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

Malaria Clinical Trial

— PAL_Cambodia  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04041973
• Other study ID #: MAL19001
• Status: Completed
• Phase: N/A
• Start date: March 11, 2020
• Est. completion date: March 17, 2021

Study information

• Verified date: May 2022
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1480
• Est. completion date: March 17, 2021
• Est. primary completion date: March 17, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 16 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Malaria

Intervention

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.

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.

Locations

Country	Name	City	State
Cambodia	Pursat Referral Hospital/Kravanh Health Center	Pursat
Cambodia	Stung Treng Referral Hospital/Siem Pang Health Center	Stung Treng

Sponsors (2)

Lead Sponsor	Collaborator
University of Oxford	Global Fund

Country where clinical trial is conducted

Cambodia, 

References & Publications (23)

Agency, E.M., European Public Assessment Report for Pyramax. 2016.

Bukirwa H, Unnikrishnan B, Kramer CV, Sinclair D, Nair S, Tharyan P. Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev. 2014 Mar 4;(3):CD006404. doi: 10.1002/14651858.CD006404.pub2. — View Citation

Dysoley L, Kaneko A, Eto H, Mita T, Socheat D, Borkman A, Kobayakawa T. Changing patterns of forest malaria among the mobile adult male population in Chumkiri District, Cambodia. Acta Trop. 2008 Jun;106(3):207-12. doi: 10.1016/j.actatropica.2007.01.007. Epub 2008 Apr 7. — View Citation

Erhart A, Ngo DT, Phan VK, Ta TT, Van Overmeir C, Speybroeck N, Obsomer V, Le XH, Le KT, Coosemans M, D'alessandro U. Epidemiology of forest malaria in central Vietnam: a large scale cross-sectional survey. Malar J. 2005 Dec 8;4:58. doi: 10.1186/1475-2875-4-58. — View Citation

Erhart A, Thang ND, Hung NQ, Toi le V, Hung le X, Tuy TQ, Cong le D, Speybroeck N, Coosemans M, D'Alessandro U. Forest malaria in Vietnam: a challenge for control. Am J Trop Med Hyg. 2004 Feb;70(2):110-8. — View Citation

Grietens KP, Xuan XN, Ribera J, Duc TN, Bortel Wv, Ba NT, Van KP, Xuan HL, D'Alessandro U, Erhart A. Social determinants of long lasting insecticidal hammock use among the Ra-glai ethnic minority in Vietnam: implications for forest malaria control. PLoS One. 2012;7(1):e29991. doi: 10.1371/journal.pone.0029991. Epub 2012 Jan 12. — View Citation

Gryseels C, Peeters Grietens K, Dierickx S, Xuan XN, Uk S, Bannister-Tyrrell M, Trienekens S, Ribera JM, Hausmann-Muela S, Gerrets R, D'Alessandro U, Sochantha T, Coosemans M, Erhart A. High Mobility and Low Use of Malaria Preventive Measures Among the Jarai Male Youth Along the Cambodia-Vietnam Border. Am J Trop Med Hyg. 2015 Oct;93(4):810-818. doi: 10.4269/ajtmh.15-0259. Epub 2015 Aug 17. — View Citation

Guerra CA, Snow RW, Hay SI. A global assessment of closed forests, deforestation and malaria risk. Ann Trop Med Parasitol. 2006 Apr;100(3):189-204. doi: 10.1179/136485906X91512. — View Citation

Imwong M, Hanchana S, Malleret B, Renia L, Day NP, Dondorp A, Nosten F, Snounou G, White NJ. High-throughput ultrasensitive molecular techniques for quantifying low-density malaria parasitemias. J Clin Microbiol. 2014 Sep;52(9):3303-9. doi: 10.1128/JCM.01057-14. Epub 2014 Jul 2. — View Citation

Imwong M, Nguyen TN, Tripura R, Peto TJ, Lee SJ, Lwin KM, Suangkanarat P, Jeeyapant A, Vihokhern B, Wongsaen K, Van Hue D, Dong le T, Nguyen TU, Lubell Y, von Seidlein L, Dhorda M, Promnarate C, Snounou G, Malleret B, Renia L, Keereecharoen L, Singhasivanon P, Sirithiranont P, Chalk J, Nguon C, Hien TT, Day N, White NJ, Dondorp A, Nosten F. The epidemiology of subclinical malaria infections in South-East Asia: findings from cross-sectional surveys in Thailand-Myanmar border areas, Cambodia, and Vietnam. Malar J. 2015 Sep 30;14:381. doi: 10.1186/s12936-015-0906-x. — View Citation

