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Lancet Infect Dis. 2018 Jun;18(6):615-626. doi: 10.1016/S1473-3099(18)30163-4. Epub 2018 Mar 27.

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.

Author information

1
Liverpool School of Tropical Medicine, Liverpool, UK. Electronic address: menno.smit@lstmed.ac.uk.
2
Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya.
3
Liverpool School of Tropical Medicine, Liverpool, UK.
4
Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya; Kenya Ministry of Health, Kisumu County, Kisumu, Kenya.
5
Radboud University Medical Center, Nijmegen, Netherlands; London School of Hygiene & Tropical Medicine, London, UK.
6
Department of Infectious Disease Epidemiology, Imperial College London, London, UK.
7
US Centers for Disease Control and Prevention, Center for Global Health, Division of Parasitic Diseases and Malaria, Atlanta, GA, USA.

Abstract

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 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 μg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment.

METHODS:

We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18-50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs ≥21 kg/m2; women: <23 vs ≥23 kg/m2), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353.

FINDINGS:

Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 μg/kg per day risk ratio [RR] 2·26, 95% CI 1·93-2·65, p<0·0001; hazard ratio [HR] 6·32, 4·61-8·67, p<0·0001; ivermectin 300 μg/kg per 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 (ivermectin 600 μg/kg per day RR 1·23, 1·01-1·50, p=0·0374; and ivermectin 300 μg/kg per day 1·21, 1·01-1·44, p=0·0337). Five (11%) of 45 patients receiving ivermectin 600 μg/kg per day, two (4%) of 48 patients receiving ivermectin 300 μg/kg per day, and none of 46 patients receiving placebo had one or more treatment-related adverse events.

INTERPRETATION:

Ivermectin at both doses assessed was well tolerated and reduced mosquito survival for at least 28 days after treatment. Ivermectin 300 μg/kg per day for 3 days provided a good balance between efficacy and tolerability, and this drug shows promise as a potential new tool for malaria elimination.

FUNDING:

Malaria Eradication Scientific Alliance (MESA) and US Centers for Disease Control and Prevention (CDC).

PMID:
29602751
DOI:
10.1016/S1473-3099(18)30163-4
[Indexed for MEDLINE]
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