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Efficacy and Safety of High-Dose Ivermectin for Reducing Malaria Transmission (IVERMAL): Protocol for a Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Trial in Western Kenya

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Smit, Menno ORCID: https://orcid.org/0000-0003-3405-6638, Ochomo, Eric, Aljayyoussi, Ghaith, Kwambai, Titus, Abongo, Bernard, Bayoh, Nabie, Gimnig, John E, Samuels, Aaron, Desai, Meghna, Phillips-Howard, Penelope ORCID: https://orcid.org/0000-0003-1018-116X, Kariuki, Simon, 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 (2016) 'Efficacy and Safety of High-Dose Ivermectin for Reducing Malaria Transmission (IVERMAL): Protocol for a Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Trial in Western Kenya'. Journal of Medical Internet Research, Vol 5, Issue 4, e213.

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Abstract

Background:
Innovative approaches are needed to complement existing tools for malaria elimination. Ivermectin is a broad spectrum antiparasitic endectocide clinically used for onchocerciasis and lymphatic filariasis control at single doses of 150‐200 mcg/kg. It also shortens the lifespan of mosquitoes that feed on individuals recently treated with ivermectin. However, the effect after a 150‐200 mcg/kg oral dose is short‐lived (6‐11 days). Modelling suggests higher doses, that prolong the mosquitocidal effects, are needed to make a significant contribution to malaria elimination. Ivermectin has a wide therapeutic index and previous studies have shown doses up to 2,000 mcg/kg, i.e. 10x the US Food and Drug Administration approved dose, are well tolerated and safe; the highest dose used for onchocerciasis is single‐dose 800 mcg/kg.
Objective:
To determine the safety, tolerability, and efficacy of ivermectin 0, 300, 600 mcg/kg/day for 3 days, when provided with a standard 3‐day course of the antimalarial dihydroartemisinin‐piperaquine, on mosquito survival.
Methods:
This is a double‐blind, randomised, placebo‐controlled, parallel‐group, 3‐arm, dose‐finding trial in adults with uncomplicated malaria. Monte Carlo simulations based on pharmacokinetic modelling were performed to determine the optimum dosing regimens to be tested. Modelling showed that a 3‐day regimen of 600 mcg/kg/day achieves similar median (5‐95 percentiles) Cmax concentrations of ivermectin to single‐dose of 800 mcg/kg, while increasing the median time above the LC50 (16 ng/mL) from 1.9 days (1.0‐5.7) to 6.8 (3.8‐13.4) days. The 300 mcg/kg/day dose was chosen at 50% of the higher dose to allow evaluation of the dose response. Mosquito survival will be assessed daily up to 28 days in laboratory‐reared Anopheles gambiae s.s. populations fed on patients’ blood taken at days 0, 2 (Cmax), 7 (primary outcome), 10, 14, 21, and 28 after the start of treatment. Safety outcomes include QT‐prolongation and mydriasis. The trial will be conducted in 6 health facilities in western Kenya and requires a sample size of 141 participants (47 per arm). Sub‐studies include: (1) rich pharmacokinetics and (2) direct skin vs membrane feeding assays.
Results:
Recruitment started July 20th, 2015. Data collection was completed on July 2nd, 2016. Unblinding and analysis will commence once the database has been completed, cleaned and locked.
Discussion:
High‐dose ivermectin, if found to be safe and well tolerated, might offer a promising new tool for malaria elimination.
Trial registration:
ClinicalTrials.gov: NCT02511353 (July 15, 2015).

Item Type: Article
Uncontrolled Keywords: Malaria, Plasmodium falciparum, ivermectin, dihydroartemisinin‐piperaquine, Anopheles gambiae s.s., insecticide, clinical trial, pharmacokinetics, Kenya, study protocol
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 250 Anti-infective agents (General)
WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI): https://doi.org/10.2196/resprot.6617
Depositing User: Helen Wong
Date Deposited: 21 Oct 2016 13:25
Last Modified: 13 Sep 2019 14:16
URI: https://archive.lstmed.ac.uk/id/eprint/6293

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