Lengeler C. Insecticide-treated bednets and curtains for preventing malaria. Cochrane Database Syst Rev. 2000;(2):CD000363. doi: 10.1002/14651858.CD000363. — View Citation

Marks VA, Latham SR, Kishore SP. On Essentiality and the World Health Organization's Model List of Essential Medicines. Ann Glob Health. 2017 May-Aug;83(3-4):637-640. doi: 10.1016/j.aogh.2017.05.005. Epub 2017 Jun 22. — View Citation

Moore SJ, Min X, Hill N, Jones C, Zaixing Z, Cameron MM. Border malaria in China: knowledge and use of personal protection by minority populations and implications for malaria control: a questionnaire-based survey. BMC Public Health. 2008 Oct 1;8:344. doi: 10.1186/1471-2458-8-344. — View Citation

Sanh NH, Van Dung N, Thanh NX, Trung TN, Van Co T, Cooper RD. Forest malaria in central Vietnam. Am J Trop Med Hyg. 2008 Nov;79(5):652-4. — View Citation

Saunders DL, Vanachayangkul P, Lon C; U.S. Army Military Malaria Research Program; National Center for Parasitology, Entomology, and Malaria Control (CNM); Royal Cambodian Armed Forces. Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med. 2014 Jul 31;371(5):484-5. doi: 10.1056/NEJMc1403007. No abstract available. — View Citation

Snow RW. Seasonal Malaria Chemoprevention: An Evolving Research Paradigm. PLoS Med. 2016 Nov 22;13(11):e1002176. doi: 10.1371/journal.pmed.1002176. eCollection 2016 Nov. — View Citation

Son DH, Thuy-Nhien N, von Seidlein L, Le Phuc-Nhi T, Phu NT, Tuyen NTK, Tran NH, Van Dung N, Van Quan B, Day NPJ, Dondorp AM, White NJ, Thwaites GE, Hien TT. The prevalence, incidence and prevention of Plasmodium falciparum infections in forest rangers in Bu Gia Map National Park, Binh Phuoc province, Vietnam: a pilot study. Malar J. 2017 Nov 6;16(1):444. doi: 10.1186/s12936-017-2091-6. — View Citation

Thang ND, Erhart A, Speybroeck N, Hung le X, Thuan le K, Hung CT, Ky PV, Coosemans M, D'Alessandro U. Malaria in central Vietnam: analysis of risk factors by multivariate analysis and classification tree models. Malar J. 2008 Jan 30;7:28. doi: 10.1186/1475-2875-7-28. — View Citation

Thang ND, Erhart A, Speybroeck N, Xa NX, Thanh NN, Ky PV, Hung le X, Thuan le K, Coosemans M, D'Alessandro U. Long-Lasting Insecticidal Hammocks for controlling forest malaria: a community-based trial in a rural area of central Vietnam. PLoS One. 2009 Oct 7;4(10):e7369. doi: 10.1371/journal.pone.0007369. — View Citation

Thanh PV, Van Hong N, Van Van N, Van Malderen C, Obsomer V, Rosanas-Urgell A, Grietens KP, Xa NX, Bancone G, Chowwiwat N, Duong TT, D'Alessandro U, Speybroeck N, Erhart A. Epidemiology of forest malaria in Central Vietnam: the hidden parasite reservoir. Malar J. 2015 Feb 19;14:86. doi: 10.1186/s12936-015-0601-y. — View Citation

Tripura R, Peto TJ, Chea N, Chan D, Mukaka M, Sirithiranont P, Dhorda M, Promnarate C, Imwong M, von Seidlein L, Duanguppama J, Patumrat K, Huy R, Grobusch MP, Day NPJ, White NJ, Dondorp AM. A Controlled Trial of Mass Drug Administration to Interrupt Transmission of Multidrug-Resistant Falciparum Malaria in Cambodian Villages. Clin Infect Dis. 2018 Aug 31;67(6):817-826. doi: 10.1093/cid/ciy196. — View Citation

West African Network for Clinical Trials of Antimalarial Drugs (WANECAM). Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial. Lancet. 2018 Apr 7;391(10128):1378-1390. doi: 10.1016/S0140-6736(18)30291-5. Epub 2018 Mar 29. — View Citation

York A. Seasonal malaria chemoprevention in the Sahel. Lancet Infect Dis. 2017 Jun;17(6):588. doi: 10.1016/S1473-3099(17)30255-4. No abstract available. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

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