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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

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Smit, Menno ORCID: https://orcid.org/0000-0003-3405-6638, Ochomo, Eric O, Aljayyoussi, Ghaith, Kwambai, Titus K, Abong'o, Bernard, Chen, Tao ORCID: https://orcid.org/0000-0002-5489-6450, Bousema, Teun, Slater, Hannah C, Waterhouse, David, Bayoh, Nabie M, Gimnig, John E, Samuels, Aaron M, Desai, Meghna R, Phillips-Howard, Penelope ORCID: https://orcid.org/0000-0003-1018-116X, Kariuki, Simon K, Wang, Duolao ORCID: https://orcid.org/0000-0003-2788-2464, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 and terKuile, Feiko ORCID: https://orcid.org/0000-0003-3663-5617 (2018) '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'. Lancet Infectious Diseases, Vol 18, Issue 6, pp. 615-626.

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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 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).

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
WA Public Health > Health Problems of Special Population Groups > WA 395 Health in developing countries
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI): https://doi.org/10.1016/S1473-3099(18)30163-4
Depositing User: Stacy Murtagh
Date Deposited: 28 Mar 2018 14:53
Last Modified: 27 Sep 2018 01:02
URI: http://archive.lstmed.ac.uk/id/eprint/8245

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