Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI). The efficacy, safety, and tolerability of CTN sustained release (SR) for adults with ADHD was demonstrated in 2 pivotal phase 3 trials (Adler LA, et al. J Clin Psychopharmacol. 2022;42:429-39).

Adults (18–55 years) meeting DSM-5 criteria for ADHD enrolled in these double-blind, multicenter, placebo-controlled trials and randomized to treatment if ADHD Investigator Symptom Rating Scale (AISRS) score was ≥28 at screening (if not receiving pharmacologic treatment for ADHD) or ≥22 at screening and ≥28 at baseline (BL) (if receiving treatment). Having had no prior benefit from ≥2 ADHD therapies of 2 different classes, taking prohibited medications, and positive alcohol/drug screen were exclusionary. Trials had 4 periods: (1) screening and washout (≤28 days), (2) single-blind placebo run-in (1 week), (3) double-blind treatment (6 weeks), and (4) follow-up (10 days after last dose). Patients with ≥30% improvement in the Adult ADHD Self-report Scale (ASRS) from start to end of screening were screen failures; those with ≥30% ASRS improvement from start to end of placebo run-in were terminated early. Patients were randomized 1:1:1 to twice-daily CTN SR (200 or 400 mg total daily dose [TDD]) or matching placebo. The 200 mg/d group received CTN SR 200 mg TDD from days 1–42; the 400 mg/d group received 200 mg TDD on days 1–7, and increased to 400 mg TDD on day 8. This analysis assessed CTN SR effects based on median BL AISRS severity score (<38 or ≥38) using a mixed model for repeated measures analysis. Least squares mean (LSM) differences (95% CI) from BL at day 42 were compared between individual CTN SR dose groups and placebo, tested at a 2-sided significance level of 0.05.

In total, 859 patients were randomized (200 mg TDD, n=287; 400 mg TDD, n=287; placebo, n=285). Significant LSM differences on the AISRS were observed vs placebo in the overall population (200 mg TDD and 400 mg TDD, P<0.0001 for each), in the low BL severity (200 mg TDD [P=0.016]; 400 mg TDD [P=0.019]), and in the high BL severity (200 mg TDD [P=0.005]; 400 mg TDD [P=0.003]) populations at day 42. Significant LSM differences vs placebo (P<0.01) began at day 7 (200 mg) and day 14 (400 mg) overall, remaining significant to day 42. Significant LSM differences were observed vs placebo (P<0.05) from day 14 (400 mg TDD) and day 21 (200 mg) in the low severity populations, and from day 21 (400 mg TDD) and day 7 (200 mg TDD) in the high severity population, remaining significant (P<0.05) to day 42.

CTN SR, a potential first-in-class NDSRI, is efficacious for patients with adult ADHD of low or high BL symptom severity, with significant improvements observed vs placebo within the first 3 weeks.

Study Registration: NCT03605680, NCT03605836

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