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MalariaPhase 3Optimal LEAPNCT07798583

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

A Phase 3 study testing Monthly DP and Quarterly DP in people with Malaria and Asymptomatic Malaria, run by Indiana University.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
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Trial summary

Malaria remains a major cause of illness among school-aged children in sub-Saharan Africa, many of whom carry asymptomatic Plasmodium falciparum infections that may contribute to anemia, inflammation, school absenteeism, and impaired cognitive performance. Read more about this study

Who is it for?
Ages 6 to 10 yearsHealthy volunteers can take part
What is being tested?
Monthly DP and Quarterly DP
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,500 participants
Where
No sites listed yet
Study dates
1 Jan 2028to 1 Jan 2033
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 6 to 10 years
  • All sexes
  • Healthy volunteers accepted
  • Child

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

No sites are listed yet. Contact the study team or a site near you to ask about taking part.

Kristen Cunningham, MPH, MS contact

317-278-5675

kricunn@iu.edu

About this study

Official title: OPTIMAL LEAP: Optimizing Preventive Treatment Intervals for Malaria to Advance Longitudinal Learning, Executive Function, Attendance, and Pathways

Malaria remains a major cause of illness among school-aged children in sub-Saharan Africa, many of whom carry asymptomatic Plasmodium falciparum infections that may contribute to anemia, inflammation, school absenteeism, and impaired cognitive performance. Intermittent preventive treatment in school-aged children (IPTsc) is recommended by the World Health Organization in settings with moderate-to-high malaria transmission, but the optimal dosing frequency remains uncertain. This cluster-randomized trial will compare monthly versus quarterly administration of dihydroartemisinin-piperaquine (DP) among 1,500 children aged 6-10 years attending six primary schools in Siaya County, Kenya. The primary objective is to determine whether monthly IPTsc results in greater improvements in executive functioning compared with quarterly IPTsc. Secondary objectives include evaluating effects on literacy, numeracy, school attendance, malaria infection, anemia, inflammatory and metabolic biomarkers, and molecular markers of antimalarial resistance.

Read the detailed description

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.

Being tested
Monthly DP, Quarterly DP
Keywords
Malaria, Plasmodium falciparum, Asymptomatic, Anemia, Cognition, School-aged Children, Intermittent preventive treatment, IPTsc, Dihydroartemisinin-piperaquine, Executive function, Literacy, Numeracy, School attendance, Antimalarial resistance, Inflammation, Metabolomics, Kenya
Medical subject headings
Malaria, Malaria, Falciparum, Anemia, Literacy, Inflammation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Monthly DPDrug

    Age- or weight-based dihydroartemisinin-piperaquine administered monthly for 24 months as intermittent preventive treatment in school-aged children (IPTsc).

  • Quarterly DPDrug

    Age- or weight-based dihydroartemisinin-piperaquine administered every three months for 24 months as intermittent preventive treatment in school-aged children (IPTsc).

Study groups in NCT07798583
Study groupRoleWhat they receive
Monthly Dihydroartemisinin-piperaquine (DP) IPTscExperimentalParticipants enrolled in schools randomized to the monthly intervention arm will receive age- or weight-basedtherapeutic course of dihydroartemisinin-piperaquine, according to protocol-defined dosing procedures, administered monthly for 24 months through a school-based intermittent preventive treatment program. Dosing will be directly observed by study staff when administered at school; make-up dosing procedures will be used for children absent on scheduled dosing days according to the protocol.
Receives: Drug: Monthly DP
Quarterly DP IPTscActive comparatorParticipants enrolled in schools randomized to the quarterly intervention arm will receive age- or weight-based therapeutic course of dihydroartemisinin-piperaquine, according to protocol-defined, dosing procedures administered every three months for 24 months through a school-based intermittent preventive treatment program. Dosing will be directly observed by study staff when administered at school; make-up dosing procedures will be used for children absent on scheduled dosing days according to the protocol.
Receives: Drug: Quarterly DP

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change from baseline to 24 months in NeuroScreen Executive Function Composite z-score

    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.

    Measured: Baseline through 24 months

Secondary outcomes (12)

  1. Change from baseline to 24 months in EGRA score

    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.

