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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.
The primary objective of the study is to assess the impact of repeated ivermectin MDA on malaria incidence in children aged ≤10 years.
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.
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.
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.
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
DERR1-10.2196/41197
Widespread implementation of new malaria control tools since the turn of the century has dramatically reduced malaria parasite transmission and malaria-related morbidity and mortality across the globe, especially in African countries. Improved access to vector control interventions (indoor residual spraying [IRS] and insecticide-treated bed nets [ITNs]), point-of-care diagnostics (rapid diagnostic tests [RDTs]), and efficacious treatment (artemisinin-based combination therapies) have all contributed to this success. ITNs appear to have made the most dramatic impact, with models estimating that 68% of the decline in
Unfortunately, despite these impactful interventions, gains against malaria have been uneven across Africa and have largely stagnated or reversed since 2015 [
In light of these challenges, it is clear that additional control methods are needed against the
Although RIMDAMAL supported the potential impact of repeated MDA with ivermectin on malaria incidence, the doses and frequency were not optimized for either maximizing efficacy or ease of implementation. In particular, low-dose ivermectin is unlikely to achieve sufficient and sustained drug levels to reduce malaria transmission if given monthly. On the basis of pharmacokinetic and pharmacodynamic modeling, we determined that a repeated monthly dose of 300 μg/kg daily for 3 days would be expected to achieve sufficient blood levels to have a clinically relevant impact on malaria rates in children [
RIMDAMAL II is a double-blind, placebo-controlled, cluster-randomized, and parallel-group trial (ClinicalTrials.gov: NCT03967054; pactr.org: PACT201907479787308) designed to determine the efficacy of adding seasonal ivermectin MDA to the standard-policy malaria control measures in Sahel (SMC in children aged 3 to 59 months, long-lasting ITN coverage, and IPTp), for reducing the incidence of uncomplicated malaria episodes among children in enrolled villages (
Overall study design showing which groups received each malaria control intervention and which age demographic constituted the active case detection (ACD) cohort [
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.
Secondary objectives include the following:
Safety—To measure whether ivermectin MDAs will increase harms for the participants (ie, safety of repeated administrations of high-dose ivermectin)
Entomology—To measure entomological indices between the intervention and control arms and over the time of the intervention phase (mosquito survival rate after blood feeding, mosquito population age structure,
Parasitology—To measure the parasitological indices obtained from blood samples collected during the active case surveillance of cohort children between the intervention and control arms and over the time of the intervention phase, including asexual parasite prevalence, species, density, multiplicity of infection, and molecular force of infection (mFOI)
Pharmacokinetics and pharmacodynamics—To characterize the pharmacokinetics and pharmacodynamics of ivermectin across the age spectrum and the relationship between ivermectin pharmacokinetics and its entomological effects via membrane feeds
The study was conducted in villages surrounding the town of Diébougou, situated in the Southwest region of Burkina Faso. The region has highly seasonal intense malaria transmission, typically lasting from June to October or November. SMC was also routinely administered in this region for the 4 months of the rainy season (July to October) to all eligible children aged 3 to 59 months. Village residents represent multiple diverse ethnic Burkinabé groups including Dagara, Mossi, Dioula, and others. Previous entomology studies in the area demonstrated that the primary vector responsible for malaria transmission is
In this region, families typically reside in clustered, grouped homes that consist of extended family households. As a first step, a catchment area for potential clusters within the Diébougou health district was determined using Google Earth Pro (version 7.3.6.9345; Google LLC) that was roughly square in shape (approximately 35 km2), bounded to the north by the Bougouriba river, to the east by road N12, to the south by the road from Tiankora to Tomena, and to the west by an artificial line that went north from Tomena to the Bougouriba river. Using these satellite images, population centers in this catchment area were outlined based on an analysis of housing structures and an approximation of the number of concessions (extended family households) within each population center. In total, 147 villages or sectors were identified from this analysis, each consisting of between 5 to >100 households. Artisanal gold mining operations were also identified using the maps. From this final map, 18.4% (27/147) of the villages (clusters) were selected based on the following criteria: (1) clusters were accessible to the clinical team during the rainy seasons via motorcycles, which would be their primary mode of transport, providing them with safe road access and allowing them to conduct field visits and return to the field station in Diébougou in 1 day; (2) clusters were at least 2 km away from an artisanal gold mine for the safety of the study team and to minimize contamination from mosquito and human movement to and from these areas; (3) clusters had clearly defined boundaries, allowing field technicians to sample from a single cluster easily without inadvertently including households from neighboring villages; (4) clusters were accessible by study car and no more than 2 km away from an accessible road to facilitate emergency transport of participants to the hospital if necessary; (5) based on an estimated 8 individuals per household, selected clusters had between 20 and 50 households—this was estimated to provide an average of approximately 100 cohort children per cluster, which would enable a single nurse to care for each cluster; and (6) clusters were at least 2 km away from any other enrolled cluster to avoid contamination from mosquito migration. As a final step, in April 2019, the study team selected the final 52% (14/27) of the villages (clusters) based on visits to each village to verify satellite data, household numbers, and village boundaries. All finalized villages and households were enumerated and mapped using handheld GPS devices.
