Background: In co-endemic areas there is a high risk of P. vivax recurrence in patients treated for P. falciparum malaria. Primauine radical cure has the potential to reduce P. vivax recurrences in patients presenting with P. falciparum as well as P. vivax malaria, but is undermined by poor adherence to the currently recommended 14 day regimen. We assessed the effectiveness of supervised primaquine radical cure in patients presenting with uncomplicated malaria. Methods: We conducted a cluster-randomised, controlled, open-label superiority trial in Papua, Indonesia. Twenty one clusters (village health post matched by location, size and malaria transmission) were assigned randomly (1:1) by a statistician independent to the trial to treat patients presenting with uncomplicated P. falciparum or P. vivax malaria with dihydroartemisinin-piperaquine plus either a supervised or unsupervised 14-day course of primaquine (0.5mg/kg per day). Patients were followed for 6 months and those representing with malaria were retreated with the same drug regimen. The primary outcome was the incidence risk and rate of P. vivax recurrent episodes over 6 months assessed in the intention to treat population. Findings: Between September 2016 and July 2018, 419 patients were enrolled. Overall the incidence risk of P. vivax recurrence in the 10 unsupervised clusters was 55.8% (95%CI, 32.3-81.8) compared to 29.7% (95%CI, 16.4-49.9) in the 11 supervised clusters (HR 0.23, 95%CI, 0.07-0.76, p=0.016). The incidence rate in unsupervised clusters was 859 (95%CI, 673-1,096) P. vivax infections per 1000 person years compared to 539 (95%CI, 390-747) in the supervised clusters (IRR 0.63, 95%CI, 0.42-0.94, p=0.025). The corresponding rates in the 224 patients presenting with P. falciparum malaria were 660 (95%CI, 446-977) and 346 (95%CI, 213-563); IRR 0.52 (95%CI, 0.28-0.98), p=0.043. There were no serious adverse events attributable to primaquine. Interpretation: In this area of moderate malaria transmission, supervision of primaquine radical cure reduced the risk of P. vivax recurrence and this was apparent for patients presenting with either P. falciparum or P. vivax malaria. Clinical Trial Registration Details: The trial was registered with the US National Library of Medicine, registered at ClinicalTrials.gov (NCT 02787070). Funding Information: The Bill and Melinda Gates Foundation, The Wellcome Trust and The Department of Foreign Affairs and Trade of the Australian Government. Declaration of Interests: No conflict of interests reported. Ethics Approval Statement: Ethical approval was obtained from the Human Research Ethics Committee of the Northern Territory Department of Health, Australia (HREC 15.2517) and the Health Research Ethics Committees of the University of Gadjah Mada, Indonesia (KE/FK/522/EC/2016).
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