Efficacy and Safety of High-dose Ivermectin for Reducing Malaria Transmission: A Dose Finding Study (IVERMAL)

Efficacy and Safety of High-dose Ivermectin for Reducing Malaria Transmission: A Dose Finding Study (IVERMAL)

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. Innovative approaches are needed to continue towards elimination. Ivermectin is a broad spectrum antiparasitic endectocide widely used for the control of onchocerciasis and lymphatic filariasis at a dose of 150-200 mcg/kg. Ivermectin at this dose has a potent, but short-lived effect for 6-11 days on mosquito survival, egg-laying, and parasite sporogony. Higher doses are needed to prolong its mosquitocidal effects. Previous studies have shown ivermectin is very well tolerated and safe even up to 2,000 mcg/kg. This dose finding study will evaluate the transmission blocking effect of high-dose ivermectin to define the optimal dose for future use of ivermectin in combination with artemisinin-based combination therapy (ACT) for mass drug administration (MDA). It explores a research question of global relevance. A prolonged transmission blocking effect of ivermectin could have substantial consequences for malaria control in the next decades. The results are expected to inform national malaria control programs in malaria endemic countries, to inform WHO guidelines, and to contribute to the regulatory process.

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: dihydroartemisinin-piperaquine; Drug: placebo; Drug: ivermectin

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 2

Contacts and Locations

Study Locations

• Kenya
  • Kisumu, Kenya, 40100
    • Jaramogi Oginga Odinga Teaching and Referral Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Symptomatic, uncomplicated Plasmodium falciparum infection
• Positive malaria microscopy or malaria RDT (pLDH)
• Age: 18-50 years
• Provide written informed consent
• Agree to be able to travel to clinic on days: 1, 2, 7, 10, 14, 21, and 28

Exclusion Criteria:

• Signs or symptoms of severe malaria
• Unable to provide written informed consent
• For women: pregnancy or lactation
• Hypersensitivity to ivermectin or DP
• QTc >460 ms on ECG
• Body Mass Index (BMI) below 16 or above 32 kg/m2
• Haemoglobin concentration below 9 g/dL
• Taken ivermectin in the last month
• Taken dihydroartemisinin-piperaquine in the last 12 weeks
• Loa loa as assessed by travel history to Angola, Cameroon, Chad, Central African Republic, Congo, DR Congo, Equatorial Guinea, Ethiopia, Gabon, Nigeria and Sudan
• History and/or symptoms indicating chronic illness
• Current use of tuberculosis or anti-retroviral medication
• Previously enrolled in the same study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; Standard 3-day course of dihydroartemisinin-piperaquine, plus once a day for 3 days: placebo 600 mcg/kg/day.	Drug: dihydroartemisinin-piperaquine; Drug: placebo; Placebo for ivermectin.
Experimental: ivermectin 300 mcg/kg; Standard 3-day course of dihydroartemisinin-piperaquine, plus once a day for 3 days: ivermectin 300 mcg/kg/day and placebo 300 mcg/kg/day.	Drug: dihydroartemisinin-piperaquine; Drug: placebo; Placebo for ivermectin.; Drug: ivermectin
Experimental: ivermectin 600 mcg/kg; Standard 3-day course of dihydroartemisinin-piperaquine, plus once a day for 3 days: ivermectin 600 mcg/kg/day.	Drug: dihydroartemisinin-piperaquine; Drug: ivermectin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mosquito survival	Survival of mosquitoes at 14 days after feeding on blood taking from study participants who started the 3-day ivermectin and DP regimen 7 days earlier.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mosquito survival		Survival of mosquitoes at each day up to day 21 or 28 after each feeding experiments performed at 0, 2 day+4h, 10, 14, 21, 28 days after start of treatment.
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	Dihydroartemisinin-piperaquine is a combination drug. As dihydroartemisinin has a very short elimination time, only the AUC for the longer acting piperaquine component will be determined.	Up to day 28.
Peak plasma Concentration (Cmax) of ivermectin		Up to day 28.
Peak plasma Concentration (Cmax) of piperaquine	Dihydroartemisinin-piperaquine is a combination drug. As dihydroartemisinin has a very short elimination time, only the Cmax for the longer acting piperaquine component will be determined.	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.
Mydriasis quantitated by pupillometry		Up to day 28.

Collaborators and Investigators

• Sponsor: Liverpool School of Tropical Medicine
• Collaborators: Centers for Disease Control and Prevention; Kenya Medical Research Institute
• Investigators: Principal Investigator: Menno R. Smit, MD, MPH, Liverpool School of Tropical Medicine; Principal Investigator: Feiko ter Kuile, Prof., Liverpool School of Tropical Medicine

Publications and helpful links

General Publications

• Smit MR, Ochomo E, Aljayyoussi G, Kwambai T, Abong'o B, Bayoh N, Gimnig J, Samuels A, Desai M, Phillips-Howard PA, Kariuki S, Wang D, Ward S, Ter Kuile FO. 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. JMIR Res Protoc. 2016 Nov 17;5(4):e213. doi: 10.2196/resprot.6617.
• Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Chen T, Bousema T, Slater HC, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, Ter Kuile FO. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018 Jun;18(6):615-626. doi: 10.1016/S1473-3099(18)30163-4. Epub 2018 Mar 27.
• Smit MR, Ochomo EO, Waterhouse D, Kwambai TK, Abong'o BO, Bousema T, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ter Kuile FO, Ward SA, Aljayyoussi G. Pharmacokinetics-Pharmacodynamics of High-Dose Ivermectin with Dihydroartemisinin-Piperaquine on Mosquitocidal Activity and QT-Prolongation (IVERMAL). Clin Pharmacol Ther. 2019 Feb;105(2):388-401. doi: 10.1002/cpt.1219. Epub 2018 Oct 9.
• Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Bousema T, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, Ter Kuile FO. Human Direct Skin Feeding Versus Membrane Feeding to Assess the Mosquitocidal Efficacy of High-Dose Ivermectin (IVERMAL Trial). Clin Infect Dis. 2019 Sep 13;69(7):1112-1119. doi: 10.1093/cid/ciy1063.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: July 15, 2015
• First Submitted That Met QC Criteria: July 27, 2015
• First Posted (Estimate): July 30, 2015

Study Record Updates

• Last Update Posted (Actual): August 23, 2018
• Last Update Submitted That Met QC Criteria: August 21, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: malaria; ivermectin; dihydroartemisinin-piperaquine; plasmodium
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Ivermectin; Piperaquine; Artenimol
• Other Study ID Numbers: 14.002; 2775 (Other Identifier: Kenya Medical Research Institute); 6720 (Other Identifier: Centers for Disease Control and Prevention)