OPTIMAL LEAP: Optimizing Dihydroartemisinin-Piperaquine IPTsc Intervals to Advance Learning, Executive Function, Attendance, and Antimalarial Resistance Surveillance in Kenyan Schoolchildren

Malaria remains a leading cause of morbidity in sub‐Saharan Africa, and school‐agedchildren represent an important reservoir of asymptomatic Plasmodium falciparuminfection. Although often clinically silent, persistent low‐density infections have beenassociated with anemia, immune activation, school absenteeism, and impaired executivefunctioning, including working memory, inhibitory control, and cognitive flexibility.These cognitive processes are critical for learning, academic achievement, and long‐termeducational attainment.The World Health Organization recommends intermittent preventive treatment forschool‐aged children (IPTsc) in settings with moderate‐to‐high malaria transmission;however, evidence is limited regarding the optimal frequency of preventive treatment.Dihydroartemisinin‐piperaquine (DP) provides extended post‐treatment prophylaxis and is apromising IPTsc regimen, but more frequent administration may also increase drugselection pressure and contribute to the emergence of antimalarial resistance.This study is a two‐arm, school‐cluster randomized trial conducted in six primary schoolsin Siaya County, Kenya. A total of 1,500 children aged 6 to 10 years will be enrolled andfollowed for 24 months. Enrollment will be balanced across one‐year age bands, withapproximately 300 children per age band at baseline. Schools will be randomized toreceive either monthly DP IPTsc or quarterly DP IPTsc. The primary outcome is change inexecutive functioning measured using the tablet‐based NeuroScreen assessment platform.Secondary outcomes include literacy and numeracy performance measured using the EarlyGrade Reading Assessment (EGRA) and Early Grade Mathematics Assessment (EGMA), schoolattendance, malaria‐associated absenteeism, P. falciparum parasitemia, hemoglobin levels,symptomatic malaria episodes, inflammatory biomarkers, metabolomic profiles, andmolecular markers of antimalarial resistance.The study will also investigate biological mechanisms linking asymptomatic malariainfection with cognitive outcomes. Longitudinal assessments of parasitemia, inflammatorycytokines and chemokines, metabolomic pathways, and genetic markers of parasiteresistance will be performed. Resistance surveillance will include evaluation of kelch13,pfcrt, pfmdr1, pfexo, and pfplasmepsin II/III markers. Findings from this trial willprovide evidence on the benefits and risks of different IPTsc dosing schedules and informmalaria prevention policies aimed at improving child health, educational achievement, andlong‐term developmental outcomes while minimizing the risk of antimalarial resistance.