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-aged children represent an important reservoir of asymptomatic Plasmodium falciparum infection. Although often clinically silent, persistent low-density infections have been associated with anemia, immune activation, school absenteeism, and impaired executive functioning, including working memory, inhibitory control, and cognitive flexibility. These cognitive processes are critical for learning, academic achievement, and long-term educational attainment.

The World Health Organization recommends intermittent preventive treatment for school-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 a promising IPTsc regimen, but more frequent administration may also increase drug selection pressure and contribute to the emergence of antimalarial resistance.

This study is a two-arm, school-cluster randomized trial conducted in six primary schools in Siaya County, Kenya. A total of 1,500 children aged 6 to 10 years will be enrolled and followed for 24 months. Enrollment will be balanced across one-year age bands, with approximately 300 children per age band at baseline. Schools will be randomized to receive either monthly DP IPTsc or quarterly DP IPTsc. The primary outcome is change in executive functioning measured using the tablet-based NeuroScreen assessment platform. Secondary outcomes include literacy and numeracy performance measured using the Early Grade Reading Assessment (EGRA) and Early Grade Mathematics Assessment (EGMA), school attendance, malaria-associated absenteeism, P. falciparum parasitemia, hemoglobin levels, symptomatic malaria episodes, inflammatory biomarkers, metabolomic profiles, and molecular markers of antimalarial resistance.

The study will also investigate biological mechanisms linking asymptomatic malaria infection with cognitive outcomes. Longitudinal assessments of parasitemia, inflammatory cytokines and chemokines, metabolomic pathways, and genetic markers of parasite resistance will be performed. Resistance surveillance will include evaluation of kelch13, pfcrt, pfmdr1, pfexo, and pfplasmepsin II/III markers. Findings from this trial will provide evidence on the benefits and risks of different IPTsc dosing schedules and inform malaria prevention policies aimed at improving child health, educational achievement, and long-term developmental outcomes while minimizing the risk of antimalarial resistance.

Inclusion criteria

• Age 6 to 10 years at enrollment
• Enrollment in a participating primary school in Siaya County, Kenya
• Residence within the participating school's catchment area with no plans to relocate during the study period
• Parent or legal guardian able and willing to provide informed consent
• Child able and willing to provide assent, as applicable according to local regulations and age requirements
• Willingness to comply with study procedures and follow-up visits

Exclusion criteria

• Known hypersensitivity or contraindication to dihydroartemisinin-piperaquine (DP)
• Severe acute illness requiring urgent medical evaluation or hospitalization at enrollment
• Known cardiac disease or history of conditions associated with increased risk of QT prolongation
• Severe malnutrition requiring urgent referral or treatment
• Recent antimalarial treatment within the protocol-defined washout period
• Severe anemia (hemoglobin <7 g/dL) at screening
• Measured fever (≥38.0°C) or acute febrile illness requiring evaluation at screening
• Any medical, social, or behavioral condition that, in the opinion of the investigators, would make participation unsafe or interfere with study participation or interpretation of study results