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 (Preprint)

Abstract

BACKGROUND Malaria gains have stagnated since 2015, threatened further by increasing resistance to insecticides and antimalarials. Improvement in malaria control necessitates a multi-pronged strategy which includes the development of novel tools. One such tool is the 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 a combined approach of seasonal malaria chemoprevention (SMC) and bed net usage with or without repeated ivermectin MDA on malaria incidence in children age ≤ 10 years. METHODS Repeat ivermectin MDA for malaria control II (RIMDAMAL II) is a double-blind placebo-controlled cluster-randomized parallel-group trial conducted in a setting with intense seasonal malaria transmission in Southwest Burkina Faso. The study included 14 discrete villages: 7 randomized to receive standard measures (SMC for children ages 3 to 59 months and bed nets) plus placebo and 7 to receive standard measures plus ivermectin MDA over two successive rainy seasons. RESULTS The trial intervention (ivermectin MDA at 300 µg/kg for consecutive 3 days, provided under supervision to all eligible village inhabitants) was conducted from July to November in 2019 and 2020, with additional sampling of humans and mosquitoes occurring through February 2022 to assess for post-intervention changes in transmission patterns. Additional human and entomological assessments were performed over the two years in a subset of households from 6 cross-sectional villages. A subset of individuals underwent additional sampling in 2020 to characterize ivermectin pharmacokinetics/pharmacodynamics. CONCLUSIONS Our trial represents the first study to directly assess the impact of a novel approach to malaria control, ivermectin MDA as an endectocide, layered into existing standard of care interventions. The study was designed to leverage current SMC deployment infrastructure and will provide evidence as to the additional benefit of ivermectin MDA in reducing malaria incidence in children. CLINICALTRIAL ClinicalTrials.gov Identifier: NCT03967054; Pan African Clinical Trials Registry (PACTR): PACT201907479787308

Clinical pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes

“…Ivermectin, with its sound safety profile in humans, unique mode of delivery, novel mode of action, and long plasma half-life, is a promising candidate as a first-in-class malaria vector control tool. Currently, several clinical trials are investigating the effect of ivermectin mass drug administration on malaria transmission by diminishing the mosquito population in endemic regions [3,[26][27][28][29]. The community delivery of ivermectin could address residual transmission, which is defined as a sustained transmission even after reaching an appropriate coverage with standard vector control tools.…”