Effectiveness and safety of high dose primaquine and tafenoquine in Plasmodium vivax patients (EFFORT)
Background  Shorter courses of primaquine and single dose tafenoquine have potential to improve effectiveness in preventing recurrent Plasmodium vivax infection, but there are limited data on their comparative effectiveness when provided unsupervised. The aim of the study was to assess the effectiveness and safety of these new treatment options.  Methods  We conducted a multi-centre, open-label individually randomised controlled superiority trial in Ethiopia, Pakistan, Indonesia and Cambodia. Adult patients 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 schizontocidal drugs (chloroquine in Ethiopia and Pakistan, dihydroartemisinin-piperaquine in Indonesia and artesunate-pyronaridine in Cambodia) and randomly assigned (1:1:1) to receive 7 days of unsupervised high-dose primaquine (total dose 7mg/kg), single dose tafenoquine (300mg) or 14 days low-dose primaquine (total dose 3.5mg/kg). Randomisation was stratified by site, by an independent statistician using randomly permuted blocks of varying sizes. The primary endpoint, assessed in a modified intention to treat population, was the cumulative incidence of any P. vivax parasitaemia within 6 months compared between the primaquine arms, secondary endpoints included comparison with the tafenoquine arm. The study was registered at ClinicalTrials.gov (NCT04411836).  Findings  Between April 2021 and September 2024, a total of 960 patients were enrolled in equal proportion (320 patients per arm). 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 arm and 18·5% (97.55% CI 13·8-24·6) in the 14-day-low-dose primaquine arm (Hazard Ratio (HR) =0·66; 97.55% CI 0·40-1·09, p=0·063). The corresponding incidence in the tafenoquine arm was 12·6% (97.55% CI 8·8-18·0); HR=0·64 (97.55% CI 0·39-1·05, p=0·041) compared to the 14-day-low-dose primaquine arm.  Of the adverse events occurring before day 42, 43% (24/56) were reported as drug related in the 7-day-high-dose primaquine arm, compared to 22% (16/72) in the tafenoquine arm and 34% (13/38) in the 14-day-low-dose primaquine arm. Two drug related serious adverse events occurred in the 7-day-high-dose primaquine arm.  Interpretation  Both unsupervised 7-day-high-dose primaquine and tafenoquine were well tolerated in G6PD normal patients and had a lower risk of P. vivax recurrence compared to 14-day-low-dose primaquine, albeit with uncertain magnitude. Our findings support the effectiveness and operational feasibility of shorter radical cure regimens across diverse malaria-endemic settings.