An Open-label Individually Randomised Controlled Trial to Assess the Efficacy of Artemether-lumefantrine Prophylaxis for Malaria Among Forest Goers in Cambodia
Phase: NA
Conditions: Malaria
Sponsor: University of Oxford

 
 
 
 
 
 
 
 
PAL_Cambodia  
 
An open-label individually randomised controlled trial to assess the efficacy of artemether-
lumefantrine prophylaxis for malaria among forest goers in Cambodia Short title: Study to assess 
efficacy of artemether-lumefantrine prophylaxis against forest malaria in Cambodia 
 
Short title: Study to assess efficacy of artemether-lumefantrine prophylaxis against forest malaria in 
Cambodia 
Protocol Version: version 2.0 dated 25 June 2019 
Trial registration number: NCT04041973 

 
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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 
 
Short title: Study to assess efficacy of artemether-lumefantrine prophylaxis against forest malaria 
in Cambodia 
ACRONYM: PAL-Cambodia 
Protocol no.: MAL19001 
OxTREC ref: 23-19 
 
Principal Investigator:  
Prof. R.J. Maude 
 
Sponsor 
 
University of Oxford 
 
 
Funder 
 
 
Global Fund Regional Component of the 
Regional Artemisinin-resistance Initiative 
(RAI2E) Grant 
 
 
 
 
 
 
 
 
 
Protocol development team:  
RJ Maude, S. Sovannaroth, R Tripura, TJ Peto, JJ Callery, M Imwong, M Dhorda, C Promnarate,  
N Waithira, M Mukaka, O Miotto, R Aguas, Z Doran, L von Seidlein, Nicholas J White  
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host institution, relevant ethics committee and regulatory 
authorities. 
 
 
 
 
 

 
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Investigator Agreement and Conflict of Interest 
 
“I have read this protocol and: 
- 
agree to abide by all provisions set forth therein. 
- 
agree to comply with the principles of the International Conference on Harmonisation 
Tripartite Guideline on Good Clinical Practice. 
- 
and declare no conflict of interest, according to the current version of the Declaration of 
Helsinki”  
 
 
 
 
 
 
Prof. Richard J. Maude                                      
Principal Investigator 
 
 
Principal Investigator’s Signature 
 
 
 
Date :  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS  ..................................................................................................................... 5 
2. 
SYNOPSIS ............................................................................................................................................... 6 
3. 
BACKGROUND  AND RATIONALE  ........................................................................................................ 8 
3.1 BACKGROUND ........................................................................................................................................ 8 
3.2 STUDY RATIONALE  ................................................................................................................................. 8 
3.3 PROPOSED ACTIVITIES ............................................................................................................................ 9 
4. 
OBJECTIVES ........................................................................................................................................... 9 
4.1.  
PRIMARY OBJECTIVE .......................................................................................................................... 9 
4.2.  
SECONDARY OBJECTIVES................................................................................................................... 9 
5. 
TRIAL DESIGN ...................................................................................................................................... 10 
5.1 STUDY SITES ........................................................................................................................................ 10 
5.2 SUMMARY OF TRIAL DESIGN .................................................................................................................. 10 
5.3 STUDY DURATION ................................................................................................................................. 10 
5.4 PRIMARY AND SECONDARY ENDPOINTS .................................................................................................. 10 
5.4.1. Co-primary  Endpoints  ............................................................................................................. 10 
5.4.2. Secondary  Endpoints  .............................................................................................................. 10 
5.5 TRIAL PARTICIPANTS ............................................................................................................................ 11 
5.5.1 
Overall  Description  of Trial  Participants  ............................................................................... 11 
5.5.2 
Inclusion  criteria  ...................................................................................................................... 11 
5.5.3 
Exclusion  criteria  ..................................................................................................................... 11 
6. 
PROCEDURES ...................................................................................................................................... 12 
6.1. 
INFORMED CONSENT ........................................................................................................................ 12 
6.2. 
SCREENING, ELIGIBILITY  AND BASELINE ASSESSMENTS .................................................................... 12 
6.2.1. Demographics  and Medical  History  ...................................................................................... 12 
6.2.2. Physical  Examination  and Vital  Signs  ................................................................................... 12 
6.2.3. Drug  history  ............................................................................................................................. 12 
6.2.4. Clinical  malaria  ........................................................................................................................ 12 
6.3. 
RANDOMISATION AND BLINDING ........................................................................................................ 12 
6.4. 
BLOOD SAMPLING ON STUDY ENROLMENT ......................................................................................... 13 
6.5. 
STUDY DRUG ADMINISTRATION .......................................................................................................... 13 
6.6. 
FOLLOW-UP ..................................................................................................................................... 13 
6.6.1 
Time windows  .......................................................................................................................... 14 
6.6.2 
Additional  visits  ....................................................................................................................... 14 
6.6.3 
Clinical  Malaria  during  Follow -up .......................................................................................... 14 
6.7. 
BLOOD VOLUMES ............................................................................................................................. 14 
6.8. 
ANALYSIS OF BLOOD SAMPLES ......................................................................................................... 15 
6.8.1 Parasite  PCR ................................................................................................................................ 15 
6.8.2 Parasite  genetic  analysis  ............................................................................................................ 15 
6.8.3 Lumefantrine  level  ....................................................................................................................... 15 
6.8.4 Serology  ....................................................................................................................................... 15 
6.9 STUDY DRUG ........................................................................................................................................ 15 
6.9.1 
Artemether -lumefantrine  ......................................................................................................... 15 
6.9.2 
Multivitamin  .............................................................................................................................. 16 
6.10 
EPIDEMIOLOGICAL  DATA ON PLACE OF RESIDENCE, WORK, TRAVEL HISTORY AND MALARIA  RISK ......... 16 
6.11 MALARIA  INCIDENCE DATA ..................................................................................................................... 16 
6.12 
ANALYSIS ........................................................................................................................................ 16 
6.12.1  
PCR for  parasites  ................................................................................................................ 16 
6.12.2  
Parasite  genetics  ................................................................................................................. 16 
6.13 
DISCONTINUATION/ WITHDRAWAL  OF PARTICIPANTS FROM THE STUDY .............................................. 16 
6.14 
SOURCE DATA ................................................................................................................................. 17 
7.  
STUDY DRUGS ...................................................................................................................................... 17 
7.1 STORAGE OF STUDY DRUGS ................................................................................................................. 17 
7.2 COMPLIANCE WITH STUDY DRUGS ........................................................................................................ 17 
7.3 ACCOUNTABILITY  OF THE STUDY TREATMENT ........................................................................................ 18 
7.4 CONCOMITANT MEDICATION .................................................................................................................. 18 

