title: 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.
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 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.
authors.affiliation: Liverpool School of Tropical Medicine (LSTM), Liverpool, United Kingdom.
authors.forename: Menno R
authors.identifier: http://orcid.org/0000-0003-3405-6638
authors.initials: MR
authors.lastname: Smit
authors.affiliation: Centre for Global Health Research, Kenya Medical Research Institute (KEMRI), Kisumu, Kenya.
authors.forename: Eric
authors.identifier: http://orcid.org/0000-0002-4042-4970
authors.initials: E
authors.lastname: Ochomo
authors.affiliation: Liverpool School of Tropical Medicine (LSTM), Liverpool, United Kingdom.
authors.forename: Ghaith
authors.identifier: http://orcid.org/0000-0002-5288-4501
authors.initials: G
authors.lastname: Aljayyoussi
authors.affiliation: Centre for Global Health Research, Kenya Medical Research Institute (KEMRI), Kisumu, Kenya.|Kisumu County, Kenya Ministry of Health (MoH), Kisumu, Kenya.
authors.forename: Titus
authors.identifier: http://orcid.org/0000-0003-1930-0911
authors.initials: T
authors.lastname: Kwambai
authors.affiliation: Centre for Global Health Research, Kenya Medical Research Institute (KEMRI), Kisumu, Kenya.
authors.forename: Bernard
authors.identifier: http://orcid.org/0000-0002-5038-604X
authors.initials: B
authors.lastname: Abong'o
authors.affiliation: Division of Parasitic Diseases and Malaria, Center for Global Health, U.S. Centers for Disease Control and Prevention (CDC), Atlanta, GA, United States.
authors.forename: Nabie
authors.identifier: http://orcid.org/0000-0002-8628-6040
authors.initials: N
authors.lastname: Bayoh
authors.affiliation: Division of Parasitic Diseases and Malaria, Center for Global Health, U.S. Centers for Disease Control and Prevention (CDC), Atlanta, GA, United States.
authors.forename: John
authors.identifier: http://orcid.org/0000-0003-4218-447X
authors.initials: J
authors.lastname: Gimnig
authors.affiliation: Division of Parasitic Diseases and Malaria, Center for Global Health, U.S. Centers for Disease Control and Prevention (CDC), Atlanta, GA, United States.
authors.forename: Aaron
authors.identifier: http://orcid.org/0000-0002-8355-8186
authors.initials: A
authors.lastname: Samuels
authors.affiliation: Division of Parasitic Diseases and Malaria, Center for Global Health, U.S. Centers for Disease Control and Prevention (CDC), Atlanta, GA, United States.
authors.forename: Meghna
authors.identifier: http://orcid.org/0000-0002-6703-3355
authors.initials: M
authors.lastname: Desai
authors.affiliation: Liverpool School of Tropical Medicine (LSTM), Liverpool, United Kingdom.
authors.forename: Penelope A
authors.identifier: http://orcid.org/0000-0003-1018-116X
authors.initials: PA
authors.lastname: Phillips-Howard
authors.affiliation: Centre for Global Health Research, Kenya Medical Research Institute (KEMRI), Kisumu, Kenya.
authors.forename: Simon
authors.identifier: http://orcid.org/0000-0003-0554-1976
authors.initials: S
authors.lastname: Kariuki
authors.affiliation: Liverpool School of Tropical Medicine (LSTM), Liverpool, United Kingdom.
authors.forename: Duolao
authors.identifier: http://orcid.org/0000-0003-2788-2464
authors.initials: D
authors.lastname: Wang
authors.affiliation: Liverpool School of Tropical Medicine (LSTM), Liverpool, United Kingdom.
authors.forename: Steve
authors.identifier: http://orcid.org/0000-0003-2331-3192
authors.initials: S
authors.lastname: Ward
authors.affiliation: Liverpool School of Tropical Medicine (LSTM), Liverpool, United Kingdom.
authors.forename: Feiko O
authors.identifier: http://orcid.org/0000-0003-3663-5617
authors.initials: FO
authors.lastname: Ter Kuile
keywords: Anopheles gambiae s.s.; Kenya; Plasmodium falciparum; clinical trial; dihydroartemisinin-piperaquine; insecticide; ivermectin; malaria; pharmacokinetics; study protocol