Single Low Dose Tafenoquine Combined with Dihydroartemisinin-Piperaquine to Reduce P. Falciparum Transmission: A Phase 2 Single Blind Randomised Clinical Trial in Ouelessebougou, Mali

Background: Tafenoquine (TQ) was recently approved as prophylaxis and radical cure for P. vivax infection, but its P. falciparum transmission-blocking efficacy is unclear. We determined efficacy and safety of single doses of TQ in combination with dihydroartemisinin-piperaquine (DP) for reducing gametocyte density and transmission to mosquitoes. Methods: In this single-blind, phase 2 randomised clinical trial, participants (12-50 years of age) with asymptomatic P. falciparum microscopy-detected gametocyte carriage (n=80) were randomized to standard treatment with DP, or with DP plus a single dose of TQ (in solution) at a final concentration of 0·42mg/kg, 0·83mg/kg, or 1·66mg/kg. The primary endpoint was percent reduction in mosquito infection rate 7 days after treatment compared to baseline. Safety endpoints included frequency and incidence of adverse events (AE). The final follow-up visit was on the 23 rd December 2021; the trial is registered on ClinicalTrials.gov (NCT04609098). Findings: Participants were enrolled from 29th October to 25th November 2020. Before treatment, 66% (53/80) of individuals were infectious to mosquitoes, infecting on average 12·5% of mosquitoes (Interquartile range [IQR] 3·64-35). Within-arm percent reduction in mosquito infection rate on day 7 was 79·95% (IQR 57·15-100) following DP (p=0·0005 for difference from baseline), 100% (IQR 98·36-100) following DP-TQ 0·42mg/kg (p=0·0005), 100% (IQR 100-100) following DP -TQ 0·83mg/kg (p<0·0001) and 100% (IQR 100-100) following DP-TQ 1·66 mg/kg (p<0·0001). 55/80 participants experienced a total of 94 AE over the course of the trial; 86 categorised as ‘mild’, 7 as ‘moderate’, and 1 as ‘severe’. No serious adverse events (SAE) occurred. No significant differences in the incidence of all AEs (p=0.73) or drug-related AEs (p=0.62) were observed between treatment arms. Interpretation: TQ was well tolerated and accelerated P. falciparum gametocyte clearance. All TQ doses demonstrated improved transmission reduction at day 7 compared to DP alone. These data support the case for further research on TQ as a transmission blocking supplement to standard antimalarials. Trial Registration: ClinicalTrials.gov (NCT04609098). Funding: Bill & Melinda Gates FoundationTrial registration: Declaration of Interest: We have no competing interests. Ethical Approval: Ethical approval was granted by the Ethics Committee of the Faculty of Medicine, Pharmacy, and Dentistry of the University of Science, Techniques, and Technologies of Bamako (Bamako, Mali), and the Research Ethics Committee of the London School of Hygiene and Tropical Medicine (London, UK).