 
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8.  
SAFETY REPORTING ........................................................................................................................... 19 
8.1 DEFINITIONS ......................................................................................................................................... 19 
8.1.1. Adverse  Event  (AE) ................................................................................................................. 19 
8.1.2 
Serious  Adverse  Event  ........................................................................................................... 19 
8.2 REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS ................................................................... 20 
8.3 EVALUATING  ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................................................... 20 
8.3.1  Assessment  of Intensity  ......................................................................................................... 20 
8.3.2  Clarification  of the difference  in meaning  between  ‘severe’ and ‘serious’ ....................... 20 
8.3.3 
Assessment  of relatedness  .................................................................................................... 21 
8.3.4 
Outcome  ................................................................................................................................... 21 
9 
STATISTICAL  CONSIDERATIONS ....................................................................................................... 22 
9.1 SAMPLE SIZE JUSTIFICATION ................................................................................................................. 22 
9.2 STATISTICAL  ANALYSES ....................................................................................................................... 22 
9.2.1 
Proportions  .............................................................................................................................. 22 
9.2.2 
Continuous  data ...................................................................................................................... 22 
9.2.3 
Safety  analysis  ......................................................................................................................... 22 
9.2.4 
Adverse  events  ........................................................................................................................ 23 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................................................ 24 
11 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ................................................. 25 
11.1 
MONITORING .................................................................................................................................... 25 
12 
ETHICS ................................................................................................................................................... 26 
12.1 
DECLARATION  OF HELSINKI .............................................................................................................. 26 
12.2 
ICH GUIDELINES FOR GOOD CLINICAL  PRACTICE .............................................................................. 26 
12.3 
APPROVALS ..................................................................................................................................... 26 
12.4 
RISKS .............................................................................................................................................. 26 
12.4.1 
Risks  of artemether -lumefantrine  ...................................................................................... 26 
12.4.2 
Risks  of multivitamin  .......................................................................................................... 26 
12.4.3 
Risk  of phlebotomy  & finger  stick  ..................................................................................... 26 
12.5 
BENEFITS ........................................................................................................................................ 26 
12.6 
ALTERNATIVES TO STUDY PARTICIPATION ......................................................................................... 27 
12.7 
INCENTIVES & COMPENSATION ......................................................................................................... 27 
12.8 
CONFIDENTIALITY ............................................................................................................................. 27 
13 
SAMPLE SHARING AND STORAGE ................................................................................................... 28 
14 
DATA HANDLING AND RECORD KEEPING ....................................................................................... 29 
15 
SPONSORSHIP AND INSURANCE ...................................................................................................... 30 
16 
PUBLICATION  POLICY ......................................................................................................................... 31 
17.  
REFERENCES ................................................................................................................................... 32 
18 
APPENDIX 1. SCHEDULE OF ASSESSMENTS .................................................................................. 33 
19 
APPENDIX 2. DOSING SCHEDULES ................................................................................................... 34 
19.1 
ARTEMETHER-LUMEFANTRINE ........................................................................................................... 34 
19.2 
MULTIVITAMIN .................................................................................................................................. 35 
20 
APPENDIX 3.  LIST OF STUDY SITES & PRINCIPAL INVESTIGATORS .......................................... 36 
21 
APPENDIX 4. AMENDMENT HISTORY ................................................................................................ 37 
 
 

 
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1. 
LIST OF ABBREVIATIONS 
ACT 
 
Artemisinin-based combination therapy 
AE 
 
Adverse event 
A/L 
 
Artemether-lumefantrine 
AQ 
 
Amodiaquine 
CNM  
National Center for Parasitology, Entomology and Malaria Control 
CRF 
 
Case record form 
CTSG  
Clinical Trials Support Group (MORU) 
DHA 
 
Dihydroartemisinin 
DNA                Deoxyribonucleic Acid 
EDC                Electronic data capture 
EDTA  
Ethylene-diamine-tetra-acetic acid  
G6PD  
Glucose-6-phosphate dehydrogenase 
GCP 
 
Good Clinical Practice 
GPS 
 
Global Positioning System 
Hb                   Haemoglobin 
Hct 
 
Haematocrit 
IRS 
 
Indoor residual spraying 
LLIN 
 
Long-lasting insecticide treated bednets 
MDR1  
Multi-Drug Resistance Gene 1 
MQ 
 
Mefloquine 
MORU  
Mahidol-Oxford Research Unit 
NMCP  
National Malaria Control Programme 
PA 
 
Pyronaridine-artesunate 
PAL 
 
Prophylaxis with artemether-lumefantrine study 
PCR 
 
Polymerase Chain Reaction 
QA 
 
Quality Assurance 
QC 
 
Quality Control 
SAE 
 
Serious Adverse Event 
SNP 
 
Single-nucleotide polymorphism 
SOP 
 
Standard Operating Procedure 
WHO  
World Health Organisation 
WWARN 
Worldwide Antimalarial Resistance Network 
 
 
 
 

 
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2. 
SYNOPSIS 
Study Title 
An open-label individually randomised controlled trial to assess the efficacy of 
artemether-lumefantrine prophylaxis for malaria among forest goers in Cambodia 
ACRONYM 
PAL-Cambodia 
Trial Design 
An open-label randomised trial comparing the ACT artemether-lumefantrine 
(Coartem) with a multivitamin preparation, evaluating efficacy in preventing malaria 
among forest goers  
Trial          
Participants 
People planning to travel the forest within the next 72 hours in areas at high risk for 
malaria  
Sample size 
4400 participant episodes, with half allocated to each study arm 
Inclusion    
Criteria 
 
Male or female, 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 
24hours) confirmed by RDT 
Planned Trial 
Period 
12 months (September 2019 – July 2020) enrolment 
Primary      
Objective 
To compare the efficacy of the ACT artemether-lumefantrine versus a multivitamin 
preparation as defined by the 28-day PCR parasite positivity rate and incidence of 
confirmed clinical malaria of any species. 
Secondary 
Objectives 
1. 
To compare the efficacy of the ACT artemether-lumefantrine versus a multivitamin 
preparation as defined by the 28-day, 56-day and 84-day PCR parasite positivity 
rate and incidence of confirmed clinical malaria for each species. 
2. 
To quantify the impact of the ACT artemether-lumefantrine as prophylaxis for 
forest goers on overall malaria transmission using mathematical modelling. 

 
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3. 
To assess the impact of artemether-lumefantrine prophylaxis on the spread of 
genetic markers of artemisinin (such as Kelch13 mutations) and partner drug 
resistance. 
4. 
To obtain data on the place of residence, work, recent travel history and risk 
behaviours of forest goers in order to improve the understanding of high risk 
groups, locations of malaria transmission and possible routes spread of malaria 
and artemisinin resistance. 
5. 
To explore the duration, location and purpose of individual forest visits. 
6. 
To obtain detailed data and GPS mapping on a subset of participants and their 
peers relating to the behaviours and risk factors associated with malaria infection 
in order to improve understanding of local malaria transmission among forest 
goers. 
7. 
To determine the prevalence of asymptomatic Plasmodium infections in high risk 
populations at varying seasonal time points. 
8. 
To determine the prevalence of other infectious diseases that affect the study 
population. 
 
Primary   
endpoints 
1. 
28-day PCR Plasmodium positivity rate of any species 
2. 
Proportion of participants with confirmed clinical malaria of any species reported 
between day 0 and day 28  
Secondary 
endpoints 
1. 
28-day, 56-day and 84-day PCR Plasmodium positivity rate for each species 
2. 
Proportion of participants with confirmed malaria reported between day 0 and day 
28 for each species 
3. 
Description of epidemiological situation of malaria in the study areas from passive 
surveillance data.  
4. 
Prevalence of Kelch13 mutations and other genetic markers of antimalarial drug 
resistance of known functional significance.  
5. 
Incidence of adverse events and serious adverse events by study arms during the 
course of prophylaxis. 
6. 
Data on the place of residence, work, recent travel history and mobile phone use. 
7. 
Detailed data and GPS mapping on a subset of participants and their peers relating 
to the behaviours and risk factors associated with malaria infection. 
8. 
Overall prevalence of Plasmodium at baseline, stratified by season and risk 
factors. 
9. 
0, 28, 56 and 84-day capillary blood levels of lumefantrine. 
10. Prevalence of serological diagnostic markers of other infectious diseases. 
Drugs 
 
(See  
Appendix 2 
for dosing 
regimens) 
  
 Artemether-lumefantrine for 3 days followed by 2 doses weekly. 
VERSUS 
 Multivitamin 3 days followed by 2 doses weekly. 

