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, DHAPQ was non-inferior to extended-age SPAQ (HR = 0.7, 95% CI 0.6-0.9) and achieved higher intervention coverage, with no serious adverse events reported. Children aged 5-9 years had a lower hazard of clinical malaria than children younger than 5 years (HR = 0.9, 95% CI 0.8-0.9). 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. Funding: NIH/NIAID-ICEMR-WAF.