Evaluating malaria elimination strategies among military forces in Cambodia: a multi-arm clinical trial comparing monthly prophylaxis and focused screening and treatment

Background: Identifying effective malaria elimination strategies for remote regions and highly mobile populations in Southeast Asia is challenging given limited resources. In this clinical trial, two malaria elimination strategies were evaluated in partnership with the Royal Cambodian Armed Forces - monthly malaria prophylaxis (MMP) and focused screening and treatment (FSAT). Methods: Eight military cohorts (1,050 volunteers total) along the Cambodian-Thai border were randomly assigned to three months of either MMP or FSAT (four cohorts in each treatment arm) with monthly malaria testing for six months. Cohorts were further randomly assigned to receive either permethrin treated (ITU) or sham-treated clothing (sITU). Volunteers in MMP cohort were given three monthly three-day doses dihydroartemisinin-piperaquine (DP) along with a ‘universal’ low-dose weekly regimen of 22.5 mg primaquine for 12 weeks, intended for use regardless of body weight or G6PD status. Volunteers in FSAT cohort were treated with appropriate first-line antimalarials if they tested positive for malaria. Results: Plasmodium falciparum (Pf) positivity in MMP cohorts was reduced by 90% (10% at enrollment to 1% at six months; absolute risk reduction (ARR) 9%) at 6 months. However, 32% of Pf cases treated with DP as MMP at baseline recrudesced, requiring rescue treatment at 1 month with artesunate-mefloquine. Pf positivity in FSAT cohorts declined 66% over six months (7.6% to 2.7%; ARR 4.9%). MMP reduced P. vivax (Pv) positivity from 9% to 0% at three months, but Pv rebounded to 6.7% at six months. FSAT failed to significantly reduce Pv positivity during the study. The 22.5 mg weekly primaquine MMP regimen was safe, even for the 15% of volunteers with G6PD-deficiency. Those wearing ITU had additional Pv parasitemia reductions compared to sITU in the FSAT but not MMP cohorts. Conclusions: MMP was safe, and superior to FSAT, suggesting greater utility to achieve malaria elimination in Cambodia. Low dose (22.5 mg) weekly primaquine was a safe adjunct in this setting, even for those with G6PD-deficiency. Permethrin-treated clothing further reduced Pv parasitemia for FSAT but not MMP. We observed that MMP may be more easily scaled to eliminate malaria and that the military may provide substantial support for regional elimination efforts. Trial registration: The study was registered on https://clinicaltrials.gov/ on 13-01-2016 prior to enrollment (NCT02653898).