 
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3. 
BACKGROUND AND RATIONALE 
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.  
3.1 
Background  
In the Greater Mekong Subregion (GMS) a large proportion of malaria transmission occurs in 
forested areas, which serve as perpetual sources of transmission [1-5]. Studies have demonstrated 
increased risk of malaria among forest goers, particularly in men of working age [6, 7] although these 
have largely been restricted to small geographical areas. Protecting forest goers from Plasmodium 
infections would not only benefit them directly but also people residing around their home. Malaria 
elimination efforts which do not consider the reinfection risk from forest workers are unlikely to 
succeed. However, preventing infections in forest workers is a major challenge. The biting rhythm 
and resting behaviour of Anopheles dirus reduces the impact of the two most commonly employed 
control measures, long-lasting insecticide treated bednets (LLIN) and indoor residual spraying (IRS). 
Several studies have also demonstrated poor use of personal protection measures against malaria 
transmission [8-10]. Two factors that increase malaria risk among forest workers are the basic 
character of overnight forest accommodation [9] and exposure to the Anopheles vectors (e.g. An. 
dirus), which tend to bite outdoors in daytime. LLIN have a high protective efficacy against nocturnal, 
indoor malaria transmission [11] but are less protective against daytime, outdoor-biting vectors like 
An. dirus. The improvised housing of forest workers is frequently poorly suited to hanging bed 
nets.[12] Imaginative interventions such as supplying forest workers with insecticide treated 
hammocks do not address the biting rhythm and resting behaviour of the vectors and have a 
disappointing uptake in field studies.[10, 12] In the absence of simple, effective, and affordable 
vector control interventions, providing forest goers with effective antimalarial prophylaxis seems a 
promising alternative approach to protect them against malaria.[13] 
 
We propose to evaluate the feasibility and protective efficacy of antimalarial prophylaxis during 
forest work. It has been demonstrated in sub-Saharan Africa that chemoprophylaxis (SMC) of 
children, the highest risk group for malaria in tropical Africa, can reduce malaria cases by 75%, is 
cost effective and safe and can be given by community health workers [14, 15]. We propose to 
provide chemoprophylaxis to forest workers, the population group with the highest malaria risk in 
the GMS. In the proposed study we compare chemoprophylaxis with an antimalarial drug, 
artemether-lumefantrine (AL). A recent mass drug administration in Cambodia demonstrated that 
DHA/piperaquine remains effective to clear low-density, subclinical P. falciparum infections, but 
there are increasing treatment failures of clinical malaria cases [16] and markers of resistance to 
piperaquine in Cambodia are increasing. Although artesunate-pyronaridine has recently been 
introduced for treatment in parts of Cambodia, there are unresolved concerns about potential liver 
toxicity[17]. Evidence to date suggests that efficacy of artemether-lumefantrine remains high in 
Cambodia and is very well tolerated with an excellent toxicity profile and  is thus the preferred 
potential option for prophylaxis by the National Malaria Control Programme. However, it must be 
taken with fat to maximize absorption. Previously it has been difficult or impossible to detect very 
low-density Plasmodium infections. The availability of more sensitive PCR methods allows us to 
detect Plasmodium infections with much lower densities [18, 19]. By use of PCR, we will be able to 
detect a difference in the prevalence of low density, subclinical P. falciparum infections between the 
two study arms in a relatively small sample of study participants. 
 
3.2 
Study Rationale 
Chemoprophylaxis of forest workers could protect this high-risk group and could reduce or even 
interrupt transmission in villages. The highly encouraging results of seasonal malaria 
chemoprophylaxis (SMC) in selected regions of sub-Saharan Africa provide hope that targeting 
another high-risk group, forest workers, could reduce malaria transmission in Cambodia and the 
wider GMS. In sub-Saharan Africa, children remain the main risk group for Plasmodium infections. 
In SE Asia the main risk group are adults working and sleeping outdoors hence we propose to 
provide chemoprophylaxis for these adults. A major challenge for this strategy is the choice of an 

 
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appropriate chemoprophylactic regimen in the GMS. The chemoprophylactic regimen of choice in 
Africa is sulfadoxine/pyrimethamine (S/P) plus amodiaquine despite high level resistance against 
the S/P component of the regimen. Similarly, we propose the use of 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. 
  
3.3 
Proposed activities  
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 day 28 post forest 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 28 days (+/-7 days) after returning from 
the forest upon completing each course of prophylaxis when temperature, symptom questionnaires, 
brief physical examinations, and malaria parasite PCR, 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. 
 
4. 
OBJECTIVES 
4.1.  
Primary Objective 
To compare the efficacy of the ACT artemether-lumefantrine versus a multivitamin preparation as 
defined by the 28-day PCR parasite positivity rate and incidence of confirmed clinical malaria of any 
species. 
4.2.  
Secondary Objectives 
1. To compare the efficacy of the ACT artemether-lumefantrine versus a multivitamin 
preparation as defined by the 28-day, 56-day and 84-day PCR parasite positivity rate and 
incidence of confirmed clinical malaria for each species. 

 
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2. To quantify the impact of the ACT artemether-lumefantrine as prophylaxis for forest goers 
on overall malaria transmission using mathematical modelling. 
3. To assess the impact of artemether-lumefantrine prophylaxis on the spread of genetic 
markers of artemisinin (such as Kelch13 mutations) and partner drug resistance. 
4. To obtain data on the place of residence, work, recent travel history and risk behaviours of 
forest goers in order to improve the understanding of high risk groups, locations of malaria 
transmission and possible routes spread of malaria and artemisinin resistance. 
5. To explore the duration, location and purpose of individual forest visits. 
6. To obtain detailed data and GPS mapping on a subset of participants and their peers 
relating to the behaviours and risk factors associated with malaria infection in order to 
improve understanding of local malaria transmission among forest goers. 
7. To determine the prevalence of asymptomatic Plasmodium infections in high risk populations 
at varying seasonal time points. 
8. To determine the prevalence of other infectious diseases that affect the study population 
 
 
5. 
TRIAL DESIGN 
5.1 
Study sites 
The study will take place at up to 50 villages in selected malaria endemic districts in Stung Treng 
and Pursat Provinces, Cambodia. As the malaria situation in these areas is dynamic, the villages 
will be identified prior to the start of the trial from analysis of up to date malaria incidence from 
passive surveillance collected by the Cambodia National Center for Parasitology Entomology and 
Malaria Control. If there are found to be insufficient villages with malaria cases in Stung Treng 
Province at the time of trial commencement, we will include additional sites in Pursat Province. 
MORU has existing study sites and teams in both provinces which will support the running of this 
trial. The rationale for choosing these areas include high forest cover and ongoing malaria 
transmission among forest goers. 
5.2 
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. 
5.3 
Study duration 
The recruitment phase of the study is expected to last 12 months following the intended start of 
recruitment in September 2019. Training and community sensitization will precede study execution 
for 3 months. Data management and analysis, sample analysis (PCR, parasite genetics), 
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. 
5.4 
Primary and secondary endpoints 
5.4.1. 
Co-primary Endpoints 
1. 28-day PCR positivity rate of Plasmodium infections of any species. 
2. Proportion of participants with confirmed clinical malaria of any species reported between 
day 0 and day 28  
 
5.4.2. 
Secondary Endpoints 
1. 28-day, 56-day and 84-day PCR Plasmodium positivity rate for each Plasmodium species 

 
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2. Proportion of participants with confirmed malaria reported between day 0 and day 28 for 
each species 
3. Description of epidemiological situation of malaria in the study areas from passive 
surveillance data.  
4. Prevalence of Kelch13 mutations and other genetic markers of antimalarial drug resistance 
of known functional significance.  
5. Incidence of adverse events and serious adverse events by study arms during the course of 
prophylaxis. 
6. Data on the place of residence, work, recent travel history and mobile phone use. 
7. Detailed data and GPS mapping on a subset of participants and their peers relating to the 
behaviours and risk factors associated with malaria infection. 
8. Overall prevalence of Plasmodium at baseline, stratified by season and risk factors. 
9. Day 0, 28, 56 and 84 capillary blood levels of lumefantrine. 
10. Prevalence of serological diagnostic markers of other infectious diseases. 
5.5 
Trial Participants 
5.5.1 
Overall Description of Trial Participants 
Male and non-pregnant female participants aged between 16 years and 65 years planning to visit 
the forest within 72 hours are the target study population. All study participants must meet the 
applicable inclusion and exclusion criteria. 
5.5.2 
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. 
5.5.3 
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. 

