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.

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

Malaria

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.

Albendazole Pill

Ivermectin Pill

Ivermectin Injectable Product

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

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

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)

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)

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)

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

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

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Locations

Location

Status