Repeat Ivermectin Mass Drug Administrations for Control of Malaria: a Pilot Safety and Efficacy Study

Study Overview
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Brief Summary
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The purpose of this study is to determine whether repeated ivermectin mass drug administrations to Burkinabé villagers, performed in three week intervals over the rainy-season, is well-tolerated and safe, and also effective in reducing local malaria transmission and thus clinical malaria episodes in treated village children.

Detailed Description
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Primary Objective: To determine the efficacy of repeated ivermectin mass drug administrations (IVM MDA) (150 µg/kg), given to the population of eligible patients in enrolled villages, for reducing the cumulative incidence of uncomplicated malaria episodes in enrolled village children (≤ 5 years of age) over the course of the treatment. Hypothesis: Repeated IVM MDA starting at the beginning of the rainy season will be well tolerated and safe, and will reduce clinical malaria episodes in children by significantly reducing malaria transmission among treated villages. Overview Study Design: Single-blind (outcomes assessor); parallel assignment with 2 arms; cluster-randomized control trial to determine the effect of repeated IVM MDA on malaria transmission and clinical malaria episodes. The unit of randomization will be the village (cluster). 8 villages total will be enrolled in two arms. The active comparator arm (4 villages) will receive a single standard MDA (IVM; 150-200 µg/kg + albendazole; 400 mg) soon after the start of the rainy season, while the experimental arm (4 villages) will receive the standard MDA on the same date, plus 5 more IVM MDA at 3 week intervals thereafter. The primary endpoint will be the cumulative incidence of clinical malaria episodes in children ≤5 year of age within each village. Sites: This study will be conducted in villages along the main east-west and north-south road corridors in the Sud-Ouest administrative region of Burkina Faso. Study Population: Indigenous Burkinabé from various ethnic groups (Dagara, Bobo, Lobi, Mossi, etc.). The entire eligible population of each enrolled village will receive the MDAs, following the standard inclusion/exclusion criteria of MDA for control of microfilaremia caused by Wuchereria bancrofti (lymphatic filariasis; LF). Clinical incidence of malaria will be assessed only in children living in enrolled villages who are ≤ 5 years of age, most of whom will not have received any treatment due to the standard MDA exclusion criteria of children < 90 cm. Study Interventions: 2 arms: 1) Active comparator arm - single standard MDA with IVM (150 µg/kg) + albendazole (ALB;400 mg) soon after the beginning of the rainy season; 2) Experimental arm, single standard MDA with IVM (150 µg/kg) + ALB (400 mg) plus 5 more MDA with IVM alone (150 µg/kg) at 3 week intervals thereafter. Community health workers and trained by local health authority of the Sud-Ouest region will perform the first MDA in both arms with logistical assistance from the study investigators. Repeated MDAs will only occur in the experimental-arm villages, and be performed by the study investigators. Follow-up Procedures: Trained nurses will visit each study village each week over the course of the study to investigate and record any adverse events or severe adverse events communicated by the study population. They will also perform active case surveillance each week on enrolled village children for clinical malaria episodes, defined as ≥38.0°C fever or history of fever in the last 24 hours + positive rapid diagnostic test for Plasmodium falciparum. Secondary measures will be collected by the nurses. Sample Size: Assuming an 80% cumulative incidence of malaria episodes in the control arm and an intracluster correlation coefficient of 0.02, 4 clusters are needed per arm and 69 children enrolled per cluster to detect a conservative 40% reduction in incidence in the treatment arm with 80% power and a statistical confidence of 95%. Safety Outcomes: • Adverse events (seriousness, causality, expectedness) Secondary Outcomes: Incidence of new P. falciparum infections acquired (molecular force-of-infection) Prevalence and intensity (eggs/larvae per gram of feces) of soil transmitted helminth infections in a subset of treated patients between 6-10 years of age. Indoor-resting Anopheles mosquito capture rate Outdoor-host seeking Anopheles mosquito capture rate Adult mosquito age structure (parity rate) in captured mosquitoes Plasmodium sporozoite rate/entomological inoculation rate in captured mosquitoes Rate of Wuchereria bancrofti in captured mosquitoes