 
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6. 
PROCEDURES 
Study procedures will be performed according to the schedule of assessments (Appendix 1). This 
will require that participants are followed up every 28 days for up to 3 periods upon completion of a 
course of prophylaxis.   
6.1. 
Informed Consent 
Prior to the start of enrollment we will conduct community mobilisation and sensitisation activities in 
each village community where the trial will recruit participants. During the trial, the participant (or 
witness if illiterate) must personally sign and date the latest approved version of the informed 
consent form before any study specific procedures are performed. Written and verbal versions of 
the participant information and informed consent in the local language will be presented to the 
participants detailing no less than: the exact nature of the study; the implications and constraints of 
the protocol; the known side effects and any risks involved in taking part. It will be clearly stated that 
participation is voluntary and that the participant is free to withdraw from the study at any time for 
any reason without prejudice to future care, and with no obligation to give the reason for withdrawal.  
The participant will be allowed as much time as possible to consider the information and take the 
opportunity to question the Investigator, or other independent parties to decide whether they will (or 
allow his/her charge to) participate in the study. Written informed consent will then be obtained by 
means of participant dated signature or thumb print (if unable to write) and dated signature of the 
person who presented and obtained the informed consent.  
A copy of the signed informed consent document(s) will be given to the participants.    
Children aged 16 - <18 years will be required to sign the latest approved version of the written 
informed assent form in addition to their parent or guardian signing a consent form. 
6.2. 
Screening, Eligibility and Baseline Assessments 
Participants who present at the participating sites will be screened to assess eligibility. Full consent 
will be obtained before any enrolment procedures are conducted. It will be made clear from the 
outset that refusal to participate will not jeopardise subsequent antimalarial treatment (if applicable). 
A screening log will be kept.   
6.2.1. 
Demographics and Medical History 
Basic demographic and epidemiological data (e.g. sex, age, weight, address, bed net use, malaria 
risk factors, travel history, prior malaria episodes, prior treatment and previous participation in this 
or previous studies), and a full medical history will be recorded by the study staff.  
6.2.2. 
Physical Examination and Vital Signs  
Brief physical examination and vital sign will be conducted by a qualified study team member. Weight 
and temperature. A symptom questionnaire will be performed. 
6.2.3. 
Drug history  
All prescribed or over-the-counter and traditional antimalarial medications used within the last 7 days 
will be recorded. Any drug allergies will be recorded.  
6.2.4. 
Clinical malaria 
Participants who are screened and are found to be febrile or have a current history of fever will not 
be enrolled (as per exclusion criteria) but will be tested for malaria and, if positive, given antimalarial 
treatment by the village malaria worker or local clinic. All this will be done in accordance with the 
current national malaria treatment guidelines in Cambodia. Individuals treated for malaria in this way 
will not be enrolled in the study as per the exclusion criteria. 
6.3. 
Randomisation and blinding 
Participants who fulfil all the inclusion criteria and have none of the exclusion criteria will be 
randomised 1:1 to one of the two treatment arms according to a randomisation schedule. 
Randomisation will be in blocks of size that will be determined by the trial statistician and the block 

 
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size will not be revealed to the investigating team. Allocation will be done by drawing the next 
sequential numbered opaque envelope (or other equally reliable randomisation administration 
procedure), which contains the study number and treatment allocation.  
The participants will be assigned a study arm through a computer-generated randomisation 
schedule.  Individual, sealed and sequentially numbered envelopes will be provided for each trial 
site with one envelope per participant, indicating the treatment allocation.  
This is an open-label study so the blinding of investigators and participants is not applicable. 
However, the randomisation procedure allows for adequate drug allocation concealment before 
envelopes are opened. All laboratory investigations will be performed without knowledge of the 
treatment allocation.   
6.4. 
Blood sampling on study enrolment 
On study enrolment, immediately before drug administration, blood will be collected for the following: 
• 
Parasite PCR (Up to 1 ml).  
• 
Dried blood spot for capillary blood level of lumefantrine (200 µl) 
• 
Storage for later identification of other causes of fever (2ml). 
6.5. 
Study drug administration 
 
 
 
 
Participants will be treated with weight-based doses according to the schedule in Appendix 2. 
The study drugs will be administered by trained study staff.  
If the participant vomits within half an hour after intake of the antimalarial drugs, the dose will be 
repeated. If vomiting occurs between half and one hour, half of the dose will be repeated. If vomiting 
occurs more than one hour after drug administration, no repeat dosing will be done. Repeat doses 
will be recorded on the CRF. If vomiting within 1 hour occurs more than one time, no repeat dosing 
is allowed. The participant will then be treated at the discretion of the investigator. 
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 during the time that the person is travelling in the forest and for 4 
weeks after leaving the forest. 
6.6. 
Follow-up 
Participants will be asked to return for a follow-up assessment any time from 28 to 35 days after 
commencing prophylaxis. This will be regardless of the duration of their visit to the forest or the 
number of times they visited it in that period. At this assessment, they will be interviewed about how 
long they spent in the forest, where they went, why, who they travelled with and about risk factors 
for infection. Brief physical examinations, vital sign and symptom questionnaire will be performed. 
They will also be asked to report any diagnostic tests and/or treatment for malaria during the 
preceding 28-35 days.  
Blood sampling at follow-up 
At each follow-up visit, the following blood will taken: 
All individuals:  
• 
Parasite PCR (Up to 1 ml).  
Overview  PAL drug  regimens  
ACT arm 
Multivitamin  arm 
Artemether -lumefantrine  x 3 days  
followed  by 1 day per week 
 
Multivitamin  x 3 days  followed  by 1 day 
per week 
 

 
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• 
Dried blood spot for lumefantrine level (0.2 ml) 
In those with confirmed clinical malaria at any time point between enrolment and follow-up: 
• 
Dry blood blots (0.4 ml, 3 spots) collected on filter papers for:  
o Parasite DNA genotyping for genetic markers of antimalarial resistance. 
o Parasite whole genome sequencing and barcoding to identify geographical origin of 
parasites and compare genotypes to identify persistent infections. 
In individuals who are planning to return again to the forest within the following 28 days after the 
follow up visit, they will be asked to continue their weekly prophylaxis according to the original 
treatment allocation on enrolment. They will then be asked to return for a second follow-up visit a 
further 28 to 35 days later when the above procedure will be repeated. This will be repeated one 
more time. If the person cannot be followed up within the scheduled period, e.g. because they do 
not return from the forest in time, then they will be followed up at the first opportunity and this will be 
recorded in the CRF. 
Thus individuals may take prophylaxis continuously for a maximum of 3 periods of 28-35 days in the 
forest plus 4 weeks after returning totaling 112 days. The choice of study medication for each 
individual will follow the initial assignment on enrolment throughout the follow-up period. 
In those who do not declare an intention to return to the forest within 28 days at any follow-up visit, 
no further follow-up visits will be offered at that time but they will be asked to complete 4 weeks of 
prophylaxis following their last day in the forest as post-exposure prophylaxis. 
Individuals who have been enrolled in the study may be enrolled into the study up to two more times 
during the 12 months study period only if a minimum period of 28 days (4 weeks) has elapsed 
following their last dose of prophylaxis. Thus they can be enrolled in the study a maximum of three 
times. If an individual is enrolled again in this way, they will be re-randomised following the same 
procedure as enrolment. 
6.6.1 
Time windows  
The time-window for the follow-up visits is 28-35 days. If a participant does not attend, the study 
team will try to locate the participant and bring them to the village. 
6.6.2 
Additional visits 
Participants presenting to the village malaria worker, mobile malaria worker or clinic with a fever or 
other symptoms at any time after enrolment that is not a scheduled study follow-up visit will be 
assessed and treated by the healthcare workers in the local healthcare system as per routine clinical 
practice in Cambodia.  
On enrolment, participants will be encouraged to attend a village malaria worker or government 
clinic for the assessment of fever or other symptoms and to report this to the study team as soon as 
possible after the symptoms occur. Information on these healthcare encounters including malaria 
test result and treatment will be recorded in the study CRF. 
6.6.3 
Clinical Malaria during Follow-up 
Participants who have an episode of confirmed clinical malaria at any time after enrolment up to the 
last follow-up visit and for one month afterwards will have blood taken for parasite genetic analysis.  
6.7. 
Blood volumes 
The blood volumes for the protocol mandated tests are as follows: 
1. PCR: 1ml 
2. Dried blood spots for lumefantrine level: 0.2ml 
3. Dried blood spots for genetics: 0.4ml 
4. Storage for serology at baseline 2ml 
Maximum blood volumes are presented below for adults for the maximum of three periods (84 
days) of follow up. The maximum blood volume is the total amount taken if the participants returns 

