BACKGROUND: Next-generation long-lasting insecticidal nets (LLINs) treated with more than one insecticide have been insufficiently evaluated in West Africa. METHODS: In this cluster randomized clinical trial, 33 clusters of villages (1-3 villages per cluster) in Côte d'Ivoire were randomly assigned (11 clusters per group) to use pyrethroid-only (py-only; MAGNet) (control), piperonyl butoxide-pyrethroid (PBO-py; Veeralin), or chlorfenapyr-pyrethroid (CFP-py; Interceptor G2) LLINs. One net was distributed for every two people, followed by door-to-door visits to assist with hanging the nets and to promote their use. The primary outcome was the incidence of malaria cases among children aged 6 months to 9 years over the year following net distribution. Incidence rate ratios compared cases per child-year between clusters randomly assigned to use PBO-py versus py-only nets and CFP-py versus py-only nets. RESULTS: A total of 25,660 LLINs were distributed to 11,283 households (py-only, n=3797; PBO-py, n=3559; and CFP-py, n=3927). The primary outcome analyses included 549, 551, and 549 children in the py-only, PBO-py, and CFP-py groups, respectively. Mean malaria incidence over 12 months was 1.11 cases per child-year in the py-only group (control), 0.84 in the PBO-py group, and 0.65 in the CFP-py group. The incidence rate ratios were as follows: PBO-py versus py-only nets, 0.72 (95% confidence interval [CI], 0.52 to 0.99; P=0.045); and CFP-py versus py-only nets, 0.57 (95% CI, 0.43 to 0.75; P<0.001). CONCLUSIONS: Malaria incidence over 12 months was significantly reduced among children aged 6 months to 9 years residing in clusters of villages in Côte d'Ivoire that were randomly assigned to use CFP-py versus py-only LLINs and PBO-py versus py-only LLINs. (Funded by The Global Fund to Fight AIDS, Tuberculosis and Malaria; ClinicalTrials.gov number, NCT05796193.).
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