Clinically Meaningful Within-Patient Change in Core Attention-Deficit/Hyperactivity Disorder Symptoms in Children and Adolescents Treated With Centanafadine: Results From Two Phase 3 Randomized Clinical Trials.

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is characterized by core symptoms of inattention, hyperactivity, and impulsivity that are persistent and can interfere with daily functioning. Centanafadine is a norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) and cental nervous symstem simulant recently FDA approved for the treatment of ADHD in both adult and pediatric patients. This secondary analysis explores the efficacy of centanafadine for the treatment of ADHD core symptoms as measured by the clinical scales, Conners 3-Parent Short and Conners 3-Self-Report Short, in a children and adolescents over 6&#x2009;weeks of treatment. Two phase 3, multicenter, randomized, double-blind, placebo-controlled trials were conducted in the United States and Canada (children: NCT05428033; adolescents: NCT05257265).This analysis included children (6-12&#x2009;years) or adolescents (13-17&#x2009;years) with a primary diagnosis of ADHD randomized (1:1:1) to receive once-daily extended-release high-dose centanafadine, low-dose centanafadine, or placebo for 6&#x2009;weeks without initial titration. Secondary outcomes presented here include the change from baseline in Conners 3-Parent Short and Conners 3-Self-Report Short Inattention and Hyperactivity/Impulsivity T-scores over Weeks 1 to 6 analyzed using a mixed-effect model for repeated measures and a prespecified integrated analysis of clinically meaningful within-patient change for the Conners 3-Parent Short analyzed via a Cochran-Mantel-Haenszel test. Low-dose centanafadine did not meet the primary endpoint; therefore, low-dose data have been excluded from this presentation, and subsequent presented <i>p</i>-values are not controlled for multiplicity. In children (mean age 9&#x2009;years, 59% male) and adolescents (mean age 15&#x2009;years, 59% male), centanafadine showed separation from placebo as early as Week 1 (the first postbaseline time point), with significant improvements in inattention at each study timepoint over Weeks 1 to 6 as reported by both caregivers (Conners 3-Parent Short) and adolescents (Conner 3-Self-Report Short). Hyperactivity/Impulsivity was also significantly improved with centanafadine in children and adolescents at each week from Weeks 1 to 6 based on the Conners 3-Parent Short T-scores and at Weeks 4, 5, and 6 for the Conners 3-Self-Report Short. Compared to placebo, children treated with centanafadine had a 55% higher chance, and adolescents had a 65% higher chance of experiencing clinically meaningful within-patient change in inattention and a 48% and 46% higher chance in hyperactivity/impulsivity, respectively. Centanafadine was efficacious in children and adolescents with ADHD, providing robust caregiver-reported and self-reported improvements when compared with placebo in the core symptoms of inattention, hyperactivity, and impulsivity. ClinicalTrials.gov identifiers: NCT05257265 and NCT05428033.