Before the rainy season of year 2, following the review of GPS satellite mapping data, it was determined that a small number of households in a subset of villages were not enrolled in 2019 despite being located at the outer boundaries of participating villages. Owing to their proximity to enrolled households and location within the initial intended catchment area, these households were added to the potential list for enrollment and approached in year 2.
Before village engagement, approvals were attained from the
Eligibility for ACD was determined at the beginning of each intervention season and retained for the remainder of that season:
Newborns were eligible for inclusion.
Children who turned 11 years during an intervention season remained eligible for the ACD cohort for the remainder of that season.
If a participant aged out of the ACD cohort in the first season, they were not eligible for the ACD cohort in the second season.
Eligibility for SMC was determined by the MoH community workers and not by the RIMDAMAL II study team. Participants may age out of SMC (>59 months) in the first season and become eligible for MDA (height ≥90 cm and aged >59 months) in the second season. They did not become eligible for MDA during the season in which this occurred, that is, individuals had to be ≥90 cm at the beginning of the season to receive ivermectin during that season. Cotreatment with ivermectin or placebo and SMC was not allowed during the study because no data were available about the safety of coadministration.
Informed consent was obtained through a multitiered process. After obtaining the permissions stated previously, the head of each household was approached by the study team. Informed consent was obtained from all willing heads of households. Following consent of the head of household, individual consent was obtained from each willing villager. For those aged <18 years, the consent of a parent or guardian was obtained, and for those aged between 12 and 17 years, an additional assent was obtained. Informed consent procedures were repeated before the year-2 intervention season for any potential new villagers who were not present for the informed consent process before the beginning of the study in year 1. Obtaining consent was also an ongoing process throughout the trial, and any participant who refused treatment or wished to withdraw from the study was able to do so without prejudice.
A subset of villages and households was selected for more intensive sampling of both humans and mosquitoes to enhance parasitological and entomological secondary studies. Before the beginning of the trial, 6 villages were chosen at random by the study pharmacist, who was unblinded, such that 3 (50%) villages were intervention clusters and 3 (50%) villages were control clusters. Within each of these villages, 8 households were chosen based on GPS mapping and location on spatial transects (east-west and north-south). Households closest to the transects were selected based on location: 2 innermost and 2 outermost households on each transect (8 households per village; 48 households in total). Selected households were subject to more frequent cross-sectional sampling of all individuals living in the household (regardless of age) and to intensive entomological sampling.
The intervention, ivermectin or ivermectin placebo (Iver P; Laboratorio Elea; 6-mg tablet) at 300 µg/kg dose estimated by height bands, was administered orally for 3 days to eligible individuals who are not receiving SMC. Per the package insert, dosing of ivermectin or placebo was according to height:
90 to 119 cm (15-25 kg)=1 tablet per day for 3 days
120 to 140 cm (26-44 kg)=2 tablets per day for 3 days
141 to 158 cm (45-64 kg)=3 tablets per day for 3 days
>158 cm (65-84 kg)=4 tablets per day for 3 days
Ivermectin tablets were stored in a temperature-controlled room at
IRS was not administered in these villages in the 7 years before the study, aside from a single village that received Actellic 300CS (Syngenta AG) in 2017, and no IRS was deployed during the study. All study villages (14/14, 100%) were part of the periodic MoH ITN distribution cycle, having received pyrethroid ITNs within 2 years before the beginning of the study via mass distribution campaigns. Following the initiation of the study, the MoH relayed that villages in the Diébougou health district were expected to receive new Interceptor G2 ITNs, which were ultimately deployed in October 2019. These new long-lasting insecticidal nets (LLINs) are made with 2 different insecticides (chlorphenapyr and α-cypermethrin) to circumvent the prevalent pyrethroid resistance seen among anophelines in Burkina Faso and much of sub-Saharan Africa.
