OPTIMAL LEAP: Optimizing Dihydroartemisinin-Piperaquine IPTsc Intervals to Advance Learning, Executive Function, Attendance, and Antimalarial Resistance Surveillance in Kenyan Schoolchildren (Optimal LEAP)
OPTIMAL LEAP: Optimizing Preventive Treatment Intervals for Malaria to Advance Longitudinal Learning, Executive Function, Attendance, and Pathways
研究概览
详细说明
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.
研究类型
注册 (估计的)
阶段
- 第三阶段
联系人和位置
学习联系方式
- 姓名：Kristen Cunningham, MPH, MS
- 电话号码：317-278-5675
- 邮箱：kricunn@iu.edu
参与标准
资格标准
适合学习的年龄
- 孩子
接受健康志愿者
描述
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
学习计划
研究是如何设计的？
设计细节
- 主要用途：预防
- 分配：随机化
- 介入模型：并行分配
- 屏蔽：单身的
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
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实验性的：Monthly Dihydroartemisinin-piperaquine (DP) IPTsc
Participants 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.
|
Age- or weight-based dihydroartemisinin-piperaquine administered monthly for 24 months as intermittent preventive treatment in school-aged children (IPTsc).
|
|
有源比较器：Quarterly DP IPTsc
Participants 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.
|
Age- or weight-based dihydroartemisinin-piperaquine administered every three months for 24 months as intermittent preventive treatment in school-aged children (IPTsc).
|
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Change from baseline to 24 months in NeuroScreen Executive Function Composite z-score
大体时间：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.
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Baseline through 24 months
|
次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Change from baseline to 24 months in EGRA score
大体时间：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.
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Baseline, 12 months, and 24 months
|
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Change from baseline to 24 months in EGMA score
大体时间：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.
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Baseline, 12 months, and 24 months
|
|
Total School Absenteeism
大体时间：Throughout 24 months of follow-up
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Number and proportion of enrolled school days missed during the 24-month follow-up period, based on school registers and teacher confirmation.
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Throughout 24 months of follow-up
|
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Malaria-Associated School Absenteeism
大体时间：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.
|
Throughout 24 months of follow-up
|
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Prevalence of qPCR-detectable P. falciparum parasitemia
大体时间：Baseline and quarterly through 24 months
|
Presence of P. falciparum infection measured by qPCR, with microscopy used to identify patent infections
|
Baseline and quarterly through 24 months
|
|
Change in Hemoglobin Concentration
大体时间：Baseline and quarterly through 24 months
|
Hemoglobin concentration measured in g/dL at baseline and quarterly through 24 months.
|
Baseline and quarterly through 24 months
|
|
Incidence rate of symptomatic malaria episodes
大体时间：Throughout 24 months
|
Number of symptomatic malaria episodes per child-year during follow-up.
|
Throughout 24 months
|
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Change in inflammatory cytokine and chemokine concentrations
大体时间：Baseline and quarterly through 24 months
|
Longitudinal changes in log-transformed inflammatory biomarker concentrations, including cytokines and chemokines implicated in malaria-associated cognitive outcomes.
|
Baseline and quarterly through 24 months
|
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Change in metabolomic and lipidomic pathway scores
大体时间：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.
|
Baseline and quarterly through 24 months
|
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Prevalence and emergence of DP resistance-associated P. falciparum polymorphisms and copy number variants
大体时间：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.
|
Baseline through 24 months
|
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Molecular force of infection
大体时间：Baseline through 24 months
|
Acquisition of new genetically distinct P. falciparum clones over time as determined by parasite diversity genotyping.
|
Baseline through 24 months
|
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Complexity or multiplicity of infection at 12 and 24 months
大体时间：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.
|
12 and 24 months
|
合作者和调查者
合作者
调查人员
- 首席研究员：Megan S McHenry, MD, MS、Indiana University
- 首席研究员：Eren Oyungu, MBChB, MMED、Moi University
出版物和有用的链接
一般刊物
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
研究记录日期
研究主要日期
学习开始 (估计的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
关键字
其他研究编号
- Optimal Leap
计划个人参与者数据 (IPD)
计划共享个人参与者数据 (IPD)？
IPD 计划说明
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.
IPD 共享时间框架
IPD 共享访问标准
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研究美国 FDA 监管的设备产品
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