52-Week Open-Label Safety and Tolerability Trial of Centanafadine Sustained Release in Adults With Attention Deficit Hyperactivity Disorder (ADHD)

Introduction Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI) in development for ADHD. In 2 pivotal adult ADHD trials, CTN sustained-release (SR) 200 mg/d and 400 mg/d, administered twice daily (BID), significantly reduced Adult ADHD Investigator Symptom Rating Scale (AISRS) total score vs placebo, with favorable safety and tolerability. Long-term effects of CTN SR 400 mg/d in adult ADHD are reported here. Methods Adults meeting DSM-5 criteria for ADHD who completed a pivotal trial or enrolled de novo were eligible for the 52-week, phase 3, open-label trial. Uncontrolled comorbid psychiatric disorder, undifferentiated diagnosis of ADHD, prohibited medicines, or positive alcohol or drug screen were exclusionary. All patients (pts) received CTN SR BID, titrated to 400 mg/d by day 8, and fixed thereafter. Safety was primarily assessed by adverse events (AEs); laboratory results, physical examinations, vital signs, ECG, Study Medication Withdrawal Questionnaire (SMWQ), and Columbia-Suicide Severity Rating Scale (C-SSRS) were also assessed. Efficacy was assessed by AISRS, Clinical Global Impression-Severity (CGI-S) and ADHD Impact Module-Adult (AIM-A). Analyses were based on observed results using descriptive statistics. Baseline was relative to the first CTN dose in the open-label trial. Results Of 662 pts enrolled (mean [SD] age 36.7 [10.1] years; 51.1% female; 82.9% White), 653 received CTN SR; 345 pts completed the trial. Common discontinuation reasons were pt withdrawal (119; 18%), AEs (81; 12.2%), and lost to follow-up (41; 6.2%); 22 (3.4%) pts discontinued for lack of efficacy. Treatment-emergent AEs (TEAEs) occurred in 401 pts (61.4%); 16 (2.5%) had severe TEAEs. Common TEAEs were insomnia (8.0%), nausea (7.7%), diarrhea, and headache (7.0% each). Serious TEAEs occurred in 12 pts (1.8%); none were CTN related. AEs of special interest (n=18; 2.8%) included rash (n=5; 1 severe), papule, rash erythematous, rash maculopapular, rash papular, and urticaria (n=1 each); 3 discontinued. Abuse potential–related AEs occurred in 31 pts (4.7%). No deaths occurred. SMWQ scores were low throughout. Suicidal ideation/behavior occurred in 13 pts (2.0%) per C-SSRS. There were no trends in laboratory, vital sign, or ECG changes. Baseline mean (SD) AISRS Total, Inattentive, and Hyperactive-Impulsive scores were 34.4 [10.3], 19.2 [5.6], and 15.2 [6.0], respectively; mean (SD) changes at week 52 were −20.4 (11.9), −11.2 (6.6), and −9.2 (6.2). Baseline mean (SD) CGI-S score was 4.2 (0.9); mean (SD) change at week 52 was −1.5 (1.1). Baseline mean (SD) AIM-A score was 6.5 (1.8); mean change at week 52 was 1.23 (2.0). Conclusions Safety, tolerability, and exploratory efficacy results from this trial demonstrate that CTN SR 400 mg is a safe and effective long-term treatment for ADHD in adults. Study Registration: NCT03605849 Previous presentation: APA Annual Meeting, May 20–24, 2023, San Francisco, CA Funding Otsuka