A Randomized Thorough QT Trial Using Concentration‐QT Analysis to Evaluate the Effects of Centanafadine on Cardiac Repolarization

Centanafadine is a norepinephrine/dopamine/serotonin reuptake inhibitor in development for treatment of attention-deficit/hyperactivity disorder. This double-blind, placebo- and moxifloxacin-controlled, 3-period crossover trial evaluated the effects of centanafadine (EB-1020) and its metabolite (EB-10601) on cardiac repolarization in 30 healthy adults (18-65 years). Dosing sequences included centanafadine sustained-release 800 mg (supratherapeutic) total daily dose, placebo, and moxifloxacin 400 mg. Electrocardiogram parameters and heart rate (HR) were assessed. The primary endpoint was placebo-corrected change from baseline QTc (ΔΔQTc), analyzed using concentration-QTc (C-QTc) analysis. The C-QTc slopes for centanafadine (-0.001 ms/[ng/mL]) and EB-10601 (-0.0003 ms/[ng/mL]) were not statistically significant. Assay sensitivity was confirmed by the statistically significant C-QTc slope for moxifloxacin (0.004 ms/[ng/mL]) and a 2-sided 90% confidence interval lower bound >5 milliseconds. No change from baseline in QTcF or placebo-corrected QTcF ≥10 milliseconds for centanafadine was observed at any postdose time point. No centanafadine-treated participants had QTcF increases of >30 milliseconds and no relevant PR/QRS interval or HR increases were observed. The predicted ΔΔQTcF values of centanafadine, EB-10601, and moxifloxacin at the geometric mean C_max were -2.72, -1.59, and 11.75 milliseconds, respectively. No serious treatment-emergent adverse events or deaths were reported. Centanafadine was generally safe and well-tolerated, with no clinically meaningful effect on cardiac repolarization.