Protocol No: ECCT/19/12/01 Date of Protocol: 14-10-2019

Study Title:

Mosquitocidal effect and pharmacokinetics of different ivermectin dose regimens in preparation for BOHEMIA cluster randomized controlled trial.

Study Objectives:

. Objectives

 Primary objective

  1. Determine cumulative mosquito mortality up to 28 days post blood feeding on volunteers who have been treated with each of the following treatments (at D0+4h, D7, D10, D14, D21, and D28 post treatment):

A.      Single oral dose of 400 mcg/Kg of ivermectin given once;

B.      Single oral dose of 300 mcg/Kg of ivermectin given on 3 consecutive days;

C.      Single oral dose of albendazole 400 mg - proposed comparator for BOHEMIA cRCT;

D.      No treatment (control).

 Secondary objective

Describe the pharmacokinetics of ivermectin during the first 7 days post treatment for each of the following IVM dose regimens: 

A. Ivermectin 400 mcg/Kg of ivermectin given once;

B. Ivermectin 300 mcg/Kg of ivermectin given on 3 consecutive days

Laymans Summary:
Lay Title

Evaluation of different deworming drugs to kill mosquitoes.

    What is the problem/background?

Ivermectin is a drug used for deworming often given to communities to prevent elephantiasis (tende). We also know that mosquitoes die after they bite someone treated with ivermectin. Currently, treating entire communities with ivermectin is being considered as a new way to kill malaria mosquitoes and so reduce malaria. We are not sure what is the best dose of ivermectin that should be used for this purpose. We want to carefully compare two different doses and see which one is better.

    What questions are we trying to answer?

a)       How do mosquitoes die if people take ivermectin once (400mcg/Kg) compared to three times (300mcg/kg once a day for 3 days)?

b)      Is the amount of ivermectin in the blood different, if people take the treatment once, or three times for three days?

c)       Do mosquitoes die if they feed on someone treated with albendazole?

Where is the study taking place, how many people does it involve and how are they selected?

The study will take place at KEMRI Centre for Geographic Medical Research -Coast (KEMRI CGMR-C) in Kilifi, Kenya. A total of 36 healthy adult (18-45 years old) volunteers from Ngerenya will be asked to participate in the study. Residents of Ngerenya will be told about the project through the community liaison group (CLG) of KEMRI CGMR-C. The study will be presented at baraza community meetings and participants will be invited to participate by community health workers and field workers. During the baraza, the study will be explained. Those interested in participating will provide their contact details o they can be informed when to come to the dispensary for screening. Before screening, all volunteers will be explained the study procedures by an experienced field worker and given an informed consent form and information sheet (ICF) in a language they understand. If a volunteer agrees to participate, clinical staff will do a physical examination and as a few questions to see if they can participate in the study. If the participant is a woman they will be asked about her family planning. A trained nurse will withdraw a small amount of venous blood (9ml - around 2 teaspoons) to check if the person is healthy enough to participate. A malaria test  will also be done. Within a few days the participants will receive their test results.  If anyone is found to have a health problem they will be referred to the closest and most appropriate government health facility.

    What does the study involve for those who are in it?

We will screen up to 200 volunteers from the Ngerenya community until a total of 36 participants are found. We will recruit 36 participants, of which 6 will be a reserve group and will only be called  to participate if another participant leaves the study.  The other 30 participants will be asked to take one of these treatments orally: 1) ivermectin once; 2) ivermectin three times; 3) albendazole once;  or 4) nothing. Participants will be told which group they are in and given a study calendar with days and times they are to visit KEMRI CGMR-C in Kilifi. Calendars will also be shared with field workers who will remind the participant before each visit. Participants will be asked to come to KEMRI CGMR-C one day before starting the study to check if they are still eligible. If the participant is taking ivermectin they will be asked to stay overnight for two nights during which they will be given a comfortable bed and meals at the Pwani University Resource Centre (PURC) facilities. At PURC, participants will be asked to stay indoors and will be in the presence of a study nurse at all times. Participants will receive their treatment in form of oral tablets, followed by breakfast. Participants who receive ivermectin will be asked to allow the study nurse to insert a cannula in their arm so it is easier to withdraw blood. On this day a nurse will withdraw between 1 and 2 teaspoons of blood every hour (until 10 hours post treatment) from the participants who had received ivermectin. Other participants will only be required to withdraw blood once that day (1 teaspoon) and will not be asked to stay overnight. Depending on the group the participant has been assigned to s/he will be asked to return to KEMRI CGMR-C on the following days post-treatment 1, 2, 3, 4, 7, 10, 14, 21, and 28 days. On each visit the participant will be asked to withdraw 1-2 teaspoons of blood from their vein, those who took ivermectin will also be asked to allow a nurse to prick their finger to obtain 8 drops of blood. The blood taken from the participants will be used for two purposes:  to measure how much ivermectin is in their blood and to feed mosquitoes and see how these die after feeding on the blood. Participants will never be in contact with mosquitoes. The mosquitoes will be fed in the laboratory. During the 28 days after taking the medication, participants will be offered medical care by the study clinician. Participation will be completely voluntary and participants will be allowed to leave the study at any time without having to explain why. If a participant is excluded or chooses to leave, a participant from the reserve group will be replace them. If everyone in the reserve group is called to participate and more participants are needed, the study team will return to Ngerenya and will recruit additional participants to complete the study.

