Effectiveness and safety of 7-day high-dose primaquine and single-dose tafenoquine versus 14-day low-dose primaquine in patients with Plasmodium vivax malaria (EFFORT): a multicentre, open-label, randomised, controlled, superiority trial

Abstract

Background: Shorter courses of primaquine and single-dose tafenoquine have potential to improve the prevention of recurrent Plasmodium vivax infections, but there are few data on their comparative effectiveness when provided unsupervised. We aimed to assess the effectiveness and safety of these new treatment options. Methods: We conducted a multicentre, open-label, randomised, controlled, superiority trial in Ethiopia, Pakistan, Indonesia, and Cambodia. Adult patients (aged ≥18 years, or aged ≥16 years in Indonesia) with uncomplicated P vivax infection and glucose-6-phosphate dehydrogenase (G6PD) activity of 70% or greater were eligible for enrolment. Patients were treated with blood schizonticidal drugs (chloroquine in Ethiopia and Pakistan, dihydroartemisinin–piperaquine in Indonesia, and artesunate–pyronaridine in Cambodia) and randomly assigned (1:1:1) by an independent statistician using randomly permuted blocks of varying sizes to receive 7 days of unsupervised high-dose primaquine (total dose 7 mg/kg), single-dose tafenoquine (300 mg), or 14 days of low-dose primaquine (total dose 3·5 mg/kg). Randomisation was stratified by site. The primary endpoint, assessed in the modified intention-to-treat population (ie, patients who received allocated treatment, and were not lost to follow-up before day 15), was the cumulative incidence of any P vivax parasitaemia within 6 months compared between the primaquine groups, with the comparison of cumulative incidence between the tafenoquine group and the 14-day low-dose primaquine group a secondary endpoint. Key safety outcomes included the numbers of adverse and serious adverse events, including the number of gastrointestinal symptoms as well as the risk of anaemia. Safety outcomes were assessed in all patients who received any doses of study drug. The study is registered at ClinicalTrials.gov, NCT04411836, and is complete. Findings: Between April 25, 2021 and Sept 13, 2024, 4850 patients were screened for eligibility, of whom 960 patients (672 [70·0%] were male and 288 [30·0%] were female) were enrolled and randomly assigned (320 patients per group). The modified intention-to-treat population of 295 patients allocated to the 7-day high-dose primaquine group, 305 patients allocated to the tafenoquine group, and 301 patients allocated to the 14-day low-dose primaquine group were considered at risk of P vivax recurrence from day 15 onwards. The cumulative incidence of P vivax recurrence at 6 months was 13·0% (97·55% CI 9·0–18·5) in the 7-day high-dose primaquine group and 18·5% (13·8–24·6) in the 14-day low-dose primaquine group (hazard ratio [HR] 0·66 [97·55% CI 0·40–1·09], p=0·063). The corresponding incidence in the tafenoquine group was 12·6% (97·55% CI 8·8–18·0), with an HR of 0·64 (97·55% CI 0·39–1·05, p=0·041) compared with the 14-day low-dose primaquine group. Of the adverse events occurring before day 42, 24 (42·9%) of 56 were considered drug related in the 7-day high-dose primaquine group, compared with 16 (22·2%) of 72 in the tafenoquine group and 13 (34·2%) of 38 in the 14-day low-dose primaquine group. Four serious adverse events occurred, of which two (gastrointestinal symptoms in two patients in the 7-day high-dose primaquine group) were considered probably related to study drug. One study drug unrelated death occurred in the 14-day low-dose primaquine group. Interpretation: Both unsupervised 7-day high-dose primaquine and single-dose tafenoquine were well tolerated in patients with normal G6PD activity and they had a lower risk of P vivax recurrence compared with those in the 14-day low-dose primaquine group, albeit with uncertain magnitude. Our findings support the effectiveness and operational feasibility of shorter radical cure regimens across diverse malaria-endemic settings. Funding: National Health and Medical Research Council of Australia and Bill and Melinda Gates Foundation.