TY  - JOUR
AU  - Smit, Menno R
AU  - Ochomo, Eric
AU  - Aljayyoussi, Ghaith
AU  - Kwambai, Titus
AU  - Abong'o, Bernard
AU  - Bayoh, Nabie
AU  - Gimnig, John
AU  - Samuels, Aaron
AU  - Desai, Meghna
AU  - Phillips-Howard, Penelope A
AU  - Kariuki, Simon
AU  - Wang, Duolao
AU  - Ward, Steve
AU  - ter Kuile, Feiko O
PY  - 2016
DA  - 2016/11/17
TI  - 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
JO  - JMIR Res Protoc
SP  - e213
VL  - 5
IS  - 4
KW  - malaria
KW  - Plasmodium falciparum
KW  - ivermectin
KW  - dihydroartemisinin-piperaquine
KW  - Anopheles gambiae s.s.
KW  - insecticide
KW  - clinical trial
KW  - pharmacokinetics
KW  - Kenya
KW  - study protocol
AB  - 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 to 200 mcg/kg. It also shortens the lifespan of mosquitoes that feed on individuals recently treated with ivermectin. However, the effect after a 150 to 200 mcg/kg oral dose is short-lived (6 to 11 days). Modeling suggests higher doses, which 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 2000 mcg/kg (ie, 10 times the US Food and Drug Administration approved dose) are well tolerated and safe; the highest dose used for onchocerciasis is a single dose of 800 mcg/kg. Objective: The aim of this study is to determine the safety, tolerability, and efficacy of ivermectin doses of 0, 300, and 600 mcg/kg/day for 3 days, when provided with a standard 3-day course of the antimalarial dihydroartemisinin-piperaquine (DP), on mosquito survival. Methods: This is a double-blind, randomized, placebo-controlled, parallel-group, 3-arm, dose-finding trial in adults with uncomplicated malaria. Monte Carlo simulations based on pharmacokinetic modeling were performed to determine the optimum dosing regimens to be tested. Modeling showed that a 3-day regimen of 600 mcg/kg/day achieved similar median (5 to 95 percentiles) maximum drug concentrations (Cmax) of ivermectin to a single of dose of 800 mcg/kg, while increasing the median time above the lethal concentration 50% (LC50, 16 ng/mL) from 1.9 days (1.0 to 5.7) to 6.8 (3.8 to 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 versus membrane feeding assays. Results: Recruitment started July 20, 2015. Data collection was completed July 2, 2016. Unblinding and analysis will commence once the database has been completed, cleaned, and locked. Conclusions: High-dose ivermectin, if found to be safe and well tolerated, might offer a promising new tool for malaria elimination. 
SN  - 1929-0748
UR  - http://www.researchprotocols.org/2016/4/e213/
UR  - https://doi.org/10.2196/resprot.6617
UR  - http://www.ncbi.nlm.nih.gov/pubmed/27856406
DO  - 10.2196/resprot.6617
ID  - info:doi/10.2196/resprot.6617
ER  -