Seven-day versus fourteen-day low-dose primaquine for Plasmodium vivax malaria in India: an open-label, non-inferiority, randomised, controlled trial.

BACKGROUND

India has a high burden of Plasmodium vivax malaria. Current malaria treatment guidelines recommend a total primaquine dose of 3·5 mg/kg administered over 14 days to prevent relapse in P. vivax infection, however, adherence is generally poor, impacting effectiveness. We aimed to determine the efficacy and safety of the same total dose of 3·5 mg/kg administered over 7 days in India.

METHODS

We conducted an open label, non-inferiority, randomised controlled trial at two sites in India. Febrile patients older than 16 years with microscopically confirmed P. vivax mono-infection and normal (≥30%) G6PD activity were eligible for enrolment. Patients were randomly assigned (1:1) using block randomisation, stratified by site, to either 3·5 mg/kg primaquine over 7 days or 3·5 mg/kg primaquine over 14 days, which is the current standard of care. Primaquine was administered in combination with chloroquine as per national treatment guidelines. The primary endpoint was the cumulative incidence of symptomatic recurrent microscopy-confirmed P. vivax parasitaemia within 6 months. Efficacy analyses were conducted on the intention-to-treat population. The study was registered with the Clinical Trials Registry of India (CTRI/2022/12/048283).

FINDINGS: Between September 2023 and October 2024, a total of 400 patients were enrolled (201 randomised to the 7-day group and 199 to the 14-day group). By 180 days of follow up, there were a total of four P. vivax recurrences, with two in each arm. The cumulative incidence of symptomatic parasitaemia by day 180 was 1·1% (95% confidence interval [CI] 0·0-4·1) in the 7-day primaquine group and 1·1% (95% CI 0·0-4·4) in the 14-day primaquine group. Sixteen patients (8%) treated with 7-day primaquine missed a primaquine dose compared with 40 patients (20%) treated with 14-day primaquine. There were 35 adverse events reported in each group, 11 of which were reported to be drug-related in the 7-day group compared with 13 in the 14-day group. Gastrointestinal side effects at day 7 were rare in both the 7-day (0·5% [1/183]) and the 14-day group (1·1% [2/180]). None of the patients had a haemoglobin fall from day 0 to days 1-14 by more than 5 g/dL or required blood transfusion.

INTERPRETATION: Compared with a 14-day primaquine regimen, a 7-day regimen of 3·5 mg/kg was well-tolerated and non-inferior within the observed 180 days of follow up. Adherence was greater among patients in the 7-day regimen. Although the overall number of recurrences was lower than anticipated, limiting the precision of the estimates, these findings are consistent with and support the current WHO recommendation for a 7-day primaquine regimen. Future studies with longer follow up could provide additional evidence for efficacy of this regimen against late P. vivax relapses.

FUNDING: Infectious Diseases Data Observatory (University of Oxford) through a grant from the Bill & Melinda Gates Foundation (INV-004713).