 
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for follow-up on 3 consecutive occasions and had all blood samples taken. The maximum blood 
volume will be approximately 10.4 ml (less than 10% of total blood volume taken over 8 weeks as 
recommended by WHO- Bulletin of the World Health Organization 2011:89:46-53). 
Allowing for the possibility that we may need to repeat blood tests, we may add 10.4 ml to these 
estimated maximum blood volumes.  
Blood samples collected from this study will be stored no longer than 10 years using codes assigned 
by the study team or their designee(s). Access to research samples will be limited using either a 
locked room or a locked freezer.  
6.8. 
Analysis of blood samples 
6.8.1 Parasite PCR 
This is required for the primary study objective. Blood samples will be analysed in the Molecular 
Tropical Medicine Laboratory, Bangkok, Thailand using PCR to identify which individuals have 
malaria parasites of any species. It is anticipated that results will be available around 3 to 6 months 
after collecting each sample, thus they will not be used to guide antimalarial treatment at the time of 
testing. The study teams will be informed which samples were positive for malaria and they will 
follow-up positive participants to conduct a brief clinical assessment. Any individuals who are 
symptomatic will be referred to the village malaria worker or clinic for testing and treatment. 
6.8.2 Parasite genetic analysis 
Blood samples (dried blood spots) for parasite genetic analysis will be obtained and stored from all 
subjects recruited with subject’s consent. In individuals in whom parasites are found by PCR, 
samples will be processed for parasite genetic analysis. Genetic samples (in the form of dried blood 
spots or extracted DNA) will be stored (for a maximum of 10 years) at the Molecular Tropical 
Medicine Laboratory, Bangkok, Thailand. In those with confirmed clinical malaria, parasite 
genotyping will be performed at the Wellcome Trust Sanger Institute in Hinxton, UK or other suitable 
laboratory using a set of informative single nucleotide polymorphisms selected from whole genome 
sequencing. The subject will be asked for consent for this transfer during the initial informed consent 
process. A material transfer agreement will be in place if required before any samples are shipped. 
The results of the parasite genotyping will not be reported back to the subjects. This analysis will 
only be done for those with confirmed clinical malaria as it is anticipated that there will be insufficient 
genetic material in samples taken from those with asymptomatic infection due to the low parasite 
burden in these individuals. 
6.8.3 Lumefantrine level 
Blood samples (dried blood spots) for lumefantrine level will be taken at each follow-up visit. These 
will be analysed in the Pharmacology Laboratory at MORU in Bangkok, Thailand. 
6.8.4 Serology 
Among those who specify by written consent, the serology samples will be analysed for diagnostic 
markers of other infectious diseases.  
  
6.9 Study drug  
6.9.1 Artemether-lumefantrine  
Currently available as standard tablets containing 20 mg artemether and 120 mg of lumefantrine, in 
a fixed-dose combination formulation. It is included in this formulation on the WHO Model List of 
Essential Medicines [21]. 
 
Target dose/range: 
The dose of artemether-lumefantrine is administered as a twice daily dose for 3 days for a total of 6 
doses (an initial dose, second dose after 8 hours and then twice daily – morning and evening – for 
the following two days) followed by twice daily once a week according to the treatment schedule in 
Appendix 2. 

 
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6.9.2 Multivitamin 
The multivitamin will be multivitamin (HEXA CMP, Chemephand Medical Co., Ltd.) or suitable 
equivalent alternative administered as a once daily dose using the treatment schedule in Appendix 
2. This multivitamin does not contain any compound with antimalarial activity. Its components are: 
Vitamin-A: 5000 USP units, Vitamin D: 400 USP Units, Ascorbic acid:  75 mg, Thiamine Mononitrate: 
2 mg, Riboflavin: 3 mg and Niacin amide: 20 mg. 
6.10 
Epidemiological data on place of residence, work, travel history and malaria risk 
In order to have a greater understanding of the possible sites of malaria transmission, and to relate 
genetic diversity to geographical location, participants will be asked a short set of questions on their 
place of residence, place of work and their history of travel plus possible risk factors for malaria. 
This is to obtain a detailed understanding of the behaviours and risk factors for malaria infection. 
We will collect GPS coordinates of the places of residence of all participants. In a subset of 
participants, GPS coordinates will be collected for their travel patterns during follow-up including 
place of work, forests, forest camps, farms or plantations to identify places where their infection may 
have occurred. The size of this subset will be determined by the availability of GPS devices with the 
number being limited to 50 participants at any one time. The GPS devices will be offered to 
unselected trial participants whenever they are available. We will collect all available local malaria 
treatment records to describe how the study population compares to the overall population who 
receive treatment for malaria and this will allow us to better understand local malaria epidemiology 
and transmission patterns. All personal information will be anonymised so that no individual can be 
identified from their treatment records, through interviews, or from mapping data.  
6.11 Malaria incidence data 
Passive surveillance data from all available sources for the study province collected by the 
Cambodia National Center for Parasitology Entomology and Malaria Control will be analysed to 
identify any changes in malaria incidence rate in study villages before, during and after the study 
where PA prophylaxis was administered compared to non-study villages. 
Enrolled participants who experience an episode of confirmed clinical malaria during follow-up will 
be linked back to their individual case records to quantify the incidence of clinical malaria in each 
study arm.  
6.12 
Analysis 
6.12.1  PCR for parasites 
PCR will be used to identify which individuals have parasites at enrolment (prior to taking the study 
medicine) and at each follow-up visit and is required for the primary study objective.  
6.12.2  Parasite genetics  
Parasite DNA will be used for genomic studies including but not limited to parasite species 
confirmation, microsatellite typing to identify parasite clones and single nucleotide polymorphisms 
(SNP) typing/whole genome sequencing to generate data for studies of the geographic origins of 
the parasites.  
6.12.3  Lumefantrine levels  
Lumefantrine levels will be used to confirm which patients had taken lumefantrine and to measure 
the amount present in the blood.  
6.12.4 Serology  
The serology sample will be used for anonymized investigation of the prevalence, incidence, 
association with fever, and risk factors for other common infectious diseases affecting the study 
population. Samples will be stored for later analysis. 
6.13 
Discontinuation/ Withdrawal of Participants from the Study  
Each participant has the right to discontinue the study drug or the study at any time. Data accrued 
up until the time of discontinuation will be used in the analysis.  

 
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In general, the investigators will be required to make every effort to perform the study procedures 
until completion of follow-up (maximum 3 visits over 84 days), including in the following situations:   
• 
Significant non-compliance with treatment regimen or study requirements 
• 
An adverse event which requires discontinuation of the study medication or results in inability 
to continue to comply with study procedures 
• 
Disease which requires discontinuation of the study medication or results in inability to continue 
to comply with study procedures 
• 
Loss to follow up (every attempt should be made to re-contact the participant) 
 
However, the investigator may discontinue participation in the study of a participant if he or she 
considers it necessary. 
In addition, the participants always have the right to withdraw consent in writing or verbally.  
The reason for withdrawal or discontinuation, if available, will be recorded in the CRF. If the study 
drug or participation in the study is discontinued due to an adverse event, the investigator will 
arrange for follow-up visits at least until the adverse event has resolved or stabilised.    
If a participant does become pregnant during participation in the study, they will be withdrawn from 
the study immediately upon it being reported to the study team. Any pregnancy must be reported 
to the Principal Investigator within one working day of awareness. The PI must take all reasonable 
efforts to discover the outcome of the pregnancy and fill out the pregnancy form. If there is a 
congenital abnormality or a still born baby, this needs to be reported as a serious adverse event.  
6.14 
Source Data 
Source documents are original documents, data, and records from which participants’ CRF data are 
obtained. These include, but are not limited to, village malaria and clinic records (from which medical 
history and previous and concurrent medication may be summarised into the CRF), clinical and 
office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and CRFs.  
CRF entries will be considered source data if the CRF is the site of the original recording (e.g., there 
is no other written or electronic record of data). In this study, the CRF will be used as the source 
document for most of the data points. 
All documents will be stored safely in confidential conditions. On all study-specific documents, other 
than the signed consent form, the participant will be referred to by the participant number and initials, 
not by name. 
 
