Efficacy, Safety, and Tolerability of Centanafadine Sustained-Release Tablets in Adults With Attention-Deficit/Hyperactivity Disorder

Abstract

Purpose/Background: Centanafadine is an inhibitor of norepinephrine, dopamine, and serotonin reuptake transporters under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD).Methods/Procedures: Two phase 3 randomized, double-blind, placebocontrolled, parallel-group studies of 200 mg/d or 400 mg/d centanafadine sustained-release tablets versus placebo included adults (18-55 years of age) with a diagnosis of ADHD. The primary and key secondary efficacy endpoints were the change from baseline at day 42 in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score and the Clinical Global Impression-Severity of Illness Scale, respectively. Findings/Results: Subjects randomized in study 1 (centanafadine 200 mg/d, n = 149; centanafadine 400 mg/d, n = 149; placebo, n = 148) and study 2 (centanafadine 200 mg/d, n = 145; centanafadine 400 mg/d, n = 143; placebo, n = 142) had moderate to severe ADHD (mean AISRS total score, 38.7 [SD, 6.8] across both studies). At day 42, statistically significant leastsquares mean differences in AISRS total score were observed in favor of centanafadine versus placebo in study 1 (200 mg/d: −3.16, P = 0.019; 400 mg/d: −2.74, P = 0.039) and study 2 (200 mg/d: −4.01, P = 0.002; 400 mg/d: −4.47, P = 0.001). Effect sizes versus placebo were −0.28 for 200 mg/d and −0.24 for 400 mg/d in study 1 and −0.37 for 200 mg/d and −0.40 for 400 mg/d in study 2. The overall rate of treatment-emergent adverse events (TEAEs) was low, but there was a small increase in TEAE occurrence with increasing dose. Incidences of serious TEAEs and abuse potential-related AEs were low. Implications/Conclusions: These are the first large-scale studies to demonstrate the efficacy and safety profiles of 200 mg/d and 400 mg/d centanafadine in adults with ADHD.

Two single arm trials of AKL-T01, a digital therapeutic for adolescents and adults with ADHD

“…Given that rating scales may be more subject to placebo effects than the TOVA (e.g., if participants previously heard about the FDA clearance of EndeavorRx and had expectancy bias), it will be important for future studies to consider the impact of AKL-T01 on ADHD symptoms and quality of life relative to an active control. Another consideration is dropout, which was higher in the adult study than in the adolescent trial or prior pediatric trials, though comparable to dropout rates in recent ADHD medication trials 30,31 . Future studies should consider possible reasons for differential dropout rates (e.g., the longer duration of treatment in the adult study; parental accountability among adolescents).…”

Treatment of ADHD: Drugs, psychological therapies, devices, complementary and alternative methods as well as the trends in clinical trials

“…Phase 2 studies indicated the therapeutic effectiveness of this drug ( Wigal et al, 2020 ). Phase 3 randomized controlled trails demonstrated centanafadine to be safe, well-tolerated and effective in addressing the core symptoms of ADHD in adults ( Adler et al, 2022 ) Currently, centanafadine is under investigation in several clinical trials assessing its efficacy and safety in children and adolescents with ADHD (e.g., NCT05279313, NCT05428033, NCT05257265). Tipepidine is a small-molecule non-narcotic antitussive drug that has been used in children in Japan since 1959.…”