Ivermectin to reduce malaria transmission- safety and efficacy results from the BOHEMIA cluster randomized trial in Mozambique.

Background: Endectocides are a novel vector control tool that reduce the survival and fertility of blood sucking arthropods that feed upon treated humans or animals. Ivermectin mass drug administration is under evaluation as a complementary strategy for malaria vector control. The BOHEMIA consortium conducted two cluster-randomized trials, one in Mozambique, reported here and one in Kenya, reported elsewhere. Methods: The trial was conducted in Mopeia, a highly endemic district in Zambezia province, with perennial transmission and over 70% coverage of both indoor residual spraying and long-lasting insecticidal nets. As per protocol, we planned to randomise 53 clusters per arm (1:1:1), to receive either (a) single 400 mcg/kg dose of ivermectin to all eligible humans, once a month for three months, (b) the same ivermectin treatment to eligible humans plus injectable ivermectin (1% solution) to all eligible pigs (300 mcg/kg) and cattle (200 mcg/kg) in the cluster once a month for three months or (c) albendazole (400 mg), to serve as control, to eligible humans, following the same schedule. The primary efficacy outcome was malaria incidence of infections determined by RDT in a cohort of children under five years that was followed monthly for six months starting with the first mass drug administration round. Dual HRP-2 and pLDH rapid diagnostic tests were used in an attempt to discriminate incident infections. The rate of adverse events was captured in all treated individuals. The analysis was done using generalized estimating equations following intention-to-treat. Findings: Before the start of mass drug administration, the study site experience floods caused by the Gombe cyclone, resulting in severe logistical constrains and the loss of 57 clusters. We present a complete case analysis of the remaining clusters. The study ran between march 17 and October 18, 2022. Overall, a total of 22,724 participants from a reduced number of 100 clusters were enrolled. Six months after the first treatment round, the malaria infection incidence was comparable between all three arms with adjusted incidence rate ratio values of 0.99 (95% CI, 0.86-1.14, P > 0.9) and 1.05 (95% CI, 0.87-1.27, P = 0.6) between the human-only and control group and the human and livestock and control group respectively. The rate of severe adverse events per 10,000 treatments was not significantly different between the combined ivermectin arms and the control (IRR = 1.29; 95% CI 0.62-2.68). Interpretation: This trial did not meet implementation goals due to operational challenges including low coverage, displaced populations and delayed start of drug distribution which render the efficacy data inconclusive. However, important aspects regarding the action of endectocides at community level which could be key for implementation are described. Additionally, valuable data regarding safety were collected (ClinicalTrials.gov number, NCT04966702). Funding: The study was funded and supported by Unitaid under the "BOHEMIA" grant.