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

BackgroundInnovative 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.ObjectiveThe 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.MethodsThis 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.ResultsRecruitment 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.ConclusionsHigh-dose ivermectin, if found to be safe and well tolerated, might offer a promising new tool for malaria elimination.

Pharmacokinetics‐Pharmacodynamics of High‐Dose Ivermectin with Dihydroartemisinin‐Piperaquine on Mosquitocidal Activity and QT‐Prolongation (IVERMAL)

“…The 28‐day exposure‐effect relationship exceeded the prediction from the pretrial PD simulation, which estimated an effect‐duration of only 7 days . The simulation was based on previously reported 7‐day LC 50 value of ivermectin of 15.9 ng/mL, whereas, in the current trial, the 7‐day LC 50 was 3.4 ng/mL.…”

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

“…Several strategies have been proposed to overcome the relative short half-life of ivermectin and increase its potential impact on malaria transmission. These include using higher doses than approved for NTDs 17 , using repeated doses at regular intervals 18 or developing slow-release formulations 8 , 19 . The comparative advantages and disadvantages of each strategy has been described elsewhere 20 .…”

Systemic and Target-Site Pharmacokinetics of Antiparasitic Agents

“…The authors developed a population PK model and discovered that a AUC for a dosing interval of the enantiomer L-EFO of > 800 h µmol/L was required for cure [20]. Repurposing of IVM for mass administration to tackle malaria has been proposed, as IVM has been shown to kill Anopheles mosquitos feeding on human blood for 28 days after treatment [21]. The PK/PD properties of IVM have been investigated in a recent trial for its mosquitocidal activity and this analysis showed a time-independent relationship of IVM [22].…”