7.  
STUDY DRUGS 
7.1 
Storage of Study Drugs 
All efforts will be made to store the study drugs in accordance with the manufacturers' 
recommendations in a secure area. This may be difficult at some sites where air-conditioned 
storage rooms are not available. The ACT should be stored between 15°C to 30°C (59°F to 86°F).   
Where this is not possible and monitored storage conditions do not meet the recommendations, the 
artemisinin-derivatives and partner drug content of batches of ACT will be retested at the end of the 
study.  
7.2 
Compliance with Study Drugs 
Study drugs will be administered as Directly-Observed-Therapy (DOT) on the first day. Where 
possible, study drugs will also be administered as DOT on days 2 and 3. Where DOTs is not 
possible, the participant will be contacted by the study team by telephone or in person to ensure 
they take the second and third doses of medication and to ensure they follow the correct procedure 
in case of vomiting. If the participant vomits, and is re-dosed; this will be recorded in the CRF. If 

 
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vomiting within 1 hour occurs again after retreatment, no repeat dosing is allowed. All drug doses 
will be recorded in the CRF. To maximise adherence to the study medication, the study will be 
preceded by a period of community sensitisation and engagement including information sessions 
on the importance of taking all three doses of medication. The participants will be requested to take 
each dose with food to maximize absorption of the lumefantrine.   
7.3 
Accountability of the Study Treatment 
All movements of study medication will be recorded. Both study medication of individual participant 
and overall drug accountability records will be kept up to date by the study staff.  
7.4 
Concomitant Medication 
Throughout the study, investigators may prescribe concomitant medications or treatments deemed 
necessary (e.g. antipyretics or anti-emetics) to provide adequate supportive care except for 
antibiotics with antimalarial activity unless unavoidable (e.g. doxycycline, azithromycin). If these are 
required the participants will be kept in the study and this will be noted as a protocol deviation.  Anti-
emetics should not be prescribed as a prophylaxis if no nausea or vomiting is present. 
Antimalarials for symptomatic, confirmed malaria infections will be prescribed as described above. 
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8.  
SAFETY REPORTING 
This trial will use drugs that have either been registered or evaluated extensively. To add to the 
evidence base for safety of AL as prophylaxis, we will record and review all Adverse Events (AEs) 
and Serious Adverse Events (SAEs) that are reported to occur in the study.  
A symptom questionnaire will be performed on enrolment and at each subsequent follow-up visit to 
the health care center, to aid in the identification of adverse events. In addition, enrolled individuals 
will be encouraged to promptly report any unexpected symptoms or illnesses between follow-up 
visits to the study team. 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an adverse event (AE) or serious adverse event (SAE), as provided in this protocol.   
All SAEs and AEs will be promptly documented from the moment of drug administration in the study 
to discontinuation of the participant from study participation. Any events occurring between 
screening and drug administration will be considered as baseline, preexisting conditions. 
All adverse events must be recorded in the AE/SAE CRF. To avoid colloquial expressions, the 
adverse event should be reported in standard medical terminology. Whenever possible, the adverse 
event should be evaluated and reported as a diagnosis rather than as individual signs or symptoms.  
If a definitive diagnosis is not possible, the individual symptoms and signs should be recorded. 
Whenever possible, the aetiology of the abnormal findings will be documented on the CRF.  Any 
additional relevant laboratory results obtained by the Investigator during the course of this study will 
be recorded on the CRF.  
 
If the event meets the criteria for “serious”, the SAE must be reported to the PAL-Cambodia safety 
team within 24 hours from the time that the event was identified. If further data is required, additional 
documentation can be submitted. All SAEs must be followed until resolution, or until the SAE is 
deemed permanent or leads to death. 
 
Samples will be shipped for PCR to a molecular laboratory where they will be analysed in batches. 
Following quality control results will be available approximately 3-6 months from the time of 
collection. The list of positive tests will be returned to the field sites. If a participant is found to have 
a plasmodium infection, and has not already received antimalarial treatment subsequent to the 
sample being collected, then these individuals will be contacted by a local health worker, and if a 
participant reports fever or illness they will offered appropriate diagnosis and treatment. 
8.1 
Definitions 
8.1.1. Adverse Event (AE) 
An AE is any undesirable event or clinical deterioration that occurs to a study participant during the 
course of the study; that is, from the time of administration of study drugs until study ends (i.e., until 
the follow up visit) whether or not that event is considered related to the study drugs, or to a 
concomitant drug or procedure: e.g.     
• any unfavourable and unintended symptom 
• physical sign 
• abnormal laboratory result 
• an illness 
Any new clinical sign or clinical deterioration that occurs between signing the consent form and the 
administration of study drugs is not an AE. This information will be recorded in the medical records, 
as a pre-existing condition.  
8.1.2 Serious Adverse Event  
A serious adverse event is an AE that: 
• 
results in death 
• 
is life-threatening i.e. the participant was at risk of death at the time of the AE 

 
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• 
requires in participant hospitalisation or prolongation of existing hospitalisation 
• 
results in persistent or significant disability/incapacity  
• 
is a congenital anomaly/birth defect 
• 
Any other significant medical condition 
All of the above criteria apply to the case as a whole and should not be confused with the outcomes 
of individual reactions/events. More than one of the above criteria can be applicable to the one 
event. Important medical events that may not be immediately life-threatening or result in death or 
hospitalisation may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardise the participant or require medical or surgical intervention to prevent one of the 
outcomes listed in the definition above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse. 
8.2 
Reporting Procedures for Serious Adverse Events 
All SAEs must be reported by the site investigator to the Study PI and PAL-Cambodia safety and 
medical monitor, within one day of his or her awareness of the SAE. The SAE report, should be 
emailed to the email paltrial@tropmedres.ac.   
Further reports should be submitted, if required, until the SAE is resolved. 
The site investigator must also report the SAEs to the local ethics committee in accordance with 
local requirements. 
8.3 
Evaluating Adverse Events and Serious Adverse Events 
8.3.1  Assessment of Intensity  
Each adverse event will be graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0 November 2017. 
If an adverse event is not listed in the CTCAE table, the Investigator will assess the severity using 
the following guidelines: 
1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL* 
3 = Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL** 
4 = Life-Threatening consequences; urgent intervention indicated 
5 = Death related to AE 
Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
8.3.2  Clarification of the difference in meaning between ‘severe’ and ‘serious’  
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache).  This is not the same as “serious”, which is based 
on the outcome or criteria defined under the serious adverse event definition. An event can be 
considered serious without being severe if it conforms to the seriousness criteria, similarly severe 
events that do not conform to the criteria are not necessarily serious.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 

 
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8.3.3 Assessment of relatedness 
The investigator is obligated to assess the relationship between study drug and the occurrence of 
each AE/SAE using the following categories of relatedness: 
• Definite: clear-cut temporal association  
• Probable: clear-cut temporal association, with improvement upon drug withdrawal, and not 
reasonably explained by the participant’s known clinical state or other aetiology. 
• Possible: less clear temporal association; other aetiologies are possible. (Other possible 
aetiologies should be recorded on the CRF). 
• Not related: no temporal association with the study drug; assessed as related to other 
aetiologies such as concomitant medications or conditions, or participant’s known clinical 
state. 
The investigator will provide the assessment of causality as per the AE/SAE data collection tool.  
 
 
8.3.4 Outcome 
The investigator will follow-up the AE and SAE until resolution or until no further medically relevant 
information can be expected. AE and SAE outcome will be classified as follows: 
• 
Continuing/ongoing  
• 
Resolved 
• 
Resolved with sequelae 
• 
Permanent  
• 
Fatal 
 
   

 
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9 
STATISTICAL CONSIDERATIONS 
9.1 
Sample size justification  
The target population for this study will be adult Cambodians who work and sleep in the forest 
(farmers, collect forest goods, hunting, etc.). 2,200 study participant episodes are required in each 
arm to have sufficient power to detect a statistically significant difference between the treatment arm 
and a control arm. The estimate of the required sample size is complicated by the scarce data on P. 
falciparum incidence in forest workers. We estimate the required sample size based on our study in 
forest rangers in Vietnam in 2016 (13) combined with an estimate of the time spent in the forest from 
ongoing studies in northeast Cambodia. In Viet Nam, we found that 1 forest ranger became infected 
per 500 person-nights spent in the forest. We estimate conservatively that during each episode, 
each participant will spend at least 10 days in a high-risk zone. We will need 20 infectious bites per 
study-arm: 2x20=40 (i.e. irrespective of protection afforded per arm). Risk days/nights needed: 
40x500= 20,000. Each participant episode contributes 10 risk days/nights: 20,000/10 = 2,000 
episodes required. The assumed loss to follow-up could be as high as 10% =200. Therefore, the 
total sample required is 2,000+200=2,200 study participant episodes. 
 
