Repeat Ivermectin Mass Drug Administrations for Malaria Control II: Protocol for a Double-blind, Cluster-Randomized, Placebo-Controlled Trial for the Integrated Control of Malaria

Abstract

Background: The gains made against malaria have stagnated since 2015, threatened further by increasing resistance to insecticides and antimalarials. Improvement in malaria control necessitates a multipronged strategy, which includes the development of novel tools. One such tool is mass drug administration (MDA) with endectocides, primarily ivermectin, which has shown promise in reducing malaria transmission through lethal and sublethal impacts on the mosquito vector.

Objective: The primary objective of the study is to assess the impact of repeated ivermectin MDA on malaria incidence in children aged ≤10 years.

Methods: Repeat Ivermectin MDA for Malaria Control II is a double-blind, placebo-controlled, cluster-randomized, and parallel-group trial conducted in a setting with intense seasonal malaria transmission in Southwest Burkina Faso. The study included 14 discrete villages: 7 (50%) randomized to receive standard measures (seasonal malaria chemoprevention [SMC] and bed net use for children aged 3 to 59 months) and placebo, and 7 (50%) randomized to receive standard measures and monthly ivermectin MDA at 300 μg/kg for 3 consecutive days, provided under supervision to all eligible village inhabitants, over 2 successive rainy seasons. Nonpregnant individuals >90 cm in height were eligible for ivermectin MDA, and cotreatment with ivermectin and SMC was not permitted. The primary outcome is malaria incidence in children aged ≤10 years, as assessed by active case surveillance. The secondary safety outcome of repeated ivermectin MDA was assessed through active and passive adverse event monitoring.

Results: The trial intervention was conducted from July to November in 2019 and 2020, with additional sampling of humans and mosquitoes occurring through February 2022 to assess postintervention changes in transmission patterns. Additional human and entomological assessments were performed over the 2 years in a subset of households from 6 cross-sectional villages. A subset of individuals underwent additional sampling in 2020 to characterize ivermectin pharmacokinetics and pharmacodynamics. Analysis and unblinding will commence once the database has been completed, cleaned, and locked.

Conclusions: Our trial represents the first study to directly assess the impact of a novel approach for malaria control, ivermectin MDA as a mosquitocidal agent, layered into existing standard-of-care interventions. The study was designed to leverage the current SMC deployment infrastructure and will provide evidence regarding the additional benefit of ivermectin MDA in reducing malaria incidence in children.

Trial registrations: ClinicalTrials.gov NCT03967054; https://clinicaltrials.gov/ct2/show/NCT03967054 and Pan African Clinical Trials Registry PACT201907479787308; https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=8219.

International registered report identifier (irrid): DERR1-10.2196/41197.

Keywords: Anopheles; clinical trial; cluster-randomized; endectocide; ivermectin; malaria; mass drug administration; mosquito; seasonal malaria chemoprevention; transmission.

Figure 1

Overall study design showing which groups received each malaria control intervention and which age demographic constituted the active case detection (ACD) cohort [1]. IPTp: intermittent preventive treatment in pregnancy; MDA: mass drug administration; PD: pharmacodynamics; PK: pharmacokinetics; SMC: seasonal malaria chemoprevention; SP: sulfadoxine-pyrimethamine.

Figure 2

Diagram of study interventions and follow-up for primary and secondary outcomes. ACD: active case detection; AE: adverse event; DMID: Division of Microbiology and Infectious Diseases; DSMB: Data Safety Monitoring Board; IRB: institutional review board; IVM: ivermectin; MoH: Ministry of Health; PD: pharmacodynamics; PK: pharmacokinetics; SMC: seasonal malaria chemoprevention.

Figure 3

Initial modeled impact of 4 monthly rounds of seasonal malaria chemoprevention (SMC) compared with 4 monthly rounds of SMC and ivermectin (IVM) 3×300. The resulting annualized incidence rates over the observation window were 1.06 in the control arm and 0.60 in the intervention arm.