Short Title: IVERMAL study

 

Background and rationale: In western Kenya the prevalence of malaria in <5 year olds has fallen from 70% in 1997 to 40% in 2008, where it has now stagnated. Innovative approaches are needed to continue towards elimination. Ivermectin is a broad spectrum antiparasitic endectocide widely used for the control of onchocerciasis and lymphatic filariasis at a dose of 150-200 mcg/kg. Ivermectin at this dose has a potent, but short-lived effect for 6-11 days on mosquito survival, egg-laying, and parasite sporogony. Higher doses are needed to prolong its mosquitocidal effects. Regulatory studies have shown ivermectin is very well tolerated and safe even up to 2,000 mcg/kg. We will conduct dose finding studies to evaluate the transmission blocking effect of high-dose ivermectin to define the optimal dose for future use of ivermectin in combination with artemisinin-based combination therapy (ACT) for mass drug administration (MDA) for malaria in Kenya. This study explores a research question of global relevance. A prolonged transmission blocking effect of ivermectin could have substantial consequences for malaria control in the next decades. We expect the results to inform the national regulator in Kenya, national malaria control programs in malaria endemic countries, to inform WHO guidelines, and to contribute to the regulatory process.

 

Primary objective: To determine the safety and efficacy of ivermectin 0, 300, 600 mcg/kg/day for 3 days, when provided with a standard 3-day course of dihydroartemisinin-piperaquine (DP) for uncomplicated malaria, on 14-day mosquito survival after feeding experiment performed at 7 days after treatment.

Hypothesis: High dose ivermectin at 600 mcg/kg daily for 3 days is well tolerated and safe and will have a longer lasting mosquitocidal effect and a greater potential impact on malaria transmission.

 

Overview Study Design: Double-blind placebo-controlled, parallel-group, 3-arm, superiority trial to determine the effect of different doses of ivermectin on mosquito survival. The unit of randomization will be the patient, and the unit of analysis will be the mosquito. The primary endpoint will be mosquito survival 14 days after a feed on blood from a patient who has started ivermectin 7 days earlier (i.e. about 5 days after the last dose of ivermectin with a 3-day regimen administering ivermectin at 0, 24, and 48 hours [days 0, 1 and 2]). Because mosquito feeding involves approximately 100 mosquitoes per feed, the study will use a cluster randomized design with the patient as the cluster unit. The study will have a nested rich pharmacokinetic component in the first 12 patients per study arm, and a sparse sampling population pharmacokinetic component in the remaining patients. The study will also compare the potential modifying effect of the method of feeding by comparing the mosquitocidal effect of ivermectin with membrane versus direct skin feeding.

Sites: The study will be conducted in the Provincial Hospital in Kisumu, western Kenya recently renamed to the Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH). Dependent on the recruitment rate, enrolment will be expanded to up to 3 other hospitals in Kisumu and Siaya counties.

Study Population: Adults with uncomplicated falciparum malaria attending out-patient clinics.

 

Study Interventions: 1. Dihydroartemisinin-piperaquine (DP) alone, DP plus ivermectin 0 mcg/kg/day for 3 days (“placebo” arm); 2. DP plus ivermectin 300 mcg/kg/day plus 300 mcg/kg/day ivermectin-placebo for 3 days (“300 mcg/kg” arm); 3. DP plus ivermectin 600 mcg/kg/day (“600 mcg/kg” arm).

Outcome Measures: Primary efficacy outcome: Mosquito survival: Survival of mosquitoes at 14 days after feeding on blood taking from study participants who started the 3-day ivermectin and DP regimen 7 days earlier. Primary safety outcome measure: Mydriasis quantitated by pupillometry. Key secondary safety outcome: QTc(F) prolongation by ECG.

 

Follow-up procedures: Treatment visits on day 1 and 2. Post-treatment follow-up at day 2 (+4 hours after last dose of ivermectin), days 7, 10, 14, 21, and 28.

Sample size: Main trial: 141 participants (47 per arm); Rich pharmacokinetic study: 36 participants (12 per arm); direct feeding vs membrane feeding 27 participants (9 per arm, day 7 post ivermectin only).

 

Data Analysis: Primary outcomes will be summarised by number (%) of events and analysed using a Generalized Estimating Equations (GEE) model with binomial distribution and log link function that includes treatment as a single predictor taking the cluster design into account, which will generate risk ratios together with their 95% confidence intervals of having a primary endpoint between two active dose groups and the placebo group. Exchangeable covariance structure will be used. The primary endpoint analysis will be based on the ITT population.

 

Partner institutions: KEMRI and CDC Collaboration, Kisumu, western Kenya; Kenya Ministry of Health, Liverpool School of Tropical Medicine; US Centers for Disease Control and Prevention

 

Funding: Malaria Eradication Scientific Alliance (MESA) which is funded through a grant from the Bill and Melinda Gates Foundation.