Formally, we anticipate that the risk of being Pf positive without receiving prophylaxis will be around 
5%. A total of 1,605 participant-episodes per arm are enough to detect a difference of at least 40% 
in the proportion of episodes with a Pf positive result as defined by the 28-day PCR parasite positivity 
rate i.e. from 5% positivity in participants without receiving antimalarial prophylaxis (i.e. multivitamin) 
to 3% positivity in participants receiving artemether-lumefantrine prophylaxis. This has been 
estimated with 80% power and 5% significance level. However, we also anticipate that we will likely 
observe multiple episodes being recruited into the study that can reduce power of the study if not 
accounted for. To compensate for the multiple episodes and any losses to follow up, we plan to 
recruit approximately 600 (i.e. 595) additional episodes in each group on top of the required 1605 
single episodes. This gives an additional 27% episodes to account for the multiple episodes and 
losses to follow up. Thus, the overall sample size will be 4,400 episodes (i.e. 2,200 episodes in the 
treatment arm and 2,200 episodes in the control arm).The sample size calculations have been 
performed in Stata version 15. 
9.2 
Statistical Analyses 
Analysis of other endpoints will be described in a Statistical Analysis Plan. A brief overview is given 
below.  
9.2.1 Proportions 
These will be compared using chi squared or Fisher’s exact test, as appropriate. Crude proportions 
will be calculated with the exact 95% confidence intervals (CI), where relevant. 
9.2.2 Continuous data 
These will be summarised by medians (IQR, ranges) and means (standard deviations, 95% CIs), as 
appropriate, and will include the parasite counts and laboratory parameters. Comparisons of 
continuous data will be assessed using the paired/unpaired t tests or the sign rank/Mann Whitney 
U tests, as appropriate.  
9.2.3 Safety analysis 
Safety analyses will be based on the whole population that get administered the study drug. Safety 
and tolerability of ACT versus multivitamin will be assessed by comparing the frequency (%) of 
adverse events and serious adverse events, with particular attention to abdominal pain, appetite 
perturbation, using the Fisher’s exact test.  Safety data will be presented in tabular and/or graphical 
format and summarised descriptively. Any clinically relevant abnormalities or values of potential 
clinically concern will be described. Participants will be analysed according to an intention to treat 
and a per protocol method where appropriate. 

 
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9.2.4 Adverse events 
Adverse events will be graded according to Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 November 2017. 
All adverse event summaries will refer to treatment emergent adverse events, i.e. adverse events 
that newly started or increased in intensity after the study drug administration. AE summaries will 
be generated for all AEs that occurred after study drug administration, until the end of the study. 
 
 

 
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10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS  
Direct access will be granted to authorised representatives from the sponsor and host institution, 
the regulatory authorities, and ethical committee (if applicable), to permit trial-related monitoring and 
inspections.   

 
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11 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES  
The study will be conducted in accordance with the current approved protocol, ICH GCP, any 
national regulations that may apply to this study and standard operating procedures. The WWARN 
will be engaged in assuring QA/QC of study execution in collaboration with the MORU Clinical Trials 
Support Group (CTSG). Their role will include but not be limited to monitoring adherence to SOPs 
for collection of laboratory specimens and quality checks (curation) of laboratory data according to 
standard methodologies.  
11.1 
Monitoring 
Study sites may have in place a system for internal monitoring. In addition, regular external 
monitoring of all sites will be performed by the MORU CTSG according to ICH GCP and a Monitoring 
Plan. Data will be evaluated for compliance with the protocol and accuracy in relation to source 
documents. The monitors will check whether the clinical trial is conducted and data are generated, 
documented and reported in compliance with the protocol, GCP and the applicable regulatory 
requirements. Evaluation of on-site monitoring schemes, such as a reciprocal monitoring scheme, 
may be undertaken at selected sites by CTSG. 

 
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12 
ETHICS 
12.1 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in compliance with the current revision of 
the Declaration of Helsinki (Fortaleza 2013). 
12.2 
 ICH Guidelines for Good Clinical Practice 
The Investigators will ensure that this study is conducted according to any National Regulations and 
that it will follow the principles of the ICH Guidelines for Good Clinical Practice. 
12.3 
 Approvals 
The study protocol and its associated documents will be submitted to the Oxford Tropical Research 
Ethics Committee (OxTREC) and the appropriate local ethics committees for written approval.   
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents.    
12.4 
 Risks 
This study will use drugs that have been studied thoroughly and their toxicities are well described. 
In general, they are all well tolerated. In the event of any serious or severe adverse event participants 
will be referred to the local Referral Hospital where best available care will be provided.  
12.4.1 Risks of artemether-lumefantrine  
The safety of artemether and lumfantrine for treatment of malaria has been evaluated in clinical trials 
and, post licensing, widespread use for treating malaria in hundreds of millions of patients per year. 
Reported AL side effects have generally been mild. Reported adverse reactions in clinical trials have 
been similar or lower in frequency and magnitude to other ACTs. The commonest (>=3%) reported 
adverse events in clinical studies with AL in adults were headache, anorexia, dizziness and asthenia. 
AL is not known to cause harmful prolongation of the QTc interval.[22]. 
12.4.2  Risks of multivitamin 
The main side-effects of multivitamin are upset stomach, unpleasant taste or headache which are 
mild to moderate in nature. Very rarely, these may cause an allergic reaction.  
12.4.3 Risk of phlebotomy & finger stick  
The primary risks of phlebotomy include local discomfort, occasional bleeding or bruising of the skin 
at the site of needle puncture, and rarely haematoma or infection. Phlebotomy will be performed by 
suitably qualified and trained staff using appropriate hygiene measures including gloves and alcohol 
swabs to clean the skin. 
12.4.4 Risk of GPS data 
Due to the potential unique nature of the GPS tracking data, it may be possible to identify individuals 
from their tracks. This will be minimized by the GPS tracking data being kept separately from any 
personally identifiable information and linked to the data collected on the study CRF only through a 
unique study code. The GPS tracking data will also be stored anonymously on the tracking device 
during collection and moved to an encrypted hard drive upon completion of collection. 
12.5 
Benefits  
There are no anticipated direct benefits to the participants in this study. However, knowledge gained 
from this study is expected to help to assess the efficacy and feasibility of prophylaxis to prevent 
malaria in forest workers, and to 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. 
 

 
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12.6 
Alternatives to Study Participation 
Participants are able to decline freely participation in this study. If so, they will receive standard care 
for their malaria (if applicable).   
12.7 
 Incentives & Compensation 
Study participants will be compensated for time lost from work as a result of trial activities, the cost 
of local transport to attend for the follow up visits and will receive a per diem to cover the costs of 
meals on those days. The amounts in monetary terms will be determined by CNM in accordance 
with local norms.  
The study will pay for treatment for drug-related SAEs or other research-related injuries. The study 
cannot pay for long term care for disability resulting from complications of the illness.  
12.8 
Confidentiality 
The trial staff will ensure that the participants’ anonymity is maintained. The participants will be 
identified only by initials and a study number on the CRF and electronic databases. All documents 
will be stored securely and be accessible to trial staff and authorised personnel only.  

 
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13 
SAMPLE SHARING AND STORAGE 
Samples collected will be used for the purpose of this study as stated in the protocol and stored for 
future use no longer than 10 years. Consent will be obtained from participants for sample storage 
and/or shipment of specific samples to collaborating institutions for investigations that cannot be 
performed locally. Any proposed plans to use samples other than for those investigations detailed 
in this protocol will be submitted to the relevant ethics committees prior to any testing. Material 
transfer agreements will be arranged and signed where appropriate/needed. 
 
