Modifying Immunity in Children With DihydROartemisinin-Piperaquine (MIC-DroP)

Study Overview
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Brief Summary
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The MIC-DroP trial will test the hypothesis that preventing early life blood-stage malaria antigenic exposure with intermittent preventive therapy (IPT) enhances protective immunity to malaria. This study will take advantage of a unique opportunity to study infants born to mothers followed in a NIH-funded randomized controlled trial of novel intermittent preventive therapy in pregnancy (IPTp) regimens (NCT04336189). MIC-DroP will leverage the parent IPTp study to enroll 924 children who will be randomized at 8 weeks of age to receive no intermittent preventive therapy in childhood (IPTc), monthly DP from 8 weeks to 1 year of age, or monthly DP from 8 weeks to 2 years of age, and then follow children to 4 years of age. The primary outcome of this study will be to compare the incidence of malaria from 2 to 4 years of age among children randomized to receive no IPTc, monthly DP for the first year of life, or monthly DP for the first two years of life. Investigators will also leverage this trial to evaluate immune development during early childhood.

Detailed Description
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This study is a phase III, double-blind, randomized controlled trial of 924 HIV- uninfected children. Children born to mothers enrolled in an ongoing clinical trial of different IPTp arms in pregnancy (NCT 04336189) will be enrolled in this study. In the parent IPTp study, 2757 HIV-uninfected pregnant women will be randomized to receive IPTp with monthly sulfadoxine pyrimethamine (SP) alone, monthly DP alone, or both monthly SP+DP, and followed through 4 weeks postpartum. At the 4-week postpartum visit, we will enroll and randomize 924 eligible children to one of three IPTc arms: no IPTc (the current standard of care), monthly DP from 8 weeks to 1 year of age, or monthly DP from 8 weeks to 2 years of age. Study drugs will be placebo controlled and all doses of study drug will be given by directly observed therapy (DOT). The intervention phase will be completed at 2 years of age, and children followed through 4 years of age. Study participants will be followed for all of their outpatient medical care in our dedicated study clinic. Malaria incidence will be measured via active case detection. Routine assessments will be performed in the study clinic for all study participants every 4 weeks, including passive surveillance for parasitemia by quantitive polymerase chain reaction (qPCR). Venous blood will be collected for immunologic assays three times annually from 8 weeks to 4 years of age. All maternal assessments conducted during the parent IPTp study, including assessment for maternal malaria exposure (e.g., placental histology) household survey, will be available and linked to each study participant.

Official Title
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Enhancing Immunity to Malaria in Young Children With Effective Chemoprevention

Conditions
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Malaria

Intervention / Treatment
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* Drug: Dihydroartemisinin-piperaquine (DP)
* Other: DP Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Born to HIV-uninfected mother enrolled in parent clinical trial of intermittent preventative treatment of malaria in pregnancy (IPTp-SP vs. IPTp-DP vs. IPTp-SP+DP, NCT 04336189) Resident of Busia District Provision of informed consent by parent/guardian Agreement to present for any illness and avoid, where possible, medications outside the study protocol. Exclusion Criteria: Intention of moving outside Busia district during the study period Active medical problem requiring in-patient evaluation or chronic medical condition requiring frequent medical attention

Ages Eligible for Study
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Maximum Age: 2 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Double blinded randomized controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IPTc DP 1 year<br>DP given from 8 weeks to 52 weeks of age; DP placebo given from 52 weeks to 104 weeks of age; No IPTc in third and fourth years of follow-up. | Drug: Dihydroartemisinin-piperaquine (DP)<br>* Duo-Cotecxin 20mg/160mg tabs by Holley-Cotec, Beijing, China Each treatment with DP will consist of half-strength tablets given once a day for 3 consecutive days according to weight-based guidelines.<br>* Other names: Duo-Cotecxin;Other: DP Placebo<br>* Placebos will be identical appearance to DP.<br>|
| Active Comparator: IPTc DP 2 years<br>DP given from 8 weeks to 104 weeks of age; No IPTc in third and fourth years of follow-up. | Drug: Dihydroartemisinin-piperaquine (DP)<br>* Duo-Cotecxin 20mg/160mg tabs by Holley-Cotec, Beijing, China Each treatment with DP will consist of half-strength tablets given once a day for 3 consecutive days according to weight-based guidelines.<br>* Other names: Duo-Cotecxin;|
| Placebo Comparator: No IPTc<br>DP placebo given from 8 weeks to 104 weeks of age; No IPTc in third and fourth years of follow-up. | Other: DP Placebo<br>* Placebos will be identical appearance to DP.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of symptomatic malaria following cessation of IPTc | The incidence of symptomatic malaria, defined as the number of incident episodes of malaria requiring treatment per time at risk, during the period after the intervention was given (2-4 years of age). Treatments within 14 days of a prior episode are not considered incident events. | 2 years to 4 years of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of complicated malaria | Any incident episode of malaria meeting World Health Organization criteria for severe malaria or danger signs per time at risk, during the period after the intervention was given (2-4 years of age). | 2 years to 4 years of age | 
| Incidence of hospital admissions and/or deaths | Admission to the pediatric ward for any cause, and deaths of any cause | 2 years to 4 years of age | 
| Prevalence of parasitemia | Proportion of routine visits with asexual parasites detected by blood smears or quantitative polymerase chain reaction (qPCR). | 2 years to 4 years of age | 
| Prevalence of anemia | Proportion of routine hemoglobin measurements <11 grams/dL | 2 years to 4 years of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dihydroartemisinin-piperaquine, intermittent preventive therapy, children, immune response