Extending seasonal malaria chemoprevention to older children: a non-inferiority randomized controlled trial of Dihydroartemisinin–piperaquine as a policy alternative in Mali

Background Seasonal malaria chemoprevention (SMC) with Sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) reduces malaria in children under five, but substantial burden remains among children 5–9 years. Emerging SP/AQ resistance and adherence challenges underscore the need for alternative regimens. Dihydroartemisinin-piperaquine (DHAPQ) is a promising option, although evidence from multi-season programmatic settings in the Sahel is limited. We aimed to evaluate the effectiveness and safety of DHAPQ compared with SPAQ when SMC was extended to children aged 3 months to 9 years. Methods We conducted a two-year, three-arm, cluster-randomized crossover trial in nine health-catchment clusters in Mali. Clusters received standard SPAQ SMC (<5 years), extended-age SPAQ (<10 years), or (3) extended-age DHAPQ (<10 years), crossing over to a different regimen in year two. The primary outcome was the incidence of clinical malaria, analyzed using mixed-effects negative binomial models that accounted for clustering, period effects, and recurrent events. Non-inferiority was predefined as an upper 95% CI < 1.25. Findings Among 12,854 children contributing 18,912 person-years, DHAPQ reduced malaria incidence by 70% (95% CI 58–79) in children under five and 90% (84–94) in those 5–9 years compared with standard SPAQ. DHAPQ was non-inferior to extendedage SPAQ (HR 0.62; 95% CI 0.48–0.81), with higher coverage and no serious adverse events. Interpretation Extending SMC to children aged 5–9 years substantially reduced malaria burden. DHAPQ was safe, effective, and operationally feasible, supporting its consideration as an alternative to SPAQ where adherence or resistance threatens SMC effectiveness.