Table 5 Major challenges during trial implementation

Taking prophylactic/unfamiliar medicine

Participants were concerned about taking a high number of tablets, especially in the arthemether-lumefantrine arm (4 tablets twice daily for 3 days followed by weekly twice a day), compared to the multivitamin arm (1 tablet twice daily for 3 days followed by weekly)

It was highlighted that the drug was safe, and the doses were standardized. Possible side effects were explained

Issues related to pregnancy

Although it was clarified to avoid becoming pregnant while taking part in the trial, eight participants were found to be pregnant following drug administration at the start of the trial. Some female participants could not join the trial as they or their partners did not want to use condoms and thus could not confirm avoiding pregnancy while on prophylaxis. Often couples were not interested in using contraceptives and wished for more children

After the first few cases of pregnant participants, the enrolment procedure was adapted: every female participant at fertile age would discuss with their partner and a team member in private. Specifically, if they were willing to use condoms during and after the written informed consent (at the start of the study), they were enrolled

Cultural considerations

In one village meeting, the VMW and village leader invited the two different ethnic groups (Muslims and Kavet) at different times for the engagement meeting and trial enrolment. The engagement team did not realize that Muslim communities were fasting because of Ramadan, when any kind of food and liquid including drugs were avoided from dawn to the dusk. When the trial team explained to couples from the Kavet ethnic minority about how to use condoms to avoid pregnancy, participants refused to join the trial as they did not want to use any contraceptives. The commune leader provided additional information that the Kavet ethnic groups like to maintain their tradition of having many children to expand the family (as assets) and so, they have never seen and used the condoms

Religious and cultural aspects were respected and taken into consideration during enrollment process. These aspects were discussed with the community and village heads prior to activities and enrolment procedures were adopted

Local perception of malaria as not a major health problem in the area

In one village with Lao ethnic minority, trial staff observed a high proportion of dropouts compared to other villages. The team thought because of their language, they may not have understood the study information. Another reason for high dropouts were that they were highly mobile, particularly they moved between places after the rice harvesting season (January) in search of jobs

The joint team identified possible reasons by interviewing participants, VMW, and the local trial staff. In December/January, after the completion of rice harvesting, most villagers did not go to the forest, so they did not feel the need to take the drugs. Participants and their group leaders were asked at enrolment if they would be able to attend the upcoming follow-up appointments

Messaging and adherence to drug regimens

On some occasions, trial staff did not involve representatives from all ethnic minority groups which meant some of these ethnic population did not understand the information about the study. Specifically, participants of Kavet minority group did not clearly understand the drug dosing schedule. Biscuits were supplied to the participants to take with drug as fatty food increases AL absorption but some participants gave the biscuits to their children, and they ran out of biscuits to take with the drug in the forest

The information about the trial activities were explained through easy to understand self-explanatory posters. If necessary, a volunteer, usually the local VMW was involved in the study clarification and discussion as a translator. Participants were provided additional biscuits and advised to take the drug with any other food containing fat

Operational challenges due to high mobility of forest goers

In one village, many participants were still in the forest on scheduled follow up days and trial staff could not reach them in time. People from most villages had farms (usually rice farms) in the forest where they stayed for several months during the rainy season and could not come back for the follow-up. Some of our participants had rice fields far away from the village and could not get back during the follow-up schedules. Some other participants when they got sick during their work in the farmlands, they sought VMWs/MMWs from other villages and thus were untraceable. Some members of forest goer groups were not going to the same location in the forest. Thus, at the follow-up, only few group members came, but not others. Some forest goer groups were big which made it difficult for group leaders to supervise intake of drugs among the members. Some people initially selected by the group as leaders of forest goer groups were illiterate

The trial team attempted to clarify at the enrolment stage whether participants would be able to attend the scheduled follow-up in a month's time. At the time of the planned follow-up, contact was made via the VMW to fix a day when participants were in their village. If necessary, the team visited villages and the farms for several days in a row and tried to establish contact with participants in the forest. In some cases, the study team also drove to the fields in the forest to conduct the follow-up at the place where the participants were staying. When group leaders of forest goers were illiterate, another member was chosen, with the groups’ agreement, even if he or she was younger than other group members

Rumors and adverse events

In one village, false rumors spread that drug causes frequent side effects e.g. stomach problems

All questions regarding the drug tolerance and safety were discussed and side effects were explained

Impact of COVID-19

First case of COVID-19 was confirmed by the Ministry of Health (MoH) of the Kingdom of Cambodia On 27 January 2020. There was serious concern among communities as news spread across the country. Villagers were particularly worried about large gatherings and meetings inside villages

In late March/April 2020, some forest goers came back to their homes instead of staying in the forest because of COVID-19. Some village leaders did not want people from outside to come to their village

Discussions took place with all stakeholders including local administration and community leaders to adjust the engagement and trial activities. Decisions were made to observe the situation on daily basis and follow the guidance from government policy and measures. All meetings were only held after prior discussion and agreement with village authorities. In some cases, it was agreed that participants would travel to the main research facility for enrolments and follow-ups. In other cases, meetings within villages were held only in small groups, complying with the current COVID-19 safety measures. All government recommendations to minimize COVID-19 transmission were followed including mask wearing, hand washing and social distancing