Broad One Health Endectocide-based Malaria Intervention in Africa (BOHEMIA) (BOHEMIA)

A Phase III Cluster-randomized, Open-label, Clinical Trial to Study the Safety and Efficacy of Ivermectin Mass Drug Administration to Reduce Malaria Transmission in Two African Settings

The BOHEMIA program consists of a combination of studies organized around a central community prevention mass drug administration protocol and four sub-studies (i.e.; social science, entomology, health economics, and environmental), each written as an individual protocol. The protocol is central but used in two separate, individually powered trials in Mozambique and Kenya. The trials have been powered on the efficacy outcome and designed to meet the requirements of WHO´s preferred product characteristics (PPC) for endectocides.

WHO´s PPC states that the desired efficacy of an endectocide as stand-alone insecticide in areas of high to moderate transmission is at least 20% reduction in the incidence of clinical malaria (as primary outcome) and incidence of infection (as secondary outcome) in children under 5 (the highest incidence age-group in areas with high-transmission), lasting for at least 1 month following a single regimen. Assessing this effect requires a cluster-randomized design with meticulous follow-up of a cohort of children for efficacy and the whole exposed population for safety outcomes, which is the design selected for the BOHEMIA trials. Two BOHEMIA cluster randomized trials will be carried out in Mozambique (Southern Africa) and Kenya (Eastern Africa). These sites encompass different transmission dynamics that increase the generalizability of results, namely: (a) a gradient of malaria transmission: moderate in Kenya and very high in Mozambique, (b) different species composition of vector population, (c) different rain patterns and environmental conditions, and (d) different livestock species and human/livestock ratios. Population Co-primary objectives are determined in different populations. Efficacy is primarily determined in a pediatric active cohort (children under 5 years of age in Mozambique and 5-15 years in Tanzania), pediatric active cohort, and safety is determined in anyone who receives the drug. Pregnant women and children under 15 kgs are not eligible for treatment. Treatment Groups Three groups of clusters will be randomized to receive (a) ivermectin in humans, (b) ivermectin in humans + livestock, or (c) albendazole control, and each study district will be subject to enhanced passive surveillance for malaria. Primary outcome measure: The primary outcome measure is proposed as incidence in a six-month period given that ivermectin is a short-acting intervention with <1% residual drug at 30 days after each dose. Efficacy assessment will continue 4 months post last dose of ivermectin, and this will include analysis of the vector population. We have proposed the appropriate duration of impact evaluation relevant to the biology of the intervention, and geared towards being able to clean the data, lock the database, and conduct the primary efficacy and safety analysis efficiently. Estimated Duration of Study: Throughout the study there will be two different groups of participants enrolled, the ones receiving the treatment (> 15 kg) and the ones in the active pediatric cohort for the main outcome of malaria incidence (the ages of highest incidence in each country, under 5 years of age in Mozambique and 5-15 years in Kenya). Each group will participate for different periods of time. Only the group enrolled in the active pediatric cohort will contribute to the primary efficacy outcome and this group will participate from date of first dose for six months. The group receiving treatment (>15 kg) will contribute to the primary safety outcome and several secondary outcomes (PK, NTDs) and this group will participate for four months. Women of child-bearing age will be visited one month after the third dose for a final pregnancy test, any pregnancy occurring during the trial will be followed for 9 months. The cross-sectional survey will enroll participants of all ages one month after the last MDA round. WHO guidance states that trial design and duration should reflect the nature of the intervention and are left at the discretion of researchers. These trials are robustly powered and are being conducted in moderate to high burden areas, so we believe the risk of failing to find an effect is low and if so, it would throw the utility of the intervention into question. Advancing the development of this new tool towards implementation in the field can be accomplished in a time frame to contribute to the 2030 GTS goals.

The BOHEMIA trials are open-label with random assignment to one of 3 treatment arms - ivermectin human/ivermectin human & livestock/control - albendazole.

The albendazole group will receive a single dose of 400 mg, given once a month for three months. Generic products will be used in both countries. Bendex in Mozambique and Albenza in Kenya

The ivermectin group will receive a single dose of 400 mcg/kg, given once a month for three months. Product to be used is Stromectol (Merck) in Mozambique and Ivermectin 3mg USP (Edenbridge) in Kenya

The ivermectin group will receive a single dose of 400 mcg/kg, given once a month for three months. Product to be used is Stromectol. For livestock, locally registered veterinary injectable ivermectin at 1% will be used

Using a MDA approach, fieldworkers will admister albendazole using directly observed treatment methodology to participants

Using a MDA approach, fieldworkers will admister ivermectin using directly observed treatment methodology to participants

To determine the safety (in humans) and efficacy of ivermectin MDA (administered to humans or humans and livestock simultaneously) for the prevention of malaria

Infection incidence across 6 months of follow up has been chosen as primary outcome based on the WHOs PPC for endectocides

To assess whether ivermectin works as a complementary vector control tool, the number of hospitalisations occuring in the efficacy cohort group during the trial will be compared to previous years' data

To assess the safety of the intervention based on the number of related SAEs reported during the trial, including pregnancy outcomes

