A Thorough QT Trial Using C-QTc to Evaluate the Effects of Centanafadine on Cardiac Repolarization

This study was funded by Otsuka Pharmaceutical Development & Commercialization, Inc. Introduction: Centanafadine is a norepinephrine/dopamine/serotonin reuptake inhibitor in development for treatment of attention-deficit/hyperactivity disorder (ADHD). The effect of centanafadine on cardiac repolarization from a thorough QT (TQT) trial is reported. Methods: This double-blind, placebo- and moxifloxacin-controlled, 3-period crossover trial randomized healthy adults (18-65 years) to dosing sequences including centanafadine (800 mg supratherapeutic dose: [400 mg in the morning and 5 hours later]), placebo, and moxifloxacin 400 mg; 72 hours separated each morning treatment. Effects on ECG (QT interval using Fridericia correction [QTcF], PR and QRS intervals, and T- and U-wave morphology), and heart rate (HR) were assessed. C-QTc, the relationship between drug concentration and placebo-corrected QTcF change from baseline (ΔΔQTcF), was the primary analysis. Results: Of 30 participants enrolled, 56.7% were male; mean (SD) age was 37.6 (14.5) years. The slope (90% CI) of the C-QTc relationship for centanafadine was −0.001 (−0.003, 0.00002) msec/[ng/mL] and was not significant. The significant C-QTc slope (90% CI) for moxifloxacin (0.004 [0.002, 0.006] msec/[ng/mL]) confirmed assay sensitivity. No ΔΔQTcF ≥10 msec was observed for centanafadine at any postdose time point. No centanafadine-treated participants had QTcF increases >30 msec; no relevant PR or QRS interval or HR increases were observed. Four participants had >25% decreases in HR and