Background In Africa, the scale-up of malaria control interventions, including seasonal malaria chemoprevention (SMC), has dramatically reduced malaria burden, but progress toward malaria elimination has stalled. We evaluated mass drug administration (MDA) as a strategy to accelerate reductions in malaria incidence in Senegal. Methods We conducted an open-label, cluster-randomised controlled trial in a low-to-moderate transmission setting of Tambacounda, Senegal. Eligible villages had a population size between 200-800. All villages received pyrethroid-piperonyl butoxide bednets and proactive community case management of malaria at baseline. Sixty villages were randomised 1:1 to either three cycles of MDA with dihydroartemisinin-piperaquine+single-low dose primaquine administered to individuals aged ≥3 months, six-weeks apart starting the third week of June (intervention), or standard-of-care, which included three monthly cycles of SMC with sulfadoxine-pyrimethamine+amodiaquine administered to children aged 3-120 months starting end of July (control). MDA and SMC were delivered door-to-door. The primary outcome was clinical malaria incidence in all ages assessed during the peak transmission season (July-December), the year after intervention. Here, we report safety, coverage, and impact outcomes during the intervention year. The trial is registered at ClinicalTrials.Gov (NCT04864444). Findings Between June 21, 2021 and October 3, 2021, 6505, 7125, and 7250 participants were administered MDA and 3202, 3174, and 3146 participants were administered SMC across cycles. Coverage of ≥1 dose of MDA drugs was 79%, 82%, and 83% across cycles. During the transmission season of the intervention year, MDA was associated with a 55% [95% CI: 28%-72%] lower incidence of malaria compared to control (MDA: 93 cases/1000 population; control: 173 cases/1000 population). No serious adverse events were reported in either arm. Interpretation In low-to-moderate malaria transmission settings with scaled-up malaria control interventions, MDA with dihydroartemisinin-piperaquine+single-low dose primaquine is effective and well-tolerated for reducing malaria incidence. Further analyses will focus on the sustainability of this reduction. Funding United States Presidents Malaria Initiative

The study was funded by the US Presidents Malaria Initiative. MER is supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (Award Number K99HD111572). JH and ABG receive salary support from the US Presidents Malaria Initiative. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health, US Centers of Disease Control and Prevention, and the US Agency for International Development.

NCT04864444

The study was funded under the US Presidents Malaria Initiative Impact Malaria Consortium. The funders participated in the design of the study and reviewed the manuscript prior to submission. The funders had no role in data collection and data analysis. The first authors had full access to the study data and final responsibility for the decision to submit the manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval of this trial was granted by the Comité National dEthique pour la Recherche en Santé (CNERS) of Senegal and the University of California, San Francisco (UCSF) Human Research Protection Program. The US Centers for Disease Control and Prevention approved reliance on UCSF. The trial was registered with ClinicalTrials.gov (NCT04864444).

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