SMC was provided and distributed by the MoH. It was administered monthly from July to October (for 3 consecutive days) with SP and AQ (eg, SPAQ-CO; Guilin Pharmaceutical). SMC was dosed as 500/25 mg SP and 153 mg AQ for children aged 12 to 59 months and 250/12.5 mg SP and 76.5 mg AQ for children aged 3 to 11 months. As per standard practice in Burkina Faso, the first dose (AQ and SP) is directly observed by MoH staff, and doses on days 2 and 3 (AQ only) are provided to the parents or guardians to administer at home. For pregnant women, IPTp is provided by the MoH and followed World Health Organization policy, which recommended at least 3 treatments, 1 month apart, starting in the second trimester (eg, Fansidar; Roche; 500/25 mg SP per tablet; 3-tablet dosage=1500/75 mg SP).
Ivermectin was also administered to all villages as part of the yearly MDA elimination campaigns, at a single dose of 150 μg/kg orally. According to MoH district leaders, study villages received ivermectin MDA as a single dose for eligible individuals from September 2, 2019, to September 7, 2019, and from November 10, 2020, to November 19, 2020, meaning that study participants received an extra dose of ivermectin 150 μg/kg during the intervention rounds in 2019 and 1 month after the intervention rounds in 2020. Ivermectin MDA was administered by the MoH and not by the study team.
The primary outcome is the incidence of malaria episodes in the ACD cohort, which comprised children aged ≤10 years, as assessed by active case surveillance by study team nurses assigned to each village and required to visit each child a minimum of once per week during the intervention phases. In this field setting, malaria incidence in children is the most clinically relevant outcome measure for an antivector intervention that targets blood-feeding mosquitoes, and its reduction following repeated ivermectin administration has been validated in our previous RIMDAMAL study [
Secondary outcomes include the following:
Safety and tolerability—AE monitoring occurred throughout the intervention periods in both years through active and passive case surveillance. AE monitoring occurred for all enrolled participants, regardless of age, and will be further characterized by their relationship to the intervention and as serious AEs based on their severity. Active AE monitoring entailed assessments 24 hours following each dose of MDA in all participants available at the time of a nurse’s visit and weekly visits for children in the ACD cohort. Nurses conducted passive AE monitoring over the course of the week during routine study activities.
Entomology—Entomological outcomes include the following. (1)
Parasitology—Parasitological outcomes include the following. (1)
Pharmacokinetics and pharmacodynamics—Outcomes include (1) the pharmacokinetic profile of ivermectin in 3 different age groups (5-10 years, 11-18 years, and >18 years) sampled over 28 days and (2) the relationship between ivermectin plasma concentration and mosquitocidal effects over time via membrane feeds.
The primary end point for the trial is the incidence rate of malaria episodes in children aged ≤10 years, as assessed by active case surveillance by study nurses with weekly visits to each child, starting at the first round of MDA in year 1, continuing for 4 months and beginning again with the fifth round of MDA in year 2, and ceasing 4 weeks after the last round of MDA. The dosing regimen, sample size, and power for RIMDAMAL II were guided by the Malaria Transmission model developed at Imperial College, London [
This effect size and resulting sample size calculations assumed a moderate level of LLIN coverage with a low-efficacy net owing to high levels of pyrethroid resistance in the region. However, during study planning, it emerged that Interceptor G2 ITNs were to be distributed toward the end of the first year of the intervention. Updating the modeled incidence rates by assuming that the new ITNs would result in an additional 30% reduction, while also increasing the number of children per cluster, meant that even with new LLIN distribution, the number of clusters was still adequate to achieve 80% power.
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.
