Efficacy and safety of high‐dose ivermectin in reducing malaria transmission (IVERMAL)
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.
The secondary objectives of the study are (1) to determine the effect of different doses of ivermectin on oocyst development; (2) to determine the pharmacokinetic profile of the different ivermectin regimens; (3) to determine if ivermectin interacts with the pharmacokinetics of piperaquine; (4) to determine whether the addition of ivermectin to DP affects the clinical and parasitological response to DP treatment; (5) to determine the role of genetic variants of CYP3A4 activity in metabolizing ivermectin; and (6) to determine the effect of direct feeding versus membrane feeding on mosquito survival.
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). Modelling 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.
Doses: ivermectin 300 mcg/kg and ivermectin 600 mcg/kg
- Primary outcome: mosquito survival at 14 days after feeding on blood taking from study participants who started the 3-day ivermectin and DP regimen 7 days earlier
- Secondary outcomes: Mosquito survival at each day up to day 21 or 28 after each feeding experiments, number of patients with malaria clinical and parasitological treatment response up to day 28, area under the plasma concentration versus time curve (AUC) of ivermectin up to day 28, area under the plasma concentration versus time curve (AUC) of piperaquine up to day 28, peak plasma concentration (Cmax) of ivermectin up to day 28, peak plasma concentration (Cmax) of piperaquine up to day 28, tolerability as assessed by adverse events reported in a general toxicity questionnaire up to day 28, CNS adverse events up to day 28, serious adverse events up to day 28, haemoglobin concentrations up to day 28, QTc interval at 52 hours, and mydriasis quantitated by pupillometry up to day 28.
Clinicaltrials.gov ID: NCT02511353
Substantial progress has been made in malaria control through the use of insecticide-treated nets (ITNs), intermittent preventive treatment, indoor residual spraying (IRS) and case management with artemisinin combination therapy (ACT). In western Kenya the prevalence of malaria in <5-year-olds has fallen from 70% in 1997 to 40% in 2008, where it has now stagnated, despite sustained interventions. Innovative approaches are needed to interrupt transmission. Ivermectin (IVM) is a broad spectrum antiparasitic endectocide widely used for the control of onchocerciasis and lymphatic filariasis. It is also active against a range of exoparasites and has potent mosquitocidal properties resulting in a high mortality of Anopheles mosquitoes taking blood meals from humans recently treated with IVM. This makes IVM a potent novel tool for malaria transmission reduction strategies including for mass drug administration (MDA) when provided in combination with ACTs. It has the potential to target outdoor feeding mosquitoes that escape the effects of ITNs or IRS, and kill vectors that are resistant to pyrethroids and other insecticides used for IRS. The standard dose used for onchocerciasis and lymphatic filariasis MDA is 150‐200 mcg/kg. IVM at this dose has a potent, but short‐lived effect for 6‐11 days on mosquito survival and parasite sporogony. Higher doses are needed to prolong the mosquitocidal period. Regulatory studies have shown IVM is very well tolerated and safe even up to 2,000 mcg/kg. A dose of 400 mcg/kg is used for head lice and for MDA against W. Bancrofti in the Southwest Pacific; 800 mcg/kg was successfully used in clinical studies in Africa involving 750 individuals with onchocerciasis. Combined clinical, entomological, and laboratory investigations of these higher doses are now required. We will conduct dose-finding studies to evaluate the mosquitocidal properties of high‐dose IVM to define the optimal dose for future use of IVM in combination with ACTs for MDA for malaria in Kenya. Primary objective: To determine the effect of single doses of 0, 200, 400 and 800 mcg/kg of IVM on day‐10 mosquito survival, when provided with dihydroartemisinin-piperaquine (DHP) for uncomplicated malaria. Secondary objectives: a) To determine the safety of single doses of 200, 400 and 800 mcg/kg of IVM, in combination with DHP, by assessing the occurrence of adverse events in each study arm in comparison with adverse events with DHP plus placebo. b) To determine the effect of single doses of 0, 200, 400 and 800 mcg/kg of IVM with DHP on vector malaria transmission capacity measured by sporozoite rates in malaria vectors.
Hospital outpatient‐based, double‐blind, randomized placebo-controlled trial. 164 nonpregnant adults with uncomplicated malaria will be allocated to one of 4 arms (41/arm): DHP plus either 0, 200, 400, or 800 mcg/kg IVM. Mosquitoes will be fed through membrane feeding on patients’ blood taken at 0, 1, 3, 7, 10, 14, 21, and 28 days post‐IVM; mosquito mortality and parasite sporogony will be measured. Primary outcome: comparison of mosquito survival. The studies benefit from parallel membrane feeding studies on the effect of low‐dose primaquine on malaria transmissibility.
This study explores the research question of global relevance. Should IVM impact on malaria transmission, it could have substantial consequences for malaria control in the next decades. We expect the results to inform the national regulator in Kenya, national malaria control programs in malaria-endemic countries, to inform WHO guidelines, and to contribute to the regulatory process. This is a collaboration between the Kenya Medical Research Institute, the Kenyan Ministry of Health, the US Centers for Disease Control and Prevention, PATH‐MACEPA, and the Liverpool School of Tropical Medicine.