RT Journal Article SR Electronic T1 Effectiveness and safety of reactive focal mass drug administration (rfMDA) using dihydroartemisinin–piperaquine to reduce malaria transmission in the very low-endemic setting of Eswatini: a pragmatic cluster randomised controlled trial JF BMJ Global Health JO BMJ Global Health FD BMJ Publishing Group Ltd SP e005021 DO 10.1136/bmjgh-2021-005021 VO 6 IS 6 A1 Sibonakaliso Vilakati A1 Nontokozo Mngadi A1 Jade Benjamin-Chung A1 Nomcebo Dlamini A1 Mi-Suk Kang Dufour A1 Brooke Whittemore A1 Khayelihle Bhangu A1 Lisa M Prach A1 Kimberly Baltzell A1 Nomcebo Nhlabathi A1 Calisile Malambe A1 Bongani Dlamini A1 Danica Helb A1 Bryan Greenhouse A1 Gugu Maphalala A1 Deepa Pindolia A1 Muhindo Kalungero A1 Getahun Tesfa A1 Roly Gosling A1 Nyasatu Ntshalintshali A1 Simon Kunene A1 Michelle S Hsiang YR 2021 UL http://gh.bmj.com/content/6/6/e005021.abstract AB Introduction To reduce malaria transmission in very low-endemic settings, screening and treatment near index cases (reactive case detection (RACD)), is widely practised, but the rapid diagnostic tests (RDTs) used miss low-density infections. Reactive focal mass drug administration (rfMDA) may be safe and more effective.Methods We conducted a pragmatic cluster randomised controlled trial in Eswatini, a very low-endemic setting. 77 clusters were randomised to rfMDA using dihydroartemisin–piperaquine (DP) or RACD involving RDTs and artemether–lumefantrine. Interventions were delivered by the local programme. An intention-to-treat analysis was used to compare cluster-level cumulative confirmed malaria incidence among clusters with cases. Secondary outcomes included safety and adherence.Results From September 2015 to August 2017, 222 index cases from 47 clusters triggered 46 RACD events and 64 rfMDA events. RACD and rfMDA were delivered to 1455 and 1776 individuals, respectively. Index case coverage was 69.5% and 62.4% for RACD and rfMDA, respectively. Adherence to DP was 98.7%. No serious adverse events occurred. For rfMDA versus RACD, cumulative incidences (per 1000 person-years) of all malaria were 2.11 (95% CI 1.73 to 2.59) and 1.97 (95% CI 1.57 to 2.47), respectively; and of locally acquired malaria, they were 1.29 (95% CI 1.00 to 1.67) and 0.97 (95% CI 0.71 to 1.34), respectively. Adjusting for imbalance in baseline incidence, incidence rate ratio for rfMDA versus RACD was 0.93 (95% CI 0.54 to 1.62) for all malaria and 0.84 (95% CI 0.42 to 1.66) for locally acquired malaria. Similar results were obtained in a per-protocol analysis that excluded clusters with <80% index case coverage.Conclusion In a very low-endemic, real-world setting, rfMDA using DP was safe, but did not lower incidence compared with RACD, potentially due to insufficient coverage and/or power. To assess impact of interventions in very low-endemic settings, improved coverage, complementary interventions and adaptive ring trial designs may be needed.Trial registration number NCT02315690.The data that support the findings of this study are not publicly available. Data are available from the authors on reasonable request and with permission of Eswatini Ministry of Health.