    Measured: Baseline, 12 months, and 24 months

  2. Change from baseline to 24 months in EGMA score

    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.

    Measured: Baseline, 12 months, and 24 months

  3. Total School Absenteeism

    Number and proportion of enrolled school days missed during the 24-month follow-up period, based on school registers and teacher confirmation.

    Measured: Throughout 24 months of follow-up

  4. Malaria-Associated School Absenteeism

    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.

    Measured: Throughout 24 months of follow-up

  5. Prevalence of qPCR-detectable P. falciparum parasitemia

    Presence of P. falciparum infection measured by qPCR, with microscopy used to identify patent infections

    Measured: Baseline and quarterly through 24 months

  6. Change in Hemoglobin Concentration

    Hemoglobin concentration measured in g/dL at baseline and quarterly through 24 months.

    Measured: Baseline and quarterly through 24 months

  7. Incidence rate of symptomatic malaria episodes

    Number of symptomatic malaria episodes per child-year during follow-up.

    Measured: Throughout 24 months

  8. Change in inflammatory cytokine and chemokine concentrations

    Longitudinal changes in log-transformed inflammatory biomarker concentrations, including cytokines and chemokines implicated in malaria-associated cognitive outcomes.

    Measured: Baseline and quarterly through 24 months

  9. Change in metabolomic and lipidomic pathway scores

    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.

    Measured: Baseline and quarterly through 24 months

  10. Prevalence and emergence of DP resistance-associated P. falciparum polymorphisms and copy number variants

    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.

    Measured: Baseline through 24 months

  11. Molecular force of infection

    Acquisition of new genetically distinct P. falciparum clones over time as determined by parasite diversity genotyping.

    Measured: Baseline through 24 months

  12. Complexity or multiplicity of infection at 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.

    Measured: 12 and 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Sep 2026
  2. Study start1 Jan 2028 (estimated)
  3. Primary completion1 Jan 2030 (estimated)
  4. Study completion1 Jan 2033 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Model description
Outcome assessors for NeuroScreen, EGRA, and EGMA and laboratory personnel will be masked to school allocation when feasible; participants and intervention staff cannot be masked due to dosing schedule differences.
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
1,500 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07798583
Sponsor's protocol ID
Optimal Leap
Acronym
Optimal LEAP
Status last verified
Aug 2026
First submitted
27 Aug 2026
Last updated
1 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: De-identified participant-level data underlying published results, including demographic variables, NeuroScreen EF scores, EGRA/EGMA scores, attendance outcomes, malaria testing results, hemoglobin, inflammatory biomarker data, processed metabolomic pathway data, and processed parasite genotyping/resistance-marker data, as appropriate. Supporting documents: Study protocol, statistical analysis plan, informed consent form as appropriate, data dictionary, analytic code, and assay metadata. Timing: Data supporting primary publications will be made available at the time of publication or by the end of the award period, consistent with NIH and repository requirements. Access criteria: Data will be de-identified before sharing. More granular child-level, school-linked, geospatial, or sensitive data may be shared through controlled-access mechanisms to protect children, families, schools, and communities.

Publications

  • McHenry MS, Ayodo G, Marete I, Hasund CM, Knight V, Cunningham KB, Gaskin EL, White G, Tu W, Neafsey DE, John CC, Tran TM. Association of asymptomatic Plasmodium falciparum infections and its treatment with short-term cognitive performance in school-aged children: a prospective cohort study in western Kenya. J Infect. 2026 Aug 19:106831. doi: 10.1016/j.jinf.2026.106831. Online ahead of print.

    PubMed 42617751

  • Kane J, Li X, Kumar S, Button-Simons KA, Brenneman KMV, Dahlhoff H, Sievert MAC, Checkley LA, Shoue DA, Singh PP, Abatiyow BA, Haile MT, Nair S, Reyes A, Tripura R, Peto T, Lek D, Kappe SHI, Dhorda M, Nkhoma SC, Cheeseman IH, Vaughan AM, Anderson TJC, Ferdig MT. A Plasmodium falciparum genetic cross reveals the contributions of pfcrt and plasmepsin II/III to piperaquine drug resistance. bioRxiv [Preprint]. 2023 Sep 17:2023.06.06.543862. doi: 10.1101/2023.06.06.543862.

