CHILD (Child Health and Infection With Low Density) Malaria

Study Overview
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Brief Summary
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This trial will assess the long-term health and socioeconomic impact of interventions targeting low-density malaria infection (LMI) among children in Tanzania

Detailed Description
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This is a 3-arm open-label randomized control trial of 600 children aged 6 months to 10 years in Tanzania, where transmission is low and a high proportion of infections are low-density. Standard of care based on passive case detection (PCD) using rapid diagnostic test (control arm) will be compared to two different approaches to detect and treat P. falciparum LMI: active case detection using molecular testing (ACDm) and PCD using molecular testing (PCDm). Aims are: To assess the impact of standard PCD plus ACDm vs standard PCD on long-term child health To assess the impact of PCDm vs standard PCD on long-term child health To evaluate the cost-effectiveness of ACDm and PCDm

Official Title
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Child Health and Infection With Low Density (CHILD) Malaria, a Randomized Controlled Trial to Assess the Long-term Health and Socioeconomic Impact of Interventions Targeting Low-density Malaria Infection (LMI) Among Children in Tanzania

Conditions
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Malaria,Falciparum, Malaria

Intervention / Treatment
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* Other: Active case detection using molecular testing (ACDm)
* Other: Passive case detection using molecular testing (PCDm)
* Other: Control (standard of care)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 6 months to 10 years of age of age at enrollment Primary residence in the study area during the study period Agree to come to study clinic for any illness Agree to avoid medications outside the study, even herbal medication Exclusion Criteria: Another child from household already randomly selected for recruitment Not able or does not provide informed consent Need for emergency intervention Known history of chronic illness requiring regular specialty care including diabetes mellitus, cancer, or Stage 3 or 4 HIV/AIDS Contraindications to artemether-lumefantrine (AL) including history of allergic reaction, weight under 5 kg Participation in another active/ongoing intervention trial

