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

Introduction Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI) in development for treatment of attention-deficit/hyperactivity disorder (ADHD). The effect of CTN on cardiac repolarization from a thorough QT (TQT) trial is reported. Methods In this double-blind, placebo (PBO)- and active-controlled, 3-period crossover TQT trial, healthy adults (18-65 years) were randomized to dosing sequences including CTN (800 mg supratherapeutic dose: 4 x 100 mg tablets in the morning and 5 hours later), CTN PBO (4 PBO tablets in the morning and 5 hours later), and active control moxifloxacin (400 mg + CTN PBO in the morning and CTN PBO 5 hours later). Morning doses were separated by 72 hours. Plasma was collected and data were extracted from continuously recorded ECGs for 24 hours following dosing. Effects on ECG parameters (QT interval with Fridericia correction factor [QTcF], PR and QRS intervals, and T- and U-wave morphology), and heart rate (HR) were assessed. The primary analysis was C-QTc, the relationship between drug concentration and PBO-corrected change from baseline in QTcF (ΔΔQTcF). Categorical analyses of ECG parameters were conducted for changes in QTcF, PR, and QRS intervals and in HR. Results Of 30 participants enrolled, 56.7% were male and 86.7% were White. Mean (SD) age was 37.6 (14.5) years; mean (SD) BMI was 26.4 (3.4) kg/m 2 . The slope (90% CI) of the C-QTc relationship for CTN was −0.001 (−0.003, 0.00002) msec/[ng/mL] and not significant. The predicted ΔΔQTcF (90% CI) at the geometric mean C max of CTN 800 mg was −2.72 (−6.92, 1.48) msec. A significant slope (90% CI) of the C-QTc relationship for moxifloxacin (0.004 [0.002, 0.006] msec/[ng/mL]) and a predicted ΔΔQTcF (90% CI) at the geometric mean C max of moxifloxacin 400 mg above 5 msec (11.75 [8.25, 15.24]) confirmed assay sensitivity. No ΔΔQTcF ≥10 msec was observed for CTN at any postdose time point; all upper limits of 90% CIs of ΔΔQTcF were <10 msec. The by-time-point analysis showed the maximum least squares mean difference in ΔQTcF (90% CI) between CTN and PBO was 1.64 (−1.40, 4.68) msec at 24 hours postdose. No CTN-treated participants had a QTcF increase of >30 msec; no relevant increases in PR or QRS interval or HR were observed. Four participants had >25% decrease in HR and <50 beats per minute. No abnormal U waves were observed; 1 participant had abnormal T-wave morphology. No serious TEAEs or deaths were reported. The most frequently reported TEAEs with CTN were nausea (24.1%), dizziness (24.1%), and decreased appetite (13.8%). Conclusions In this TQT trial, centanafadine, a potential first-in-class NDSRI in development for treatment of ADHD, had no clinically meaningful effect on cardiac repolarization and was generally safe and well tolerated. Previous presentation: 2023 ACCP Annual Meeting, September 10–12, 2023, Bellevue, WA Funding Otsuka