Single low-dose tafenoquine combined with dihydroartemisinin-piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial

Abstract

Background: Tafenoquine was recently approved as a prophylaxis and radical cure for Plasmodium vivax infection, but its Plasmodium falciparum transmission-blocking efficacy is unclear. We aimed to establish the efficacy and safety of three single low doses of tafenoquine in combination with dihydroartemisinin-piperaquine for reducing gametocyte density and transmission to mosquitoes.

Methods: In this four-arm, single-blind, phase 2, randomised controlled trial, participants were recruited at the Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako in Mali. Eligible participants were aged 12-50 years, with asymptomatic P falciparum microscopy-detected gametocyte carriage, had a bodyweight of 80 kg or less, and had no clinical signs of malaria defined by fever. Participants were randomly assigned (1:1:1:1) to standard treatment with dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus a single dose of tafenoquine (in solution) at a final dosage of 0·42 mg/kg, 0·83 mg/kg, or 1·66 mg/kg. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. Dihydroartemisinin-piperaquine was administered as oral tablets over 3 days (day 0, 1, and 2), as per manufacturer instructions. A single dose of tafenoquine was administered as oral solution on day 0 in parallel with the first dose of dihydroartemisinin-piperaquine. Tafenoquine dosing was based on bodyweight to standardise efficacy and risk variance. The primary endpoint, assessed in the per-protocol population, was median percentage change in mosquito infection rate 7 days after treatment compared with baseline. Safety endpoints included frequency and incidence of adverse events. The final follow-up visit was on Dec 23, 2021; the trial is registered with ClinicalTrials.gov, NCT04609098.

Findings: From Oct 29 to Nov 25, 2020, 1091 individuals were screened for eligibility, 80 of whom were enrolled and randomly assigned (20 per treatment group). Before treatment, 53 (66%) individuals were infectious to mosquitoes, infecting median 12·50% of mosquitoes (IQR 3·64-35·00). Within-group reduction in mosquito infection rate on day 7 was 79·95% (IQR 57·15-100; p=0·0005 for difference from baseline) following dihydroartemisinin-piperaquine only, 100% (98·36-100; p=0·0005) following dihydroartemisinin-piperaquine plus tafenoquine 0·42 mg/kg, 100% (100-100; p=0·0001) following dihydroartemisinin-piperaquine plus tafenoquine 0·83 mg/kg, and 100% (100-100; p=0·0001) following dihydroartemisinin-piperaquine plus tafenoquine 1·66 mg/kg. 55 (69%) of 80 participants had a total of 94 adverse events over the course of the trial; 86 (92%) adverse events were categorised as mild, seven (7%) as moderate, and one (1%) as severe. The most common treatment-related adverse event was mild or moderate headache, which occurred in 15 (19%) participants (dihydroartemisinin-piperaquine n=2; dihydroartemisinin-piperaquine plus tafenoquine 0·42 mg/kg n=6; dihydroartemisinin-piperaquine plus tafenoquine 0·83 mg/kg n=3; and dihydroartemisinin-piperaquine plus tafenoquine 1·66 mg/kg n=4). No serious adverse events occurred. No significant differences in the incidence of all adverse events (p=0·73) or treatment-related adverse events (p=0·62) were observed between treatment groups.

Interpretation: Tafenoquine was well tolerated at all doses and accelerated P falciparum gametocyte clearance. All tafenoquine doses showed improved transmission reduction at day 7 compared with dihydroartemisinin-piperaquine alone. These data support the case for further research on tafenoquine as a transmission-blocking supplement to standard antimalarials.

Funding: Bill & Melinda Gates Foundation.

Translations: For the French, Portuguese, Spanish and Swahili translations of the abstract see Supplementary Materials section.

Conflict of interest statement

Declaration of interests We declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile G6PD=glucose-6-phosphate dehydrogenase.

Figure 2

Participant infectivity, proportion of mosquitoes infected, and oocyst density in direct membrane feeding assays (A) Participant infectivity. Error bars are 95% CIs. p values from generalised linear models (family: binary) testing differences within treatment groups with baseline as reference are shown. The denominator for the proportion of infectious participants is the total number of participants still enrolled at a given timepoint, rather than the number tested at that time point for infectivity; infectivity assays were discontinued when a participant did not infect mosquitoes at two subsequent timepoints and were thereafter considered non-infectious. Full mosquito infection data including the proportion of infectious participants with denominator as total participants tested is shown in appendix 5 (p 6). (B) Mosquito infection rate. Each line represents one participant. Statistical analyses are shown in appendix 5 (p 6). (C) Oocyst density. Box plots show the median (central line), IQR (box limits), upper and lower quartiles plus 1·5 × IQR (whiskers), and outliers for mean oocyst densities in infected mosquitoes within each participant. Wilcoxon sign rank tests for differences in average oocyst density are shown. NC=not calculable.

Figure 3

Male and female gametocyte density and prevalence (A) Gametocyte prevalence. Error bars are 95% CIs. (B) Gametocyte density, shown for gametocyte positive individuals only (ie, male or female density >0·01 per μL). Box plots show the median (central line), IQR (box limits), upper and lower quartiles plus 1·5 × IQR (whiskers), and outliers. Within and between group statistical analyses of gametocyte density and prevalence are shown in appendix 5 (p 8). Gametocyte circulation time, area under the curve, and other outcomes are shown in appendix 5 (pp 7–11).