The randomization unit was the study village (cluster). Before a public randomization event, the study pharmacist, who is the only nonblinded member of the study team, initiated the masking procedure in private, whereby 14 identical cards were made with the numbers 1 to 14 written on them, and these were placed in a container, mixed, and then randomly pulled from the container. In total, 7 numbered cards were randomly placed in each of 2 other containers labeled
The study pharmacist was in charge of the drug stock rooms, and he allocated the tablets for each MDA round according to the original randomization throughout the trial. Drug was distributed in sealed containers labeled with the number code. All study personnel, apart from the pharmacist, remained blinded throughout the study.
Enrollment forms were completed after obtaining consent from all participants in years 1 and 2 and recorded on study tablets. Year-2 enrollment forms included a reassessment of eligibility criteria and captured additional information about the village participants who were not eligible for MDA owing to them sleeping in the village ≥3 nights per week. Baseline pre-MDA filter paper samples were obtained from a subset of ACD participants in year 1 from each village and from all study participants in year 2.
Active case surveillance was conducted by study nurses visiting each enrolled ACD cohort child weekly following the beginning of the first MDA and ending 30 days following the last MDA of the season. At each visit, the nurse recorded patient information in the electronic case record form, measured the child’s temperature, recorded whether either a history of fever in the past 24 hours or current fever was present, and obtained a blood sample by capillary finger prick method (for RDT, blood smear slide and filter paper [Whatman 3MM] samples were collected). The RDT detected both parasite-derived histidine-rich protein 2 and lactate dehydrogenase (SD Bioline Malaria Ag Pf/Pan; Abbott). All clinical decisions were made based on the RDT result, and if positive for either antigen, results were recorded, and participants were treated with artemether-lumefantrine, according to the Burkina Faso MoH guidelines. Episodes of malaria were classified as complicated based on standard World Health Organization criteria [
During each weekly visit, the nurse inquired about any AEs following the receipt of MDA doses or during any intervening time since the last visit. Passive AE monitoring was performed if AEs were communicated to the nurse during other nonstudy visit encounters. Household surveys were performed over the course of the study to ascertain the use of malaria control measures and gather other demographic and social information. In year 2, infection prevention and control measures were implemented to limit the risk of COVID-19 among study staff and participants. Measures included the use of personal protective equipment and the purchase and use of washing stations within each village.
As noted previously, active and passive AE monitoring occurred in all enrolled villagers, regardless of age. Study nurses and physicians were trained on how to monitor, record, and report AEs. In addition, AEs were followed to resolution when feasible. Severity assessments by the study physicians were performed in consultation with the study nurses and on-site physicians. AEs were graded on a 5-point scale and grouped according to body system and preferred terms using Medical Dictionary for Regulatory Activities. Relationship to the study intervention was determined by the study physician and reviewed by the study’s principal investigators before unblinding.
Before the beginning of MDA 1 in year 1, cross-sectional households were visited to complete a baseline questionnaire and collect a capillary finger prick sample on filter paper. In year 1, additional blood samples were obtained on filter paper in the middle of the season and approximately 4 weeks following the last MDA. In year 2, filter paper samples were obtained from all cross-sectional household participants before each MDA and 4 weeks following the last MDA. In addition, before and after each season, a hemoglobin measurement was performed using point-of-care HemoCue. Entomology collections in cross-sectional households are described in the following sections. Cross-sectional questionnaires were administered to ascertain the use of malaria control measures and to assess housing and environmental aspects related to malaria risks.
Parasite prevalence and speciation will be determined using molecular assays on DNA extracted from filter paper samples using established methods.
Mosquito sampling was conducted in a subset of cross-sectional villages, within the cross-sectional transect households only. Overall, 2 sampling methods were used; the first method was indoor aspirations of resting mosquitoes collected in the morning in all cross-sectional household sleeping rooms, and the second was light traps placed in 1 cross-sectional household located in the center of the village to collect host-seeking anophelines overnight. For the light traps, one was placed outdoors hanging under the rain tarp of a camping tent that was occupied by a sleeping person, and another was placed indoors hanging next to a person sleeping under a bed net. Mosquito sampling intervals occurred in these 6 cross-sectional villages over the course of a week and were conducted 1 week after each MDA and 3 weeks after each MDA for a total of 16 sampling intervals across the entire intervention period.
