Centanafadine for Attention-Deficit/Hyperactivity Disorder in Adolescents: A Randomized Clinical Trial.

OBJECTIVE This randomized, double-blind, placebo-controlled trial evaluated the efficacy, safety, and tolerability of centanafadine-a norepinephrine, dopamine, serotonin reuptake inhibitor-in the treatment of attention-deficit/hyperactivity disorder (ADHD) in adolescents. METHOD Adolescents (ages 13-17 years, inclusive) with a primary diagnosis of ADHD were randomized to once-daily centanafadine 164.4 mg, 328.8 mg, or placebo for 6 weeks. Dosing was not titrated. The primary endpoint was change from baseline in the ADHD Rating Scale, version 5 (ADHD-RS-5) symptoms total raw score at Week 6. This trial is registered with ClinicalTrials.gov (NCT05257265). RESULTS Of 459 participants (centanafadine 164.4 mg, n=155; 328.8 mg, n=155; placebo, n=149), 451 received ≥1 dose of study drug and 371 (80.8%) completed the trial. At Week 6, improvements in ADHD-RS-5 symptoms total raw score were significantly greater with centanafadine 328.8 mg than with placebo (-18.50 [0.93] vs -14.15 [0.93]; p=0.0006); centanafadine 164.4 mg did not meet the primary endpoint. Centanafadine 328.8 mg showed separation from placebo at Week 1, the first post-baseline timepoint, with the effect maintained throughout the study. Treatment-emergent adverse events (TEAEs) occurred in 48/153 (31.4%, 164.4 mg), 76/151 (50.3%, 328.8 mg), and 35/147 (23.8%, placebo) participants. The most common (≥5% any group) TEAEs were decreased appetite, nausea, headache, and rash. Most TEAEs were of mild or moderate severity; 3 events were severe: liver function test increased (n=1, 164.4 mg); aggression (n=1, 164.4 mg); and somnolence (n=1, placebo). CONCLUSION Centanafadine 328.8 mg was efficacious for ADHD treatment in adolescents. Both doses were generally safe and well tolerated.