    What are the benefits and risks/costs of the study for those involved?

Participants will not have any direct benefit from participating in the study. In the long term there may be benefits for the community, as the study will contribute help develop a new way of controlling malaria mosquitoes  that may one day be used in Kenya. However, participants will benefit from being dewormed with ivermectin or albendazole. The control group as well as the participants from the reserve group who were not called to participate, will not be dewormed during the study period; however, they will be offered albendazole at the end of the 28-day follow-up period so they may also have the same benefit. Both ivermectin and albendazole are licensed in Kenya and regularly used. Both medications are usually well tolerated with  rare side-effects. However, there is a risk the drugs may not be well tolerated in participants with certain health problems, for this reason we will check if  participants are healthy enough before recruiting them. Albendazole is licensed in Kenya and causes very few side-effects, however sometimes people may get a skin rash, feel nausea, or have diarrhea. Ivermectin at the dose we want to test (400mcg/Kg) is not approved in Kenya, however this dose is approved in European countries against tende (filariasis). Ivermectin taken on three consecutive days is also not currently licensed in Kenya, however, other studies done in Kenya found this dose to be safe. Ivermectin can sometimes cause temporary side-effects such as blurry vision, tiredness, headache, tremors, dizziness, loss of appetite and stomach discomfort. Those involved in the study may suffer mild discomfort during finger pricks, inserting of the venous cannula and the withdrawing blood as there is a risk of bruising and a slight risk of infection caused by the procedure. Blood withdrawals will not exceed the volumes recommended by the Pharmacy and Poisons Board (PPB) of Kenya. Participants will be compensated for their travel and out-of-pocket expenditure according to existing KEMRI-CGMR-C guidelines.

    How will the study benefit society? 

The project will benefit society by informing the design of a clinical trial investigating the mass drug administration of ivermectin as new way to control malaria mosquitoes. The development of this intervention may contribute towards malaria elimination.

    When does the study start and finish?

The study is planned to start once ethical approval is obtained and will be completed within 10 months post approval.

Abstract of Study:

Malaria continues to claim the lives of more than 435’000 people each year, largely in Africa1.  Its elimination is not guaranteed without the development of new control strategies. Ivermectin is a well-known anti-parasitic drug which is being evaluated as a complementary malaria vector control tool. In a previous field randomized controlled trial (RCT) conducted in Burkina Faso (RIMDAMAL), investigating mass drug administration (MDA) of ivermectin (IVM), community members were treated using a single dose of 200mcg/Kg every three weeks for six rounds, leading to a 20% reduction in clinical malaria in children. Despite no indication of increased harm by the repeated 200mcg/kg doses, six rounds of treatment throughout the rainy season may not be easily implementable by control programmes. A dose-finding study conducted in Kenya (IVERMAL) determined the mosquito-killing effect and safety of two alternative dose regimens given on three consecutive days: 300 mcg/kg and 600 mcg/kg. Both three-day regimens resulted in a significant increase in mosquito mortality lasting 21 to 28 days after the last drug intake. The 300mcg/Kg x 3 regimen is not being evaluated for use in MDA programs for malaria control. However, although the dose regimen was found to have a good safety profile, the feasibility of administering three consecutive doses every month and its acceptability by the community may negatively impact adherence to the intervention. The BOHEMIA trial (Broad One-Health Endectocide-based Malaria Intervention in Africa) aims at evaluating MDA of IVM to reduce malaria transmission in Eastern and Southern Africa. The BOHEMIA consortium proposes using three rounds of a single dose of 400mcg/Kg IVM (currently included in the EU label for MDA) based on available pharmacokinetic data and mathematical modelling of plasma levels expected to kill mosquitoes. A direct comparison of this dose regimen and 300mcg/Kg x 3 regimen with entomological and pharmacokinetic outcomes has not yet been done. The current protocol proposes an open-label RCT to support the dose regimen choice of the BOHEMIA trial by comparing the pharmacokinetics (PK) and mosquitocidal effect of single dose 300mcg/Kg IVM on three consecutive days to single dose 400mcg/Kg IVM on one day as well as albendazole as it is being considered as potential comparator. For this purpose, the trial will randomize a total of 30 healthy individuals from Ngerenya to receive one of the four following treatments (2:1:1:1):  1) Single dose oral IVM 400 mcg/Kg (12 participants); 2) Single dose oral IVM 300 mcg/Kg given on three consecutive days (six participants); 3) single dose oral 400mg albendazole (six participants); and 4) no treatment (six participants). Participants will be followed-up up to 28 days, depending on their treatment allocation, during which blood samples will be drawn at regular intervals and its mosquitocidal effect will be assessed. The same blood will be sent to University of Basel in Switzerland for determining the PK of IVM using standard and novel methodologies that will be used during the BOHEMIA field trial.