Mass Drug Administration of Ivermectin and Dihydroartemisinin-piperaquine as an Additional Intervention for Malaria Elimination

Study Overview
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Brief Summary
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This is a community-based cluster-randomized trial in which a novel approach to interrupt residual malaria transmission by mass drug administration (MDA) with ivermectin (IVM) combined with dihydroartemisinin-piperaquine (DP) will be tested. This cluster-randomized trial will involve 32 villages in the Upper River Region of The Gambia that will be randomized to MDA with IVM and DP or to standard of care in a ratio 1:1. This trial aims at establishing whether MDA with IVM and DP can reduce or interrupt malaria transmission in medium to low transmission settings by reducing vector survival and the human reservoir of infection. MDA with IVM and DP will be implemented in the intervention villages and all human settlements in the buffer zone, with the aim of minimizing spillover effects. Control clusters will receive standard malaria control interventions as implemented by the National Malaria Control Program. The primary outcomes will be the prevalence of malaria infection determined by molecular methods in all age groups at the peak of the second transmission season (November-December 2019) and the vector's parous rate 7-14 days after MDA.

Detailed Description
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The hypothesis of this project is that mass drug administration (MDA) with ivermectin (IVM) and dihydroartemisinin-piperaquine (DP) can reduce or interrupt malaria transmission in medium to low transmission settings by reducing vector survival and the human reservoir of infection. The research questions include the following: Will MDA with IVM plus DP (3 rounds per transmission season) in communities with high coverage of vector control interventions further reduce malaria transmission (up to local elimination)? Will MDA with IVM suppress the vector population? What is the most socially acceptable and sustainable way of achieving and maintaining high coverage of MDA with IVM and DP, and of embedding it within local communities and stakeholders? What is the impact of MDA with IVM on prevalence of ectoparasites and helminths What is the cost and cost-effectiveness of this intervention compared to standard malaria control measures?

Official Title
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Mass Drug Administration of Ivermectin and Dihydroartemisinin-piperaquine as an Additional Intervention for Malaria Elimination

Conditions
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Malaria

Intervention / Treatment
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* Drug: dihydroartemisinin-piperaquine (DP)
* Drug: ivermectin (IVM)
* Other: standard malaria control interventions only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age/anthropometry For IVM: weight ≥ 15kg or height ≥90 cm; For DP: age > 6 months Willingness to comply with trial procedures Individual written informed consent obtained at the beginning of the study Exclusion Criteria: Exclusion criteria for both IVM and DP will include the following: Known chronic illness (eg HIV, TB, hepatitis and severe malnutrition). Additionally for IVM: Pregnancy (any trimester) and breast feeding Hypersensitivity to IVM Travel to Loa loa endemic countries (e.g. Central Africa) Additionally for DP: First trimester pregnancy Hypersensitivity to DP Taking drugs that influence cardiac function or prolong QTc interval

Ages Eligible for Study
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Minimum Age: 6 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: Parallel Assignment
Interventional Model Description: This cluster-randomized trial will involve 32 villages in the Upper River Region of The Gambia that will be randomized to MDA with IVM and DP or to standard of care in a ratio 1:1
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intervention: IVM and DP<br>Mass Drug Administration with ivermectin (IVM) and dihydroartemisinin-piperaquine (DP) will be given to participants in the intervention villages plus the NMCP standard malaria control intervention | Drug: dihydroartemisinin-piperaquine (DP)<br>* DP will be available as tablets of 320/40mg and 160/20mg piperaquine/ dihydroartemisinin per tablet. Administration of a full course of DP will be done as per manufacturer's guidelines once daily for 3 days and according to body weight. DP will be taken orally with water and without food<br>Drug: ivermectin (IVM)<br>* IVM will be available as tablets of 3mg or 6mg strength. It will be given at 300-400μg/kg/day over 3 days (to the nearest whole tablet). IVM will also be taken on an empty stomach with water<br>Other: standard malaria control interventions only<br>* this is the standard malaria control interventions in the Gambia<br>|
| Active Comparator: control: standard malaria control intervetions<br>Participants in the control clusters will receive only standard malaria control interventions such as Artemether Lumefantrine, LLINs, IRS, SMC and IPTp as implemented by the National Malaria Control Program (NMCP) of the Gambia | Other: standard malaria control interventions only<br>* this is the standard malaria control interventions in the Gambia<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| prevalence of malaria infection | Prevalence of malaria infection determined by molecular methods number of participants with a positive varATS quantitative PCR divided by the total number of participants sampled | at 12 months | 
| Vector's parous rate | Malaria prevalence will be used as an indicator of on-going malaria transmission, while vector's parous rate will quantify the effect of IVM on vector survival and mosquito population age structure. Proportion: number of parous vectors divided by the total number of collected vectors | 7-14 days after mass drug administration (MDA) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| malaria prevalence | malaria prevalence at the peak of the first transmission season of number of participants with a positive varATS quantitative PCR divided by the total number of participants sampled | at 6 months | 
| incidence of clinical (laboratory confirmed) malaria cases | incidence of clinical (laboratory confirmed) malaria cases at health facilities of Number of clinical malaria cases observed divided by person-years of follow-up | after MDA over 6 months period | 
| serological markers of recent malaria | serological markers of recent malaria infection by Mean Fluorescent Intensity of the different antigens will be determined and presented as a geometric mean | after MDA over 6 months period | 
| serological markers of recent Anopheles exposure | serological markers of recent Anopheles exposure by Mean Fluorescent Intensity of the different antigens will be determined and presented as a geometric mean | after MDA over 6 months period | 
| mosquito density | Total number of mosquitoes collected during the study period across both intervention and control villages | over 24 months after MDA | 
| mosquito mortality | mosquito mortality after feeding on IVM treated individuals Number of mosquitoes that die after a blood meal 21 days post-treatment divided by total number of mosquitoes blood fed | 21 days post treatment | 
| sporozoite rates in field-caught mosquitoes | Number of P. falciparum circumsporozoite antibody (CSP) positive mosquitoes divided by the total number of mosquitoes caught | over 24 months after MDA | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transmission, reduction