Efficacy of Centanafadine in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and High Executive Dysfunction: A Post Hoc Analysis of Two Phase 3 Trials

Objectives: High levels of executive dysfunction associated with attention-deficit/hyperactivity disorder (ADHD) have been linked to poorer response to pharmacotherapy. This post hoc analysis assessed the efficacy of centanafadine in the treatment of ADHD core symptoms and associated features in a subgroup of children and adolescents with high executive dysfunction. Methods: Data were pooled from two phase 3, multicenter, randomized, double-blind, placebo-controlled trials conducted in the United States and Canada in children (6–12 years) and adolescents (13–17 years) with a primary diagnosis of ADHD who received centanafadine or placebo for 6 weeks. High levels of executive dysfunction were defined using a baseline Conners 3–Parent Short Executive Function T-score of ≥70. Efficacy outcomes assessed change from baseline in ADHD core symptoms and associated features. The p values were not controlled for multiplicity. Effect sizes were calculated using Cohen’s d method based on mixed models for repeated measures estimates and are shown for outcomes that separated from placebo. Results: Among 435 participants with high executive dysfunction, baseline ADHD Rating Scale-5 (ADHD-RS-5) total scores and Conners 3–Parent Short T-scores for Inattention, Hyperactivity/Impulsivity, Defiance/Aggression, and Learning Problems were all greater than in the low dysfunction subgroup. By Week 6, ADHD-RS-5 scores in the centanafadine-treated high dysfunction subgroup were similar to those in the centanafadine-treated low dysfunction subgroup and were lower than in the placebo-treated subgroups. Over Weeks 1–6, effect sizes in the high executive dysfunction subgroup ranged from 0.35 to 0.51 for ADHD-RS-5, 0.33 to 0.56 for Conners 3–Parent Short Inattention, 0.33 to 0.43 for Hyperactivity/Impulsivity, 0.34 to 0.53 for Executive Function, 0.36 to 0.52 for Learning Problems, and 0.19 to 0.36 for Defiance/Aggression. No new safety concerns were identified. Conclusions: Individuals aged 6–17 years with high levels of executive dysfunction achieved greater improvements in ADHD core symptoms and in several associated features, including executive dysfunction and emotional dysregulation, following centanafadine treatment when compared with placebo.