Clinical trial NCT02511353: Efficacy and Safety of High-dose Ivermectin for Reducing Malaria Transmission: A Dose Finding Study
Official title: Efficacy and Safety of High-dose Ivermectin for Reducing Malaria Transmission: A Dose Finding Study (IVERMAL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malaria
Keywords: malaria
plasmodium
dihydroartemisinin-piperaquine
ivermectin
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Kenya Medical Research Institute
name: Centers for Disease Control and Prevention
First posted: 2015-07-30
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Mosquito survival
timeFrame: 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 outcomes:
measure: Mosquito survival
timeFrame: 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.
measure: Number of patients with malaria clinical and parasitological treatment response
timeFrame: Up to day 28.
measure: Area under the plasma concentration versus time curve (AUC) of ivermectin
timeFrame: Up to day 28.
measure: Area under the plasma concentration versus time curve (AUC) of piperaquine
timeFrame: Up to day 28.
measure: Peak plasma Concentration (Cmax) of ivermectin
timeFrame: Up to day 28.
measure: Peak plasma Concentration (Cmax) of piperaquine
timeFrame: Up to day 28.
measure: Tolerability as assessed by adverse events reported in a general toxicity questionnaire
timeFrame: Up to day 28.
measure: CNS adverse events
timeFrame: Up to day 28.
measure: Serious adverse events
timeFrame: Up to day 28.
measure: Haemoglobin concentrations
timeFrame: Up to day 28.
measure: QTc interval
timeFrame: At 52 hours.
measure: Mydriasis quantitated by pupillometry
timeFrame: Up to day 28.
Other outcomes:
Locations:
city: Kisumu
country: Kenya
facility: Jaramogi Oginga Odinga Teaching and Referral Hospital
Study officials:
affiliation: Liverpool School of Tropical Medicine
name: Menno R. Smit, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Liverpool School of Tropical Medicine
name: Feiko ter Kuile, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.