 

 
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14 
DATA HANDLING AND RECORD KEEPING 
Study data will be recorded on Case Report Forms (CRF) at the study sites and stored in a secure 
database. Validation checks will be built into the study database to identify missing values, 
inconsistencies, or invalid data. Additionally, study data will be profiled using statistical software to 
check for outliers and errors not detected by the database. All tasks related to data management 
will be carried out in accordance with the study data management plan.   
 
Data sharing 
With participant’s consent, participant’s data and results from blood analyses may be shared with 
other researchers in the future, in an anonymized form. 
 

 
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15 
SPONSORSHIP AND INSURANCE  
The University of Oxford has a specialist insurance policy in place: - Newline Underwriting 
Management Ltd, at Lloyd’s of London – which would operate in the event of any Participant 
suffering harm as a result of their involvement in the research. 

 
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16 
PUBLICATION POLICY 
Any data published in the peer-reviewed medical literature will protect the identity of the participants. 
This trial will be registered in a web based protocol registration scheme. All those who have made 
a substantial contribution will be co-authors on publications. The sites have the right to publish their 
data individually and to include members of the sponsor’s team who have made a significant 
contribution. There will also publications of pooled data which will be coordinated by the MORU 
group. All sites will have the opportunity to contribute to these publications.  
All the research findings from the programme and from relevant research outside the Programme 
will be analysed and integrated, and through the WHO Global Malaria Programme will be 
disseminated to policy makers, National Malaria Control Programmes (NMCPs) and other 
researchers.  
 

 
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17.  
REFERENCES 
 
 
1. 
Guerra, C.A., R.W. Snow, and S.I. Hay, A global assessment of closed forests, deforestation 
and malaria risk. Ann Trop Med Parasitol, 2006. 100(3): p. 189-204. 
2. 
Thanh, P.V., et al., Epidemiology of forest malaria in Central Vietnam: the hidden parasite 
reservoir. Malar J, 2015. 14: p. 86. 
3. 
Erhart, A., et al., Epidemiology of forest malaria in central Vietnam: a large scale cross-
sectional survey. Malar J, 2005. 4: p. 58. 
4. 
Sanh, N.H., et al., Forest malaria in central Vietnam. Am J Trop Med Hyg, 2008. 79(5): p. 
652-4. 
5. 
Thang, N.D., et al., Malaria in central Vietnam: analysis of risk factors by multivariate analysis 
and classification tree models. Malar J, 2008. 7: p. 28. 
6. 
Erhart, A., et al., Forest malaria in Vietnam: a challenge for control. Am J Trop Med Hyg, 
2004. 70(2): p. 110-8. 
7. 
Dysoley, L., et al., Changing patterns of forest malaria among the mobile adult male 
population in Chumkiri District, Cambodia. Acta Trop, 2008. 106(3): p. 207-12. 
8. 
Moore, S.J., et al., 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. 8: p. 344. 
9. 
Gryseels, C., et al., 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. 93(4): p. 
810-8. 
10. 
Grietens, K.P., et al., 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): p. e29991. 
11. 
Lengeler, C., Insecticide-treated bednets and curtains for preventing malaria. Cochrane 
Database Syst Rev, 2000(2): p. CD000363. 
12. 
Thang, N.D., et al., Long-Lasting Insecticidal Hammocks for controlling forest malaria: a 
community-based trial in a rural area of central Vietnam. PLoS One, 2009. 4(10): p. e7369. 
13. 
Son, D.H., et al., 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. 16(1): p. 444. 
14. 
York, A., Seasonal malaria chemoprevention in the Sahel. Lancet Infect Dis, 2017. 17(6): p. 
588. 
15. 
Snow, R.W., Seasonal Malaria Chemoprevention: An Evolving Research Paradigm. PLoS 
Med, 2016. 13(11): p. e1002176. 
16. 
Tripura, R., et al., A Controlled Trial of Mass Drug Administration to Interrupt Transmission 
of Multidrug-Resistant Falciparum Malaria in Cambodian Villages. Clin Infect Dis, 2018. 
67(6): p. 817-826. 
17. 
Pryce, J. and P. Hine, Pyronaridine-artesunate for treating uncomplicated Plasmodium 
falciparum malaria. Cochrane Database Syst Rev, 2019. 1: p. CD006404. 
18. 
Imwong, M., et al., High-throughput ultrasensitive molecular techniques for quantifying low-
density malaria parasitemias. J Clin Microbiol, 2014. 52(9): p. 3303-9. 
19. 
Imwong, M., et al., 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. 14: p. 381. 
20. 
Saunders, D.L., et al., Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med, 
2014. 371(5): p. 484-5. 
21. 
Organization, W.H., WHO Model List of Essential Medicines. 2017. 
22. 
Haeusler, I.L., et al., The arrhythmogenic cardiotoxicity of the quinoline and structurally 
related antimalarial drugs: a systematic review. BMC Med, 2018. 16(1): p. 200. 
 
 
 

 
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18 APPENDIX 1. SCHEDULE OF ASSESSMENTS     
    
  
TEST/APPLICATION
SCREENING
D0
D1
D2
CCM* D28-35 CCM* D56-63
CCM*
D84-91
CCM* up 
to D112
Informed consent
X
Demographics
X
Risk history
X
X
X
X
Travel history
X
X
X
X
Medical and drug history
X
Symptoms questionnaire
X
X
X
X
Temperature
X
Weight
X
Randomisation and assign study ID
X
AL/multivitamin doses to be given
X
X
X
Plasmodium PCR
X
X
X
X
Blood for storage (serology)
X
Plasmodium genetic analysis (DBS)
X*
X*
X*
X*
*CCM = episode of confirmed clinical malaria between enrolment and follow-up

 
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19 
APPENDIX 2. DOSING SCHEDULES 
 
19.1 
Artemether-lumefantrine 
 
Artemether -lumefantrine  dosing  schedule  
One tablet  AL contains  20 mg artemether  and 120 mg lumefantrine  (Coartem)  
 
No. of tablets  recommended  at approximate  timing  of dosing  
 
Day 1 
Day 2 
Day 3 
Day 8 
Weekly  
Weight:  
Kilogram  
0h 
 
8h 
24h 
 
36h 
48h 60h 
 
168h 
 
176h 
336h
… 
 
344h
… 
15 - <25 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
25 - <35 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
≥35 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
Alternative  preparation:  one tablet  AL contains  80 mg artemether  and 480 mg 
lumefantrine  (Artefan)  
 
No. of tablets  recommended  at approximate  timing  of dosing  
 
Day 1 
Day 2 
Day 3 
Day 8 
Weekly  
Weight:  
Kilogram  
0h 
 
8h 
24h 
 
36h 
48h 60h 
 
168h 
 
176h 
336h
… 
 
344h
… 
≥35 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 

 
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19.2 
Multivitamin 
Multivitamin  dosing  schedule  
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 
Or suitable  equivalent  alternative  
 
No. of tablets  recommended  at approximate  timing  of dosing  
 
Day 1 
Day 2 
Day 3 
Day 8 
Weekly  
Weight:  
Kilogram  
0h 
 
24h 
 
48h 
 
168h 
336h … 
≥15 
1 
1 
1 
1 
1 
 
 

 
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20 
APPENDIX 3.  LIST OF STUDY SITES & PRINCIPAL INVESTIGATORS 
 
CAMBODIA 
CNM:  Dr Huy Rekol (Principal investigator) Dr Siv Sovannaroth (Co-Principal Investigator)  
MORU : Dr. Rupam Tripura (Local investigator), Dr. James Callery (Local investigator), Dr. Tom 
Peto (Local Investigator), Dr Lorenz von Seidlein (Local Investigator), Professor RJ Maude (Principal 
Investigator), MORU, Thailand.  
 
Site office: Stung Treng Referral Hospital/Siem Pang Health Center, Stung Treng Province. 
Site office: Pursat Referral Hospital/Kravanh Health Center, Pursat Province. 
 

 
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21 
APPENDIX 4. AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version No. 
Date 
issued 
Author(s) 
of changes 
Details of Changes made 
Not applicable