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

March 18, 2024 updated by: University of Oxford

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

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.

Funder: Wellcome Trust of Great Britain grant number 106698/Z/14/Z and 220211.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

1480

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Cambodia
      • Pursat, Cambodia
        • Pursat Referral Hospital/Kravanh Health Center
      • Stung Treng, Cambodia
        • Stung Treng Referral Hospital/Siem Pang Health Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ACT arm
Artemether-lumefantrine (AL) x 3 days followed by 1 day per week
Drug: Artemether-lumefantrine

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.
Active Comparator: Multivitamin arm
Multivitamin x 3 days followed by 1 day per week
Dietary supplement: Multivitamin

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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.
Time Frame: 84 days
84 days

Secondary Outcome Measures

Outcome Measure
Time Frame
28-day, 56-day, and 84-day PCR Plasmodium positivity rate for each species
Time Frame: 28, 56 and, 84 days
28, 56 and, 84 days
Proportion of participants with confirmed malaria reported between day 0 and day 28 for each species
Time Frame: 28 days
28 days
Incidence of confirmed clinical malaria cases as reported to government health facilities and village malaria workers.surveillance data.
Time Frame: 1 year
1 year
Prevalence of Kelch13 mutations and other genetic markers of antimalarial drug resistance of known functional significance.
Time Frame: 28 days
28 days
Incidence of adverse events and serious adverse events by study arms during the course of prophylaxis.
Time Frame: 28 days
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
Time Frame: 28 days
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.
Time Frame: 28 days
28 days
Overall prevalence of Plasmodium at baseline, stratified by season and risk factors.
Time Frame: Day 0
Day 0
Day 0, 28, 56 and 84 capillary blood levels of lumefantrine.
Time Frame: 84 days
84 days
Prevalence of serological diagnostic markers of other infectious diseases.
Time Frame: Day 0
Day 0

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oxford

Collaborators

Global Fund

Investigators

  • Principal Investigator: Richard J Maude, M.D., Mahidol Oxford Tropical Medicine Research Unit

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 11, 2020

Primary Completion (Actual)

March 17, 2021

Study Completion (Actual)

March 17, 2021

Study Registration Dates

First Submitted

April 23, 2019

First Submitted That Met QC Criteria

July 30, 2019

First Posted (Actual)

August 1, 2019

Study Record Updates

Last Update Posted (Actual)

March 20, 2024

Last Update Submitted That Met QC Criteria

March 18, 2024

Last Verified

May 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MAL19001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified, individual participant data from this study will be available to researchers whose proposed purpose of use is approved by the data access committee at Mahidol Oxford Tropical Medicine Research Unit. Inquiries or requests for the data may be sent to datasharing@tropmedres.ac.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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