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

Study Overview
=================
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.

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

Conditions
-----------------
Malaria

Intervention / Treatment
-----------------
* Drug: ivermectin
* Drug: placebo
* Drug: dihydroartemisinin-piperaquine


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
plasmodium, malaria, dihydroartemisinin-piperaquine, ivermectin