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.

• Monthly DP (Drug): Age- or weight-based dihydroartemisinin-piperaquine administered monthly for 24 months as intermittent preventive treatment in school-aged children (IPTsc).
• Quarterly DP (Drug): Age- or weight-based dihydroartemisinin-piperaquine administered every three months for 24 months as intermittent preventive treatment in school-aged children (IPTsc).

Primary outcomes

• Change from baseline to 24 months in NeuroScreen Executive Function Composite z-score [Baseline through 24 months]: Executive function will be assessed quarterly using tablet-based NeuroScreen tasks measuring working memory, inhibitory control/attention, and cognitive flexibility. The primary endpoint will be the adjusted change in the EF composite z-score from baseline to 24 months. Higher scores indicate better performance.

Secondary outcomes

• Change from baseline to 24 months in EGRA score [Baseline, 12 months, and 24 months]: Literacy will be assessed using Early Grade Reading Assessment subtests adapted for the local language and educational context. Scores will be analyzed as standardized continuous outcomes; higher scores indicate better reading performance.
• Change from baseline to 24 months in EGMA score [Baseline, 12 months, and 24 months]: Numeracy will be assessed using Early Grade Mathematics Assessment subtests adapted for the local educational context. Scores will be analyzed as standardized continuous outcomes; higher scores indicate better mathematics performance.
• Total School Absenteeism [Throughout 24 months of follow-up]: Number and proportion of enrolled school days missed during the 24-month follow-up period, based on school registers and teacher confirmation.
• Malaria-Associated School Absenteeism [Throughout 24 months of follow-up]: Number of school days missed due to suspected or confirmed malaria illness, based on study assessments, clinic records when available, and caregiver/teacher illness reports.
• Prevalence of qPCR-detectable P. falciparum parasitemia [Baseline and quarterly through 24 months]: Presence of P. falciparum infection measured by qPCR, with microscopy used to identify patent infections
• Change in Hemoglobin Concentration [Baseline and quarterly through 24 months]: Hemoglobin concentration measured in g/dL at baseline and quarterly through 24 months.
• Incidence rate of symptomatic malaria episodes [Throughout 24 months]: Number of symptomatic malaria episodes per child-year during follow-up.
• Change in inflammatory cytokine and chemokine concentrations [Baseline and quarterly through 24 months]: Longitudinal changes in log-transformed inflammatory biomarker concentrations, including cytokines and chemokines implicated in malaria-associated cognitive outcomes.
• Change in metabolomic and lipidomic pathway scores [Baseline and quarterly through 24 months]: Longitudinal changes in prespecified metabolomic and lipidomic pathways related to inflammation, oxidative stress, mitochondrial energy metabolism, lipid-mediated inflammation, tryptophan-kynurenine metabolism, and iron handling. Analyses may be conducted in a prespecified longitudinal subset, with targeted validation in the broader cohort.
• Prevalence and emergence of DP resistance-associated P. falciparum polymorphisms and copy number variants [Baseline through 24 months]: Molecular surveillance will assess resistance-associated markers including kelch13, pfcrt, pfmdr1, pfexo, and pfplasmepsin II/III copy number variation. Sequence variants will be assessed using multiplex amplicon sequencing, and copy number variation will be confirmed by qPCR or ddPCR when appropriate.
• Molecular force of infection [Baseline through 24 months]: Acquisition of new genetically distinct P. falciparum clones over time as determined by parasite diversity genotyping.
• Complexity or multiplicity of infection at 12 and 24 months [12 and 24 months]: Complexity/multiplicity of infection will be estimated from parasite diversity markers to quantify the number of genetically distinct parasite clones within infections and compare differential protection conferred by monthly versus quarterly IPTsc.

Sex: All, ages: 6 Years to 10 Years, accepts healthy volunteers

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

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• Megan S McHenry, MD, MS, Principal investigator, Indiana University
• Eren Oyungu, MBChB, MMED, Principal investigator, Moi University