Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial

Abstract

Summary Background Ivermectin is widely used in mass drug administrations for controlling neglected parasitic diseases, and can be lethal to malaria vectors that bite treated humans. Therefore, it could be a new tool to reduce plasmodium transmission. We tested the hypothesis that frequently repeated mass administrations of ivermectin to village residents would reduce clinical malaria episodes in children and would be well tolerated with minimal harms. Methods We invited villages (clusters) in Burkina Faso to participate in a single-blind (outcomes assessor), parallel-assignment, two-arm, cluster-randomised trial over the 2015 rainy season. Villages were assigned (1:1) by random draw to either the intervention group or the control group. In both groups, all eligible participants who consented to the treatment and were at least 90 cm in height received single oral doses of ivermectin (150–200 μg/kg) and albendazole (400 mg), and those in the intervention group received five further doses of ivermectin alone at 3-week intervals thereafter over the 18-week treatment phase. The primary outcome was cumulative incidence of uncomplicated malaria episodes over 18 weeks (analysed on a cluster intention-to-treat basis) in an active case detection cohort of children aged 5 years or younger living in the study villages. This trial is registered with ClinicalTrials.gov , number NCT02509481 . Findings Eight villages agreed to participate, and four were randomly assigned to each group. 2712 participants (1333 [49%] males and 1379 [51%] females; median age 15 years [IQR 6–34]), including 590 children aged 5 years or younger, provided consent and were enrolled between May 22 and July 20, 2015 (except for 77 participants enrolled after these dates because of unavailability before the first mass drug administration, travel into the village during the trial, or birth), with 1447 enrolled into the intervention group and 1265 into the control group. 330 (23%) participants in the intervention group and 233 (18%) in the control group met the exclusion criteria for mass drug administration. Most children in the active case detection cohort were not treated because of height restrictions. 14 (4%) children in the intervention group and 10 (4%) in the control group were lost to follow-up. Cumulative malaria incidence was reduced in the intervention group (648 episodes among 327 children; estimated mean 2·00 episodes per child) compared with the control group (647 episodes among 263 children; 2·49 episodes per child; risk difference −0·49 [95% CI −0·79 to −0·21], p=0·0009, adjusted for sex and clustering). The risk of adverse events among all participants did not differ between groups (45 events [3%] among 1447 participants in the intervention group vs 24 events [2%] among 1265 in the control group; risk ratio 1·63 [1·01 to 2·67]; risk difference 1·21 [0·04 to 2·38], p=0·060)...

Reducing malaria burden and accelerating elimination with long-lasting systemic insecticides: a modeling study of three potential use cases

“…At 60% coverage, simulations predict that SI-60 will also result in around 20% burden reduction, but shorter-lasting systemic insecticides continue to have minimal impact. We observe a 17% reduction in incidence with SI-60 in children under 5 despite this group being excluded from the systemic insecticide MDA (Additional file 1 row B), which is similar to results from the field trial of 6 MDA rounds of ivermectin [16].…”

“…SMC is a commonly used intervention for burden reduction in the Sahel [32], where burden is still high. In a recent study, systemic insecticides were distributed over 6 rounds at 3-week intervals, alongside an SMC campaign, to everyone excluding young children, pregnant women, and women nursing infants under 1 week old, resulting in a 20% drop in clinical incidence [16]. However, short-duration systemic insecticides distributed over multiple rounds may prove operationally challenging at scale, especially during the wet season.…”

“…A single round of SI-30 or SI-14, concurrently distributed with a standard SMC campaign, has minimal effect on further reducing burden even at 100% coverage. Given safety concerns surrounding the administration of this class of drugs to women of childbearing age [13] and children under 5 [16], only long-lasting systemic insecticides of duration 90 days improve burden reduction in a meaningful way. However, in the event this class of drugs is found to be safe for use in nursing and pregnant women, and children under 5 years, a single round of SI-60 in parallel with standard SMC can still further reduce burden with coverage of around 60%.…”

“…There has been recent interest in developing longer-lasting systemic insecticide formulations for malaria control and potential elimination, including slow release formulations [12] and high-dose ivermectin, which has been observed to reduce mosquito survival 28 days post-treatment in the field [15]. A recent study in Burkina Faso observed a 20% reduction in clinical incidence in an intervention group receiving ivermectin 6 times over 18 weeks at 3 week intervals, with young children, pregnant women, and women nursing newborns excluded from MDA eligibility [16]. Another drug class, isoxazolines, shows promise to maintain mosquitocidal activity up to 50-90 days [17], although safety concerns still need to be addressed [18].…”

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial

“…The outcome measure was malaria incidence in children under 5 years. In some subgroups a marked and highly significant malaria incidence reduction (50%) could be observed; the authors attributed this observation to a partial prophylactic effect of ivermectin [16].…”