Protocol for a multicentric open-label randomized controlled trial comparing low-dose (0.25 mg/kg) and standard-dose (0.75 mg/kg) primaquine for gametocytocidal efficacy and safety in Plasmodium falciparum malaria.

Abstract

Introduction: World Health Organization (WHO) in 2010, recommended 0.75 mg/kg single dose primaquine for killing gametocytes after ruling out glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, considering the practical feasibility of G6PD testing, WHO revised the recommendation in 2012 to 0.25 mg/kg single dose primaquine on day-1. This study aims to investigate the efficacy and safety of single-low dose primaquine (0.25 mg/kg) administered on day-1 to intervention arm compared to standard regimen, high-dose primaquine (0.75 mg/kg) administered on day-2 to control arm.

Methods and analysis: This is a hospital based, open-label, multi-centric, randomized-controlled trial being conducted at four different sites in India, with a target sample size of 496 i.e., 124 participants per site. Participants above 18 years of age with uncomplicated P. falciparum malaria and normal glucose-6-phosphate dehydrogenase (G6PD) activity, defined as > 4.0 IU/g Hb using the point-of-care test, weight > 40 kg, haemoglobin > 8 g/dL are treated with ACT and randomized to either control or intervention arm. Efficacy assessment is based on gametocytemia as inferred from examination of stained peripheral blood smears during enrolment and follow-up. In addition, quantitative nucleic acid sequence-based amplification (QT-NASBA) for Pfs25 mRNA, will be used to quantify the gametocytes on day 1, 2/3, 7, and 14. Safety assessment during 14-day follow-up will be based on percentage of participants with more than 25% drop in haemoglobin, haemoglobin drop of 5 g/dl, haemoglobin value less than 8 g/dl, mean of maximum drop in haemoglobin during 28-day follow-up; and frequency of adverse events reported during the follow-up in both the arms. The primary outcome of the study is based on gametocyte density and point prevalence of gametocyte (efficacy) and haemoglobin concentration (safety) from enrolment to day 14 (for efficacy) and day 28 (for safety).

Ethics and dissemination: Study has been approved by Institutional Ethics Committee (NIMR/IEC-M/2023/970/v6-Jun/01). The study findings will be disseminated through publications in peer-reviewed journals as well as academic presentations. The findings will support evidence-based recommendations for national malaria control programs in India, potentially advocating for the adoption of the lower dose primaquine regimen.

Trial registration number: CTRI/2025/07/091988 (CTRI registration).

Trial status: Enrollment started in August, 2025. The trial is going on.