plus one of four artemisinin-based combination therapies in treating intestinal schistosomiasis. 540 children aged 9-15 years with Schistosoma mansoni infection were randomly assigned (1:1:1:1:1) to receive a single oral dose of praziquantel (40mg/kg/day) alone or in combination with a 3-day course of artesunate plus sulfalene/pyrimethamine or artesunate plus amodiaquine or artesunate plus mefloquine or dihydroartemisinin-piperaquine. The primary endpoint was the cure rate assessed at six weeks in a per-protocol population. The noninferiority margin was defined as the lower limit of 95%CI of the risk difference in cure rates less than -10%. Results: Cure rates were available for 523 children. Overall, 82.5%, 81.7%, 76.2%, 88.7% and 85.7% of patients on praziquantel, praziquantel plus artesunate-sulfalene/pyrimethamine, praziquantel plus artesunate-amodiaquine, praziquantel plus artesunate-mefloquine, and praziquantel plus dihydroartemisinin-piperaquine, respectively, were cured. Non-inferiority was declared for praziquantel plus artesunate-mefloquine (difference 6.2 [95%CI -3.3 to 15.6]) and praziquantel plus dihydroartemisinin-piperaquine (3.2 [-6.7 to 13.1]) but not for praziquantel plus artesunate-sulfalene/pyrimethamine (-0.8 [-11.2 to 9.6]) or praziquantel plus artesunate-amodiaquine (-6.3 [-17.3 to 4.6]). A significantly lower number of adverse events were reported in the praziquantel arm than in the combined treatment arm. No serious adverse events were observed. Conclusions: Combination therapy using praziquantel with artesunate plus mefloquine or praziquantel with dihydroartemisinin-piperaquine is a promising complementary transmission control strategy, but further research is needed to investigate strategies to improve the effectiveness and safety outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial PACTR202001919442161, retrospectively registered. We applied for trial registration before the end of participant enrolment. However, there was a delay between registration application and approval. The registration was approved soon after the participant enrolment ended. ### Funding Statement Yes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Scientific and Ethics Review Unit, at the Kenya Medical Research Institute. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.