Study to Assess Efficacy of Artemether-lumefantrine Prophylaxis Against Forest Malaria in Cambodia (PAL_Cambodia)

Study Overview
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Brief Summary
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In the Greater Mekong Subregion (GMS) adults are at highest risk for malaria. The most relevant disease vectors bite during daytime and outdoors which makes forest work a high-risk activity for malaria. The absence of effective vector control strategies and limited periods of exposure during forest visits suggest that chemoprophylaxis could be an appropriate strategy to protect forest workers against malaria. The investigators propose the use of Artemether-lumefantrine (AL), a drug whose efficacy remains high in the GMS, unlike, for example DHA/piperaquine [20]. The proposed study will help to assess the efficacy and feasibility of prophylaxis to prevent malaria in forest workers, help to identify the optimal regimen, and predict its efficacy in reducing overall transmission. The proposed study is a critical step for future use of chemoprophylaxis to protect forest workers in the GMS against malaria.

Detailed Description
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Summary of trial design An open-label randomised trial among forest goers comparing the ACT AL with a multivitamin with no antimalarial activity to evaluate the efficacy of prophylaxis, and to better understand high risk groups and locations of malaria transmission. Artemether-lumefantrine prophylaxis trial The study of AL versus a multivitamin will be a two-arm randomised open label comparative study. Laboratory assessments of malaria infection at baseline and days 28, 56, and 84 will be performed blind to treatment allocation and incidence of clinical cases during follow-up will be recorded. Activities/outcomes The main activity proposed is an in vivo clinical assessment of prophylaxis to prevent malaria in 4400 participant episodes in 50 villages in Stung Treng and Pursat Provinces, Cambodia. The subjects will be randomized in a one-to-one ratio between the ACT AL and a multivitamin preparation with no antimalarial activity. The study sites have been chosen based on current information on incidence of malaria, known predominance of malaria among forest goers, presence of an established clinical research programme and feasibility to perform the proposed research activities. Efficacy of AL ACT will be assessed through follow up visits every 28 days during a course of prophylaxis when temperature, symptom questionnaires, brief physical examinations, and malaria parasite PCR, lumefantrine levels, and, in selected individuals, parasite genetics will be performed. Episodes of confirmed clinical malaria among study participants at any time point between enrolment and follow-up will also be recorded. All the organisations in this collaboration will work closely with local counterparts including the National Malaria Control Programmes (NMCPs), non-governmental and other relevant organisations. Training is an integral part of this collaborative working relationship, and the building of local research capacity is an essential component of all research plans. All research-related activities, from study design, planning, implementation through to analysis and writing of reports will be performed jointly with local counterparts. Both on-the-job training and formal training will be provided when needed, in particular for Good Clinical Practice (GCP) skills. The close interaction between WHO and its regional offices will ensure that new knowledge is disseminated efficiently and effectively throughout the region. Study duration The recruitment phase of the study is expected to last 12 months following the intended start of recruitment in July 2019. Training and community sensitization will precede study execution for 3 months. Data management and analysis, sample analysis (PCR, parasite genetics, lumefantrine levels), mathematical modelling and report writing are expected to take about 5 months. Therefore, the total time to complete the study will be about 20 months. Funder: Global Fund Regional Component of the Regional Artemisinin-resistance Initiative (RAI2E) Grant

Official Title
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An Open-label Individually Randomised Controlled Trial to Assess the Efficacy of Artemether-lumefantrine Prophylaxis for Malaria Among Forest Goers in Cambodia

Conditions
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Malaria

Intervention / Treatment
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* Drug: Artemether-lumefantrine
* Dietary Supplement: Multivitamin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male or female, adults aged between 16 and 65 years. Planning to travel to the forest within the next 72 hours and stay overnight. Written informed consent. Willingness and ability of the participants to comply with the study protocol for the duration of the study. Exclusion criteria For females: known pregnancy or breast feeding Participants who have received artemisinin or a derivative or an artemisinin-containing combination therapy (ACT) within the previous 7 days. History of allergy or known contraindication to artemisinins, lumefantrine or multivitamins Documented or claimed history of cardiac conduction problems Severe vomiting or diarrhoea Signs/symptoms of clinical malaria (febrile or history of fever in the previous 24 hours) confirmed by RDT.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACT arm<br>Artemether-lumefantrine (AL) x 3 days followed by 1 day per week | Drug: Artemether-lumefantrine<br>* One tablet AL contains 20 mg artemether and 120 mg lumefantrine The prophylaxis will start with a 3-day course of twice daily AL. This will be followed by 2 doses 8 hours apart on one day per week for up to 3 28-35 day consecutive follow-up periods and for 4 weeks after leaving the forest.<br>|
| Active Comparator: Multivitamin arm<br>Multivitamin x 3 days followed by 1 day per week | Dietary Supplement: Multivitamin<br>* One tablet contains Vitamin-A : 5000 USP units, Vitamin D: 400 USP Units, Ascorbic acid: 75 mg, Thiamine Mononitrate: 2 mg, Riboflavin: 3 mg, Niacin amide: 20 mg. The prophylaxis will start with a 3-day course of twice daily AL. This will be followed by 2 doses 8 hours apart on one day per week for up to 3 28-35 day consecutive follow-up periods and for 4 weeks after leaving the forest.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite endpoint of either clinical malaria with any Plasmodium species within 1-28, 29-56 or 57-84 days, or subclinical infection detected by PCR on days 28, 56 or 84. |  | 84 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day, 56-day, and 84-day PCR Plasmodium positivity rate for each species |  | 28, 56 and, 84 days | 
| Proportion of participants with confirmed malaria reported between day 0 and day 28 for each species |  | 28 days | 
| Incidence of confirmed clinical malaria cases as reported to government health facilities and village malaria workers.surveillance data. |  | 1 year | 
| Prevalence of Kelch13 mutations and other genetic markers of antimalarial drug resistance of known functional significance. |  | 28 days | 
| Incidence of adverse events and serious adverse events by study arms during the course of prophylaxis. |  | 28 days | 
| a. Number of people living in each village b. Number of people working in each reported location c. Number of people who have travelled to different locations within the preceding 2 months d. Number of people who have a mobile phone for their own use |  | 28 days | 
| Latitude and longitude of the study participant over time in decimal degrees as recorded every 10-30 minutes by a GPS logging device. |  | 28 days | 
| Overall prevalence of Plasmodium at baseline, stratified by season and risk factors. |  | Day 0 | 
| Day 0, 28, 56 and 84 capillary blood levels of lumefantrine. |  | 84 days | 
| Prevalence of serological diagnostic markers of other infectious diseases. |  | Day 0 |