Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial

Background

Ivermectin is being considered for mass-drug-administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single-doses of 150-200 mcg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal-effect (<7 days). Ivermectin is well-tolerated up to 2,000 mcg/kg. Multi-day regimens of high-doses of ivermectin could generate longer mosquitocidal-effects required for malaria elimination.

Methods

Randomized, double-blind, placebo-controlled trial comparing the safety, tolerability, and efficacy of 3-day ivermectin 0, 300, or 600 mcg/kg/day, co-administered with dihydroartemisinin-piperaquine, in randomly assigned (1:1:1) adults with uncomplicated malaria in Kenya. Randomisation lists were computer-generated. Sequentially numbered, opaque envelopes concealed allocation. Patients’ blood taken on post-treatment days 0, 2+4h (Cmax), 7, 10, 14, 21, and 28, was fed to laboratory-reared Anopheles gambiae s.s.; mosquito survival was assessed daily for 28-days post-feeding. The primary outcome was 14-day-cumulative-mortality of mosquitoes fed 7-days post-treatment; secondary outcomes included 14-day-survival-time of mosquitoes fed at each post-treatment visit. Safety outcomes included pupil-diameter, QT-interval, and adverse events. Analyses were by intention-to-treat. Ivermectin’s effect on malaria transmission was modelled. Trial registration:ClinicalTrials.gov-NCT02511353.

Findings

Between 20-Jul-2015 and 07-May-2016, 141 patients were randomized to ivermectin 600 mcg/kg/day (n=47), 300 mcg/kg/day (n=48), or placebo (n=46). 128 patients (90.8%) attended the primary outcome visit 7-days post-treatment. Compared to placebo, ivermectin was associated with higher 14-day-post-feeding mosquito mortality when fed on blood taken 7-days-post-treatment (600 mcg/kg/day: risk ratio [RR] 2.26, 95% confidence interval [1.93-2.65], p<0.0001; hazard ratio [HR] 6.32 [4.61-8.67], p<0.0001; 300 mcg/kg/day: RR=2.18 [1.86-2.57], p<0.0001; HR=4.21 [3.06-5.79], p<0.0001). Mosquito mortality remained significantly increased 28-days-post-treatment. The incidence of related adverse events were: 5/45 (11%), 2/48 (4%), and 0/46 (0%) with 600, 300, and 0 mcg/kg/day. Ivermectin didn’t modify piperaquine’s QT-prolonging-effect. Modelling predicted that adding 3-day ivermectin 600 or 300 mcg/kg/day to mass drug administration with dihydroartemisinin-piperaquine enhances malaria prevalence reduction by an additional 56% (600 mcg) and 44% (300 mcg) in low prevalence areas (10%), and 61% (600 mcg) and 54% (300 mcg) in high prevalence areas (30%).

Interpretation

3-day ivermectin at both 600 and 300 mcg/kg/day is well tolerated and reduces mosquito survival for at least 28-days-post-treatment. The latter regimen would provide a good balance between efficacy and tolerability. Ivermectin shows promise as a potential new tool for malaria elimination.

Funding

The Malaria Eradication Scientific Alliance (MESA) and U.S. Centers for Disease Control and Prevention (CDC).