Supervised versus unsupervised primaquine radical cure for the treatment of falciparum and vivax malaria in Papua, Indonesia: a cluster-randomised, controlled, open-label superiority trial

Jeanne Rini Poespoprodjo, Faustina Helena Burdam, Freis Candrawati, Benedikt Ley, Niamh Meagher, Enny Kenangalem, Ratni Indrawanti, Leily Trianty, Kamala Thriemer, David J. Price, Julie A. Simpson, Ric N. Price

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Abstract

Background: There is a high risk of Plasmodium vivax recurrence in patients treated for Plasmodium falciparum malaria in co-endemic areas. Primaquine 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 aimed to assess the efficacy and safety of supervised versus unsupervised primaquine radical cure in patients presenting with uncomplicated malaria.

Methods: We did a cluster-randomised, controlled, open-label superiority trial in Papua, Indonesia. 21 clusters of village health posts, matched by annual parasite index, were randomly assigned (1:1) to treat patients (age >12 months and body weight >5 kg) presenting with confirmed uncomplicated P falciparum or P vivax malaria with oral dihydroartemisinin–piperaquine plus either a supervised or unsupervised 14-day course of oral primaquine (0·5 mg/kg per day). Patients in the supervised group were supervised taking their primaquine dose on alternate days. Patients were followed-up for 6 months and those who presented again with malaria were retreated with the same drug regimen. Masking was not possible due to the nature of the study. The primary outcome was the incidence risk of P vivax malaria over 6 months, assessed in the modified intention-to-treat population (all patients who were assigned to a treatment group, excluding patients who were lost to follow-up after their first visit). This trial is now complete, and is registered with ClinicalTrials.gov, NCT02787070.

Findings: Between Sept 14, 2016, and July 31, 2018, 436 patients were screened for eligibility and 419 were enrolled; 223 (53%) patients in 11 clusters were assigned to supervised primaquine treatment and 196 (47%) in ten clusters to unsupervised primaquine treatment. 161 (72%) of 223 patients in the supervised group and 151 (77%) of 196 in the unsupervised group completed 6 months of follow-up. At 6 months, the incidence risk of P vivax recurrence in the supervised group was 29·7% (95% CI 16·4–49·9) versus 55·8% (32·3–81·8) in the unsupervised group (hazard ratio 0·23 [95% CI 0·07–0·76]; p=0·016). The incidence rate for P vivax recurrence was 539 (95% CI 390–747) infections per 1000 person-years in the supervised group versus 859 (673–1096) in the unsupervised group (incidence rate ratio 0·63 [95% CI 0·42–0·94]; p=0·025). The corresponding rates in the 224 patients who presented with P falciparum malaria were 346 (95% CI 213–563) and 660 (446–977; incidence rate ratio 0·52 [95% CI 0·28–0·98]; p=0·043). Seven serious adverse events were reported (three in the supervised group, four in the unsupervised group), none of which were deemed treatment-related, and there were no deaths.

Interpretation: In this area of moderate malaria transmission, supervision of primaquine radical cure treatment reduced the risk of P vivax recurrence. This finding was apparent for patients presenting with either P falciparum or P vivax malaria. Further studies are warranted to investigate the safety and efficacy of radical cure for patients presenting with uncomplicated falciparum malaria in other co-endemic areas.

Funding: The Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Foreign Affairs and Trade of the Australian Government. Translation: For the Indonesian translation of the abstract see Supplementary Materials section.

Original languageEnglish
Pages (from-to)367-376
Number of pages10
JournalThe Lancet Infectious Diseases
Volume22
Issue number3
Early online date25 Oct 2021
DOIs
Publication statusPublished - Mar 2022

Bibliographical note

Funding Information:
This trial was funded by the Gates Foundation (INV-007122) and the Department of Foreign Affairs of the Australian Government (72904). RNP is a Wellcome Trust Senior Fellow in Clinical Science (200909), JAS is funded by an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowship (1104975), and KT is a CSL Centenary Fellow. This work was supported by the Australian Centre for Research Excellence on Malaria Elimination (ACREME), funded by the NHMRC of Australia (1134989). We thank all the patients, health staff, and the study team who took part in this study. We thank Dr Rintis Noviyanti (Eijkman Institute for Molecular Biology, Jakarta, Indonesia) for her assistance in supervising laboratory works. We thank members of the Data Safety Monitoring Board (Dr Paul Hariyanto [Department of Internal Medicine, University of Sam Ratulangi, Manado, Indonesia], Dr Ayodhia Pitaloka [Department of Child Health, Faculty of Medicine, University of North Sumatra, Medan, Indonesia], and Dr Lorenz von Seidlein [Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand]). We are grateful for Pak Reynold Rizal Ubra (District Health Office, Papua, Indonesia) and Prof Yati Soenarto (Universitas Gadjah Mada, Yogyakarta, Indonesia) for their continuing support to our works in Timika, Indonesia.

Funding Information:
This trial was funded by the Gates Foundation (INV-007122) and the Department of Foreign Affairs of the Australian Government (72904). RNP is a Wellcome Trust Senior Fellow in Clinical Science (200909), JAS is funded by an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowship (1104975), and KT is a CSL Centenary Fellow. This work was supported by the Australian Centre for Research Excellence on Malaria Elimination (ACREME), funded by the NHMRC of Australia (1134989). We thank all the patients, health staff, and the study team who took part in this study. We thank Dr Rintis Noviyanti (Eijkman Institute for Molecular Biology, Jakarta, Indonesia) for her assistance in supervising laboratory works. We thank members of the Data Safety Monitoring Board (Dr Paul Hariyanto [Department of Internal Medicine, University of Sam Ratulangi, Manado, Indonesia], Dr Ayodhia Pitaloka [Department of Child Health, Faculty of Medicine, University of North Sumatra, Medan, Indonesia], and Dr Lorenz von Seidlein [Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand]). We are grateful for Pak Reynold Rizal Ubra (District Health Office, Papua, Indonesia) and Prof Yati Soenarto (Universitas Gadjah Mada, Yogyakarta, Indonesia) for their continuing support to our works in Timika, Indonesia.

Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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