Clinical trial NCT04966702: Broad One Health Endectocide-based Malaria Intervention in Africa (BOHEMIA)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Keywords: ivermectin
malaria
vector control
Lead sponsor: Barcelona Institute for Global Health
Sponsor class: OTHER
Collaborators: name: UNITAID
First posted: 2021-07-19
Enrollment: 48145
Sex: ALL
Minimum age (years): 1
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The BOHEMIA trials are open-label with random assignment to one of 3 treatment arms in Mozambique and 2 in Kenya: (a) ivermectin in humans, (b) ivermectin in humans + livestock (only in Mozambique), or (c) albendazole control.
Primary purpose: TREATMENT

Brief summary: 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 World Health Organization's (WHO) preferred product characteristics (PPC) for endectocides.

Detailed description: 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 years old (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 (in Mozambique).

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 Kenya), and safety is determined in anyone who receives the drug. Pregnant women and children under 15 kgs are not eligible for treatment.

Treatment Groups:

Two groups of clusters (three in Mozambique) will be randomized to receive (a) ivermectin in humans, (b) ivermectin in humans + livestock (only in Mozambique), or (c) albendazole control. In Mozambique, the 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, Neglected Tropical Diseases \[NTDs\]) 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 until birth. The cross-sectional survey will enroll participants of all ages one month after the last Mass Drug Administration (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 Global Technical Strategy (GTS) goals.

Eligibility criteria: 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 Kenya)
* Residents of the study area
* Parent/guardian's able to provide consent for minors
* Minors aged 12 to 15 in Kenya 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

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 (Mozambique):

* Received ivermectin less than four weeks ago
* Intention to milk or slaughter the animal for human consumption during the withdrawal period (28 days after dosing)
* Calves under 8 weeks and piglets under 6 weeks of age

Primary outcomes:
measure: To determine the safety (in humans) and efficacy of ivermectin MDA, administered to humans, or humans and livestock simultaneously (only in Mozambique) for the prevention of malaria.
timeFrame: 6 months
measure: To determine the safety (in humans) and efficacy of ivermectin MDA, administered to humans, or humans and livestock simultaneously (only in Mozambique) for the prevention of malaria.
timeFrame: 6 months
Secondary outcomes:
measure: To assess the efficacy of the intervention using complementary methods (efficacy).
timeFrame: 6 months
measure: To assess the efficacy of the intervention using complementary methods (efficacy).
timeFrame: 6 months
measure: To assess the efficacy of the intervention using complementary methods (efficacy).
timeFrame: 6 months
measure: To assess the efficacy of the intervention using complementary methods (efficacy).
timeFrame: 6 months
measure: To assess the efficacy of the intervention using complementary methods (efficacy).
timeFrame: 6 months
measure: To assess the safety of the intervention with complementary methods (safety).
timeFrame: 12 months
measure: To assess the safety of the intervention with complementary methods (safety).
timeFrame: 12 months
measure: To assess the safety of the intervention with complementary methods (safety).
timeFrame: 12 months
measure: To assess the PK of the proposed ivermectin dose/regime in its relationship with efficacy and safety outcomes (efficacy and safety).
timeFrame: 72 hours
measure: To assess the impact of ivermectin MDA at the proposed regimen on the prevalence of selected ectoparasitic NTDs (efficacy on NTDs and acceptability).
timeFrame: 6 months
measure: To assess the relationship between malaria incidence in children (under 5 years in Mozambique and 5-15 years in Kenya) and community prevalence at the peak of the malaria season.
timeFrame: 6 months
measure: To assess the relationship between malaria incidence in children (under 5 years in Mozambique and 5-15 years in Kenya) and community prevalence at the peak of the malaria season.
timeFrame: 6 months
measure: To assess the relationship between active and passive surveillance for malaria at health facility (only Mozambique).
timeFrame: 18 months
measure: To assess the accuracy for malaria diagnosis of two the different malaria rapid diagnostic tests (RDTs) used in comparison to Polymerase Chain Reaction (PCR) (Mozambique).
timeFrame: 6 months
measure: To assess the accuracy for malaria diagnosis of two the different malaria rapid diagnostic tests (RDTs) used in comparison to PCR (Mozambique).
timeFrame: 6 months
measure: To assess the accuracy for malaria diagnosis of two the different malaria rapid diagnostic tests (RDTs) used in comparison to PCR (Mozambique).
timeFrame: 6 months
Other outcomes:
measure: To assess the relationship between self-reported pregnancy status, last menstrual period (LMP), and the results of pregnancy tests in women of reproductive age participating in the study.
timeFrame: 3 months
measure: To assess all-cause and malaria-related mortality in intervention and control arms (Mozambique only).
timeFrame: 18 months
measure: To assess all-cause and malaria-related mortality in intervention and control arms (Mozambique only).
timeFrame: 18 months
measure: To estimate the prevalence of relevant CYP and P-gp variations in the target population and subjects suffering from Central Nervous System (CNS)-AEs (Mozambique only).
timeFrame: 3 months
Locations:
city: Kwale
country: Kenya
facility: KEMRI
city: Mopeia
country: Mozambique
facility: CISM
state: Zambezia
Study officials:
affiliation: Barcelona Institute of Global Health
name: Regina Rabinovich
role: PRINCIPAL_INVESTIGATOR
affiliation: Barcelona Institute of Global Health
name: Carlos Chaccour
role: PRINCIPAL_INVESTIGATOR
References: