Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of Single-Dose Tafenoquine in Healthy Volunteers

Abstract

Introduction Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria. Objective This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina. Methods This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers. Adult healthy volunteers were randomized (2:1) to receive either a single 300-mg oral dose of tafenoquine or matched placebo on day 1. Ophthalmic assessments, including spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF), were conducted at baseline and day 90 and evaluated for pre-determined endpoints by an independent, masked reading center. Results One subject in each group met the composite primary endpoint for retinal changes identified with SD-OCT or FAF, i.e., one out of 306 (0.3%) with tafenoquine, one out of 161 (0.6%) with placebo. Both cases had unilateral focal ellipsoid zone disruption at day 90 with no effect on best-corrected visual acuity. The tafenoquine-treated subject had this abnormality at baseline, and was enrolled in error. There was no difference in ophthalmic safety between tafenoquine and placebo. Conclusion There was no evidence of any pharmacodynamic effect of 300-mg single-dose tafenoquine on the retina or any short-term clinically relevant effects on ophthalmic safety. This clinical trial is registered with ClinicalTrials.gov (identifier: NCT02658435). Electronic supplementary material The online version of this article (10.1007/s40264-019-00839-w) contains supplementary material, which is available to authorized users.

Tafenoquine: a toxicity overview

“…If the corrected QT (QTc) interval is greater than 500ms there is a propensity to develop torsades de pointes, a potentially fatal dysrhythmia. Chloroquine, piperaquine, and amodiaquine [51], which are 4-aminoquinolines, can cause a prolonged QTc interval.…”

Safety and Efficacy of Tafenoquine for Plasmodium vivax Malaria Prophylaxis and Radical Cure: Overview and Perspectives

“…Reassuringly, no conclusive evidence of short-term ocular toxicity of clinical significance has been found in patients who received a single therapeutic dose of 300 mg of TQ, 77 nor in individuals who took 400 mg/day for three days. 78 Some minor and temporary ophthalmic changes were recorded, 77 , 78 as other authors have reported too.…”

“…Reassuringly, no conclusive evidence of short-term ocular toxicity of clinical significance has been found in patients who received a single therapeutic dose of 300 mg of TQ, 77 nor in individuals who took 400 mg/day for three days. 78 Some minor and temporary ophthalmic changes were recorded, 77 , 78 as other authors have reported too. 73 In one study, no clinically significant ocular effects were detected at a dosing regimen of 200 mg of TQ daily for three consecutive days (this being a 600 mg loading dose), followed by 200 mg once weekly for 23 weeks.…”

Authors' response

“…Regarding the study quoted by Sharma et al 1 , i.e . Ackert et al 14 , in 2019, we would like to inform you that this study was not available to us at the time of compiling our manuscript and that was the probable reason due to which we were not able to include this study as well as any studies or updates published after the submission of our manuscript. Furthermore, we fail to understand how discussing ‘TQ use in the prophylaxis setting’ can be misleading when one of the approved indications of TQ is prophylaxis of P. vivax malaria.…”