Official Title
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Repeat Ivermectin Mass Drug Administrations for Control of Malaria: a Pilot Safety and Efficacy Study

Conditions
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Malaria, Lymphatic Filariasis

Intervention / Treatment
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* Drug: Ivermectin
* Drug: Albendazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Residence in the study site Able to understand the information and willing to give consent and assent (parent or guardian consent if study participant age is < 18 years) Exclusion Criteria: Residence outside of in the study site Height ≤ 90 cm Permanent disability, serious medical illness that prevents or impedes study participation and/or comprehension Pregnancy Breast feeding if infant is within 1 week of birth Known allergy to the study drugs
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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Single MDA<br>Single mass drug administration of ivermectin (150 µg/kg) + albendazole (400 mg) performed after the start of the rainy season as part of public health efforts to eliminate lymphatic filariasis. | Drug: Ivermectin<br> <br> * Other names: Mectizan;Drug: Albendazole<br> <br> |
| Experimental: Repeated MDA<br>Same at Active Comparator, but then followed by five more mass drug administrations of ivermectin only (150 µg/kg) every three weeks thereafter. | Drug: Ivermectin<br> <br> * Other names: Mectizan;Drug: Albendazole<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Clinical Malaria Episodes | Cumulative incidence of malaria episodes in a cohort of village children ≤ 5 years of age (as assessed by active case surveillance in study villages - malaria episode defined as ≥38.0°C fever or history of fever in the last 24 hours + positive rapid diagnostic test for Plasmodium falciparum). Incidence is reported as malaria episodes per child over the course of the trial, a higher incidence is a worse outcome. | Approximately 18 weeks, from the start of the first MDA to 3 weeks following the last MDA in the Experimental arm | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | The number of adverse events. Adverse events data were collected via passive case detection from total population. | Approximately 18 weeks, from the start of the first MDA to 3 weeks following the last MDA in the Experimental arm | 
| Entomological Indicator of Parasite Transmission | Change in human IgG reactivity (optical density; ∆OD) to an Anopheles salivary gland antigen (peptide gSG6-P1) over the trial period. A score of 0 indicates no change in seroreactivity from from immediately before to immediately after the trial, suggesting consistent mosquito biting throughout the trial. A positive score indicates increasing seroreactivity and thus increasing mosquito biting on participants from immediately before to immediately after the trial. A negative score indicates decreasing seroreactivity and thus decreasing mosquito biting on participants from immediately before to immediately after the trial. | Approximately 20 weeks, from before the start of the first MDA to 4 weeks following the last MDA in the Experimental arm | 
| Molecular Force of P. Falciparum Infection | Examination of new P. falciparum clones acquired from the beginning to the end of the intervention (molecular force of infection; mFOI) per child. Molecular genotyping used capillary blood taken at the time of diagnosis of each positive malaria episode and consisted of nPCR of the msp2 gene. We calculated the multiplicity of infection (MOI) per malaria episode, and then calculated the molecular force of infection (mFOI) associated with malaria episodes per child (over course of the trial) | Approximately 18 weeks, from the start of the first MDA to 3 weeks following the last MDA in the Experimental arm | 
| Number of 6-10 Year Old Participants With Soil Transmitted Helminths (STH) | Prevalence of soil transmitted helminth infections in children between 6-10 years old from the beginning to the end of the intervention | Approximately 20 weeks, from before the start of the first MDA to 4 weeks following the last MDA in the Experimental arm | 
| Entomological Inoculation Rate | The entomological inoculation rate (EIR per week per person) is the measure of the human biting rate per person per week, multiplied by the sporozoite rate (in biting mosquitoes) per week, an estimated from sampling mosquitoes from 8 households located in the center of each study village. The EIR was calculated for each of the 6 sampling weeks of the treatment phase. | 6 sampling periods over 18 weeks, starting in week 2 following the first MDA, and sampling every 3 weeks thereafter until week 17 of the treatment phase. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, lymphatic filariasis, mosquito, ivermectin, mass drug administration