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 10 Years

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: Parallel Assignment
Interventional Model Description: Individual randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Case Detection using molecular testing (ACDm)<br>Per standard of care, children will receive passive case detection (PCD) using rapid diagnostic test (RDT) if they present with fever. Children will receive malaria active case detection (ACD) using RDT and qPCR (quantitative polymerase chain reaction) three times yearly with treatment using artemether-lumefantrine (AL) if RDT or qPCR positive. | Other: Active case detection using molecular testing (ACDm)<br>* In the ACDm arm, children will receive ACD using RDT and qPCR 3x yearly with treatment using artemether-lumefantrine (AL) if RDT or qPCR positive. With fevers, participants will receive standard PCD using RDT.<br>|
| Experimental: Passive Case Detection using molecular testing (PCDm)<br>Children who present with fever will receive PCD using RDT and qPCR with treatment using AL if RDT or qPCR positive. Per standard of care, children will not receive malaria ACD. | Other: Passive case detection using molecular testing (PCDm)<br>* With fevers, participants will receive PCDm, in which qPCR will be done in RDT negatives with treatment using AL if positive.<br>|
| Active Comparator: Standard passive case detection (PCD)<br>Per standard of care, children will receive PCD using RDT. Per standard of care, children will not receive malaria ACD. | Other: Control (standard of care)<br>* With fevers, participants will receive standard PCD using RDT with treatment using AL if positive.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of all-cause sick visits | Number of sick visits to health facility per person time, excluding planned admissions for medical care, elective surgery, and trauma. | 24 months from enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of anemia | Proportion of routine Hb measurements that are low (<11 g/dL) or moderate-severe low (<8 g/dL) | 24 months from enrollment | 
| Prevalence of underweight status | Prevalence of underweight status will be defined as the percentage of participants with low weight for age z-scores of less than -2. The World Health Organization (WHO) anthropometric indices will be utilized for standards. | 24 months from enrollment | 
| Prevalence of stunting | Prevalence of stunting will be defined as the percentage of participants with low height for age z-scores of less than -2. The World Health Organization (WHO) anthropometric indices will be utilized for standards. | 24 months from enrollment | 
| Prevalence of wasting | Prevalence of wasting will be defined as the percentage of participants with low weight for height z-scores of less than -2. The World Health Organization (WHO) anthropometric indices will be utilized for standards. | 24 months from enrollment | 
| Prevalence of malnutrition | Prevalence of malnutrition will be defined as the percentage of participants with a z-score of -3 to -2 indicating moderate malnutrition or a z-score of less than -3 indicating severe malnutrition in any of the following: weight for age, height for age, or weight for height. | 24 months from enrollment | 
| Prevalence of vomiting following administration of study drugs | Vomiting immediately or within 30minutes following administration of study drugs and measures of non-adherence. | 24 months from enrollment | 
| All-cause fever episodes | Number of documented fever episodes (axillary temperature of ≥37.5°C) per person time and number of fever episodes (documented and reported) per person time | 24 months from enrollment | 
| Incidence of clinical symptoms | Number of days with overall symptoms reported as moderate (≥3 on a 5-point scale) per person time | 24 months from enrollment | 
| Incidence of clinical malaria | New episodes of positive malaria test (with fever or other clinical symptoms) per person time | 24 months from enrollment | 
| Proportion of fever episodes with clinical failure | Proportion of fever episodes that lead to clinical failure, defined as persistent or worsening symptoms assessed 7 and 28 days after initial evaluation. | 24 months from enrollment | 
| Prevalence of parasitemia | Proportion of routine samples with parasites detected by microscopy or quantitative polymerase chain reaction (qPCR). | 24 months from enrollment | 
| Incidence in antibiotics prescribed | Number of antibiotic regimens prescribed per person time | 24 months from enrollment | 
| Cognitive ability among children 0-3.4 years of age on the Global Scales of Early Development (GSED) | GSED is a validated instrument that measures population-level early childhood development. The tool measures children's early skills and behaviors in four primary domains: motor, cognitive, language, and social-emotional development.Measures will be normalized within our sample to mean 0 and standard deviation 1, with higher scores indicating better test performance. | 24 months from enrollment | 
| Cognitive ability among children 3.5-5 years of age on the International Development and Early Learning Assessment (IDELA) | The IDELA is a validated, global tool that uses direct child assessment to measure early learning and development across 4 core domains (Emergent Literacy, Emergent Numeracy, Motor, Social-emotional). Scores range from 0-100% as a percentage of correct tasks averaged across the 4 domains. Measures will be normalized within our sample to mean 0 and standard deviation 1, with higher scores indicating better test performance. | 24 months from enrollment | 
| Cognitive ability among children 6-12 years of age on the East Africa Neurodevelopment Assessment Tool | The East African Neurodevelopment Assessment Tool is a locally adapted modification of the Kaufman Brief Intelligence Test 2nd Ed. The test assesses 3 core metrics including general intelligence, executive function, literacy skills - in addition to behavioral and emotional development. Measures will be normalized within our sample to mean 0 and standard deviation 1, with higher scores indicating better test performance. | 24 months from enrollment | 
| Sustained attention among children 5-8 years of age on the Pencil Tapping Test | The pencil tapping test is one of the tasks in the Preschool Self-Regulation Assessment (PSRA) and is used to assess inhibitory control in younger children. The child and an assessor have pencils, and child is instructed to tap one/two times(s) depending on what assessor does, with the number of correct responses scored. Measures will be normalized within our sample to mean 0 and standard deviation 1, with higher scores indicating better test performance. | 24 months from enrollment | 
| Sustained attention among children 9-12 years of age on the Code Transmission Test, a local adaptation of the Test of Everyday Attention for Children(TEA-Ch) | Code transmission test is a sub-test of Test of Everyday Attention for Children (TEA-Ch) used for assessment of sustained attention in children. In the test, the child must remember spoken digits, and remember the digit that comes before sequence of numbers. Child is scored on completed and correct answers. Measures will be normalized within our sample to mean 0 and standard deviation 1, with higher scores indicating better test performance. | 24 months from enrollment | 
| Incidence of school absenteeism | The number of days of school absenteeism for any reason including illness. | 24 months from enrollment | 
| School performance | School performance will be defined as the incidence of school advancement to the next grade. | 24 months from enrollment | 
| Socioeconomic costs to participant | Estimated long-term income loss due to impaired early childhood development | 24 months from enrollment | 
| Socioeconomic costs to family | Total caregiver-reported costs of sick visits and transport to sick visits plus estimated loss of income from number of days of caregiver work absenteeism. | 24 months from enrollment | 
| Socioeconomic costs to health system | Estimated costs of testing and treatment for caregiver-reported number of sick visits. | 24 months from enrollment | 
| Cost effectiveness | Cost per outcome averted (e.g., per sick visit averted, per disability adjusted life years (DALYs), and per economic dollar saved, etc.) | 24 months from enrollment | 
| Prevalence of systemic inflammation | Proportion of sick visits with elevated elevated C-reactive pep-tide (CRP) | 24 months from enrollment | 
| Proportion with antimalarial antibodies against P.falciparum | Percentage of patients with antimalarial antibodies | 24 months from enrollment | 
| Proportion with biomarkers of inflammation | Percentage of patients with elevated cytokines | 24 months from enrollment | 
| Proportion with general antibody responses to vaccines | Percentage of patients with vaccine antibodies | 24 months from enrollment | 
| Proportion with general antibody responses to common pathogens | Percentage of patients with common pathogen antibodies | 24 months from enrollment | 
| Incidence of adverse events (AEs) | Number of AEs per person time. AEs will be considered as any grade 3-4 AE or serious adverse event (SAE); individual AEs; or AEs related to study drugs. | 24 months from enrollment | 
| Incidence of wasting | Incidence proportion of wasting will be defined for each age range of measurement. It is defined as the proportion of children not wasted at the start of the period who became wasted during the age period (the proportion of children who had the onset of new episodes during the period). Incident wasting episodes are defined as a change in weight-for-length z-scores from above -2 Z in the prior measurement to below -2 Z in the current measurement. We will define incident severe wasting analogously using a -3 Z cutoff. We will assume a 60-day washout period before a new wasting episode could occur. | 24 months from enrollment | 
| Incidence of stunting | Incidence proportion of stunting will be defined for each age range of measurement. It is defined as the proportion of children not stunted at the start of the period who became stunted during the age period. Incident stunting episodes will be defined as a change in length-for-age z-scores from above -2 Z in the prior measurement to below -2 Z in the current measurement. We will define incident severe stunting analogously using a -3 Z cutoff. | 24 months from enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, child health, chronic infection, subclinical infection, patent infection, subpatent infection, active case detection, passive case detection, fever case management