PK results from a sub-sample of the participant population are compared with actual or modelled parameters for the currently label-approved doses of ivermectin to determine optimal dosing and regimen

Assess the impact of ivermectin MDA at the proposed regimen on the prevalence of selected ectoparasitic neglected tropical diseases (NTDs)

o assess the impact of ivermectin MDA at the proposed regimen on the prevalence of selected ectoparasitic neglected tropical diseases (NTDs) (scabies, headlice, tungiasis, and bed bugs)

Using RDT results to compare malaria incidence in children under 5 with community prevalence one month post last dose

To assess the relationship between malaria incidence in children under 5 and community prevalence one month post last dose using data from RDTs in the efficacy cohort (this serves for prevalence outcomes and paves the way for future studies using prevalence as outcome which is much less resource-consuming than incidence)

Using data from health facility malaria registers (passive surveillance) to compare with data from active case finding in the community by healthworkers to establish trends, relationships and patterns between the two.

Staff based in health facilities will capture malaria data from facility records which will be compared to data collected in the field to assess the relationship between active and passive surveillance for malaria at health facility (this serves as validation of passive surveillance and paves the way for future studies using passive surveillance as outcome which is much less resource-consuming than active surveillance, ensuring no key safety events are missed)

To assess the accuracy for malaria diagnosis of two different malaria rapid diagnostic tests (RDTs) used in comparison to polymerase chain reaction (PCR) (this is directly linked to efficacy as determined by RDTs)

Using a rapid serologic test to determine the prevalence of COVID-19 antibodies in a sub-sample of the participant population in Mozambique

Use of rapid serologic tests to provide more accurate data on the sero-prevalence of COVID-19 in the district of Mopeia

Using a rapid serologic test to determine the incidence of COVID-19 antibodies in a sub-sample of the participant population in Mozambique

Use of rapid serologic tests to provide more accurate data on the sero-incidence of COVID-19 in the district of Mopeia

Using transcriptomic and antibody response patterns to assess whether ivermectin effects the immune response

Samples from a sub-sample of participants will be collected to assess the potential direct or indirect effect of ivermectin on the immune response to the malaria parasite

To assess whether self-reported Last Menstrual Period (LMP) can be used as a tool for determining conception.

To evaluate the correlation between self-reported pregnancy status, the LMP and the results of urine pregnancy tests in women of reproductive age participating in the study

Using verbal autopies to assess all-cause and malaria-related mortality in intervention and control arms

To estimate the prevalence of relevant CYP and P-gp variations in the target population and subjects suffering from CNS-AEs

Samples will be collected from the first 100 participants reporting CNS AEs for pharmacogenetic testing for CYP 3A5 and ABCB1 SNPs

Inclusion Criteria: For human treatment/safety cohort Residents of the study area Male or female weighing more than 15kg Adult able to provide written consent Minors aged 12 to 17 able to provide assent Parent/guardian's able to provide consent for minors Negative pregnancy test for women aged between 13 and 49 Agreement to adhere to study visits and procedures For pediatric active cohort: Children in the age of highest burden at the time of enrollment (under 5 years of age in Mozambique or 5-15 in Tanzania) Residents of the study area Parent/guardian's able to provide consent for minors Minors aged 12 to 15 in Tanzania able to provide assent For cross sectionals Residents of the area for at least 3 months prior to enrolment Parent/guardian's consent for minors Ability to provide assent for minors aged 12 to 17 Written consent from adults For livestock treatment: Owner/guardian able to provide consent Animal expected to spend at least one week every study month inside the cluster border Exclusion Criteria: 5.2.1. For human treatment/safety cohort: Known hypersensitivity to ivermectin or albendazole Risk of Loa as assessed by travel history to Angola, Cameroon, Chad, Central African Republic, Congo, DR Congo, Equatorial Guinea, Ethiopia, Gabon, Nigeria or Sudan Pregnant women Lactating women in the first week postpartum Children < 15 kg Currently participating in another clinical trial Unwilling to provide informed consent or assent Unwilling to adhere to study visits and/or procedures Severely ill either self-reported or in the eyes of the investigator, e.g. defined as need for clinical care, or active or progressive disease interfering with activities of daily living. If in doubt, these criteria can be confirmed after a call with either the site PI/MD/safety officer against a pre-defined list. Currently under treatment with inhibitors of CYP3A or P-gp or other drugs that can interfere with the study For incidence cohort: Non-residents Currently enrolled in other clinical trial For cross sectionals • Non-residents For livestock treatment Received ivermectin three weeks than four weeks ago Intention to milk or slaughter the animal for human consumption during the withdrawal period Calves under 8 weeks and piglets under 6 weeks of age

In order to ensure that the Project Results may be shared and ISGlobal will make the fully anonymized data generated by the Project publicly available on open access terms in an appropriate online data repository: (i) at the same time as publication, in relation to data supporting, or which may be necessary to validate, the main findings of any publication; (ii) no later than six (6) months after the end of the Project Term, in relation to all other data which may have public health value

Protocol and ICF: upon ethical approval SAP: before finishing enrolment CSR and code: within 12 months of completion of the trial