    PubMed 37745488

  • Amato R, Lim P, Miotto O, Amaratunga C, Dek D, Pearson RD, Almagro-Garcia J, Neal AT, Sreng S, Suon S, Drury E, Jyothi D, Stalker J, Kwiatkowski DP, Fairhurst RM. Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study. Lancet Infect Dis. 2017 Feb;17(2):164-173. doi: 10.1016/S1473-3099(16)30409-1. Epub 2016 Nov 3.

    PubMed 27818095

  • McHenry MS, Mukherjee D, Bhavnani S, Kirolos A, Piper JD, Crespo-Llado MM, Gladstone MJ. The current landscape and future of tablet-based cognitive assessments for children in low-resourced settings. PLOS Digit Health. 2023 Feb 23;2(2):e0000196. doi: 10.1371/journal.pdig.0000196. eCollection 2023 Feb.

    PubMed 36821551

  • Andrade CM, Fleckenstein H, Thomson-Luque R, Doumbo S, Lima NF, Anderson C, Hibbert J, Hopp CS, Tran TM, Li S, Niangaly M, Cisse H, Doumtabe D, Skinner J, Sturdevant D, Ricklefs S, Virtaneva K, Asghar M, Homann MV, Turner L, Martins J, Allman EL, N'Dri ME, Winkler V, Llinas M, Lavazec C, Martens C, Farnert A, Kayentao K, Ongoiba A, Lavstsen T, Osorio NS, Otto TD, Recker M, Traore B, Crompton PD, Portugal S. Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season. Nat Med. 2020 Dec;26(12):1929-1940. doi: 10.1038/s41591-020-1084-0. Epub 2020 Oct 26.

    PubMed 33106664

  • Salgado C, Ayodo G, Macklin MD, Gould MP, Nallandhighal S, Odhiambo EO, Obala A, O'Meara WP, John CC, Tran TM. The prevalence and density of asymptomatic Plasmodium falciparum infections among children and adults in three communities of western Kenya. Malar J. 2021 Sep 17;20(1):371. doi: 10.1186/s12936-021-03905-w.

    PubMed 34535134

  • Cohee LM, Opondo C, Clarke SE, Halliday KE, Cano J, Shipper AG, Barger-Kamate B, Djimde A, Diarra S, Dokras A, Kamya MR, Lutumba P, Ly AB, Nankabirwa JI, Njagi JK, Maiga H, Maiteki-Sebuguzi C, Matangila J, Okello G, Rohner F, Roschnik N, Rouhani S, Sissoko MS, Staedke SG, Thera MA, Turner EL, Van Geertruyden JP, Zimmerman MB, Jukes MCH, Brooker SJ, Allen E, Laufer MK, Chico RM. Preventive malaria treatment among school-aged children in sub-Saharan Africa: a systematic review and meta-analyses. Lancet Glob Health. 2020 Dec;8(12):e1499-e1511. doi: 10.1016/S2214-109X(20)30325-9. Epub 2020 Oct 22.

    PubMed 33222799

  • Clarke SE, Jukes MC, Njagi JK, Khasakhala L, Cundill B, Otido J, Crudder C, Estambale BB, Brooker S. Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial. Lancet. 2008 Jul 12;372(9633):127-138. doi: 10.1016/S0140-6736(08)61034-X.

    PubMed 18620950

  • Johnson AE, Upadhye A, Knight V, Gaskin EL, Turnbull LB, Ayuku D, Nyalumbe M, Abuonji E, John CC, McHenry MS, Tran TM, Ayodo G. Subclinical Inflammation in Asymptomatic Schoolchildren With Plasmodium falciparum Parasitemia Correlates With Impaired Cognition. J Pediatric Infect Dis Soc. 2024 May 30;13(5):288-296. doi: 10.1093/jpids/piae025.

    PubMed 38512283

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Monthly DP and Quarterly DP in people with Malaria and Asymptomatic Malaria, run by Indiana University.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 1 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Kristen Cunningham, MPH, MS (317-278-5675, kricunn@iu.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change from baseline to 24 months in NeuroScreen Executive Function Composite z-score (time frame: Baseline through 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07798583, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2026.

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