Repeat Ivermectin Mass Drug Administrations for Control of Malaria: a Pilot Safety and Efficacy Study

Primary Objective: To determine the efficacy of repeated ivermectin mass drug administrations
(IVM MDA) (150 µg/kg), given to the population of eligible patients in enrolled villages, for
reducing the cumulative incidence of uncomplicated malaria episodes in enrolled village
children (≤ 5 years of age) over the course of the treatment.

Hypothesis: Repeated IVM MDA starting at the beginning of the rainy season will be well
tolerated and safe, and will reduce clinical malaria episodes in children by significantly
reducing malaria transmission among treated villages.

Overview Study Design: Single-blind (outcomes assessor); parallel assignment with 2 arms;
cluster-randomized control trial to determine the effect of repeated IVM MDA on malaria
transmission and clinical malaria episodes. The unit of randomization will be the village
(cluster). 8 villages total will be enrolled in two arms. The active comparator arm (4
villages) will receive a single standard MDA (IVM; 150-200 µg/kg + albendazole; 400 mg) soon
after the start of the rainy season, while the experimental arm (4 villages) will receive the
standard MDA on the same date, plus 5 more IVM MDA at 3 week intervals thereafter. The
primary endpoint will be the cumulative incidence of clinical malaria episodes in children ≤5
year of age within each village.

Sites: This study will be conducted in villages along the main east-west and north-south road
corridors in the Sud-Ouest administrative region of Burkina Faso.

Study Population: Indigenous Burkinabé from various ethnic groups (Dagara, Bobo, Lobi, Mossi,
etc.). The entire eligible population of each enrolled village will receive the MDAs,
following the standard inclusion/exclusion criteria of MDA for control of microfilaremia
caused by Wuchereria bancrofti (lymphatic filariasis; LF). Clinical incidence of malaria will
be assessed only in children living in enrolled villages who are ≤ 5 years of age, most of
whom will not have received any treatment due to the standard MDA exclusion criteria of
children < 90 cm.

Study Interventions: 2 arms: 1) Active comparator arm - single standard MDA with IVM (150
µg/kg) + albendazole (ALB;400 mg) soon after the beginning of the rainy season; 2)
Experimental arm, single standard MDA with IVM (150 µg/kg) + ALB (400 mg) plus 5 more MDA
with IVM alone (150 µg/kg) at 3 week intervals thereafter. Community health workers and
trained by local health authority of the Sud-Ouest region will perform the first MDA in both
arms with logistical assistance from the study investigators. Repeated MDAs will only occur
in the experimental-arm villages, and be performed by the study investigators.

Follow-up Procedures: Trained nurses will visit each study village each week over the course
of the study to investigate and record any adverse events or severe adverse events
communicated by the study population. They will also perform active case surveillance each
week on enrolled village children for clinical malaria episodes, defined as ≥38.0°C fever or
history of fever in the last 24 hours + positive rapid diagnostic test for Plasmodium
falciparum. Secondary measures will be collected by the nurses.

Sample Size: Assuming an 80% cumulative incidence of malaria episodes in the control arm and
an intracluster correlation coefficient of 0.02, 4 clusters are needed per arm and 69
children enrolled per cluster to detect a conservative 40% reduction in incidence in the
treatment arm with 80% power and a statistical confidence of 95%.

Safety Outcomes:

• Adverse events (seriousness, causality, expectedness)

Secondary Outcomes:

- Incidence of new P. falciparum infections acquired (molecular force-of-infection)

- Prevalence and intensity (eggs/larvae per gram of feces) of soil transmitted helminth
infections in a subset of treated patients between 6-10 years of age.

- Indoor-resting Anopheles mosquito capture rate

- Outdoor-host seeking Anopheles mosquito capture rate

- Adult mosquito age structure (parity rate) in captured mosquitoes

- Plasmodium sporozoite rate/entomological inoculation rate in captured mosquitoes

- Rate of Wuchereria bancrofti in captured mosquitoes

Inclusion Criteria:

- Residence in the study site

- Able to understand the information and willing to give consent and assent (parent or
guardian consent if study participant age is < 18 years)

Exclusion Criteria:

- Residence outside of in the study site

- Height ≤ 90 cm

- Permanent disability, serious medical illness that prevents or impedes study
participation and/or comprehension

- Pregnancy

- Breast feeding if infant is within 1 week of birth

- Known allergy to the study drugs