In October 2020, following the third round of ivermectin MDA, a pharmacokinetics and pharmacodynamics substudy was performed for individuals residing in 6 villages (n=3, 50% intervention and n=3, 50% control villages). In total, 178 participants were enrolled in the substudy, approximately 90 each from the intervention and control villages, with all team members except the pharmacist blinded to the village study arm. Participants were enrolled to achieve roughly equal numbers from three age groups: (1) 5 to 10 years, (2) 11 to 18 years, and (3) >18 years. Sparse pharmacokinetics sampling was conducted for each individual at up to 7 time points over 28 days, with additional blood collected for entomological and safety assessments (chemistries and blood counts). Pharmacokinetics data will be analyzed using nonlinear mixed effects modeling, and entomological assessments will be performed using membrane feeds on participant plasma.
Data were gathered in an electronic data capture system (REDCap [Research Electronic Data Capture; Vanderbilt University] database system). All electronic case report forms containing participant demographic and clinical data (active case surveillance data on the children cohort and AE data for all participants) were entered on password-protected tablets that were maintained and updated daily by the clinical team working at the field site. Only the study team will have access to the source data. Long-term maintenance of the participant codes is held only by the study’s principal investigators on password-protected computers and files. Database records were individually checked for inconsistencies and cross-checked with the study team and other data sources, as applicable. Study data devoid of identifiers will be provided to the research community following the publication of the primary outcomes.
Institutional review board approvals were obtained and maintained from the Colorado State University (19-9144H/1691), Yale Human Investigations Committee (under a Streamlined, Multisite, Accelerated Resources for Trials Institutional Review Board Reliance platform agreement with the Colorado State University; 2000024138),
We will use an intention-to-treat analysis method for our primary clinical outcome, which is the incidence rate in children in the ACD cohort [
The primary analysis will evaluate the efficacy of ivermectin treatment as described previously. The robustness of this conclusion will be evaluated through analyses that will adjust for other covariates and assess the strength of the rate ratio in key subgroups. Sensitivity analysis will be performed to assess the impact of censoring a participant’s time at risk for 14 days following the diagnosis and treatment of malaria owing to the impacts of treatment on risk of recurrent malaria.
Subgroup analyses will be performed to help inform the mechanism of action of ivermectin and determine whether the effects are similar across important subgroups. Subgroups include (1) children aged 0 to 3 months, who receive neither SMC nor intervention; (2) children aged 3 to 59 months, who receive SMC only; (3) children aged >59 months but are <90 cm in height, and therefore do not receive SMC or the intervention; and (4) those who receive MDA only (height ≥90 cm and aged ≤10 years).
Consent process and recruitment for the study began on July 13, 2019. The first round of MDA began on July 26, 2019, and the last round of MDA in year 1 began on October 16, 2019. MDA in year 2 began on July 20, 2020, and the last round of MDA began on October 12, 2020. SMC and ivermectin MDA distribution occurred on the same days for all MDA except MDA 1 in 2019, in which ivermectin MDA was delayed relative to SMC by 2 days. Statistical analysis will be conducted once the database is completed, cleaned, and locked, and the clinical trial protocol is publicly available. The study team will be unblinded after the clinical trial protocol and statistical plan is finalized and publicly available.
With gains in malaria stagnating since 2015 and reversals being seen in several countries, particularly in sub-Saharan Africa, novel control methods are urgently needed [
RIMDAMAL II builds on these insights and will assess whether the high dose of ivermectin MDA, when administered in operational conjunction with SMC delivery, is associated with significant reduction in malaria incidence in children aged <10 years, as compared with standard interventions alone (SMC and ITN use). Malaria incidence was chosen as the primary outcome, as this was felt to reflect a meaningful outcome measure that could have an impact on policy decisions. The study is cluster randomized and placebo controlled, with all study investigators being blinded to intervention allocation, which is a rigorous design to test the community-level impact of this novel intervention. The study intervention was also conducted over 2 seasons and involved both active and passive follow-up of AEs for all enrolled participants, thus providing a strong evidence base to assess the safety of repeated high-dose ivermectin for malaria transmission reduction. Secondary outcomes will provide parasitological, entomological, and pharmacokinetic outcome measures to further enhance our understanding of the mechanisms by which ivermectin may exert its effects. Additional sampling in the year following the intervention will provide information on any postintervention effects of ivermectin MDA.
Community-level trials are subject to several challenges during planning and execution. The identification of appropriate clusters that are sufficiently distanced from one another to avoid contamination and of appropriate size to enable rigorous surveillance of all participants can be challenging, but it also reflects the reality of spatial demographics in rural African settings. During the planning stages, attempts were made to identify ideal villages for inclusion, while balancing with practical limitations in the field (refer to previous sections).
Cluster-randomized, community-based trials are also open to external factors that can challenge the execution phases of the study. During RIMDAMAL II, the COVID-19 pandemic spread around the globe just before the beginning of the second intervention season. In recognition of the potential impact that the COVID-19 pandemic could have on multiple aspects of the study (safety of the staff and participants, availability of supplies, ability to differentiate malaria and COVID-19, etc), extensive discussions and preparations occurred before year 2 of the study. Efforts included the training of the staff on appropriate infection prevention and control measures, purchase and shipment of personal protective equipment from the United States to Burkina Faso, and purchase of handwashing stations for each village. At the conclusion of year 2 of the intervention, there was no overt evidence of COVID-19–related clinical impacts in our enrolled villages; however, precise data on COVID-19 case counts in the region were not available.
A second challenge was the decision by the Burkina Faso MoH and certain research partners to deploy ITNs with different insecticide chemistries in Southwest Burkina Faso. In the region of Diébougou, new Interceptor G2 ITNs were deployed in October 2019, at the end of year-1 intervention season. The timing of distribution created challenges and opportunities, which will be assessed in the analysis, as both year-1 and year-2 outcomes largely occurred under the use of deltamethrin and chlorphenapyr or α-cypermethrin nets.
RIMDAMAL II will be the first cluster-randomized trial to directly assess the impact of repeated high-dose ivermectin MDA on malaria incidence. The trial uses high-dose, monthly ivermectin coupled operationally with SMC, and the assessment of primary outcome includes children who received only SMC (those aged 3-59 months) and those who received only ivermectin (and no SMC; those aged 60 months to 10 years). Statistical analysis planning supports the adequacy of the cluster size and the approach to assess the primary outcome [
RIMDAMAL II will be the first cluster-randomized trial to directly assess the impact of repeated high-dose ivermectin MDA on malaria incidence in children. The results will inform policies and future studies on the use of mosquitocidal agents as novel components for malaria control.
active case detection
adverse event
amodiaquine
Agent de santé Communitaire
Consolidated Standards of Reporting Trials
human biting rate
intermittent preventive treatment in pregnancy
indoor residual spraying
insecticide-treated bed net
Efficacy and Safety of High-Dose Ivermectin for Reducing Malaria Transmission
long-lasting insecticidal net
mass drug administration
molecular force of infection
Ministry of Health
rapid diagnostic test
Research Electronic Data Capture
Repeat Ivermectin Mass Drug Administration for Malaria Control
relative risk
seasonal malaria chemoprevention
sulfadoxine-pyrimethamine
The authors would like to thank the study nurses, laboratory technicians, and entomology team for their contribution. The authors would like to thank the Burkina Faso Ministry of Health, local health care providers, and villagers who participated in the study. The authors thank Laboratorio Elea, Argentina, for providing ivermectin and the placebo. The trial was funded by the National Institute of Allergy and Infectious Diseases (grant 5U01AI138910).
Data for the trial will be made available on the Clinical Epidemiology Database Resources [
BDF, SP, and RKD conceived of the study. SP and BDF drafted the manuscript. AFS and GC served as the study coordinators. AS was the primary medical officer and oversaw the field activities. BDF and RKD oversaw the design and entomology activities. TM, BDF, AS, LG, MC, and SP oversaw the creation and management of the database. MW oversaw laboratory management at Yale. TB assisted with the study design. SR, CLJ, HCS, and JK provided the modeling and statistical analysis plan. KR performed regulatory oversight.
In October 2020, BDF and SP joined the Scientific Advisory Board as consultants for the IMPACT project being run by MedinCell. RKD and AFS are investigators for the IMPACT project. BDF also performed a 1-time consultation for Lyndra Therapeutics Inc in July 2020.