Executive Function Outcome of Treatment with Viloxazine Extended-Release Capsules in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Post-Hoc Analysis of Four Randomized Clinical Trials

Abstract

Aim The aim of this study was to evaluate the effect of viloxazine extended-release capsules (viloxazine ER; Qelbree™) on executive function deficits (EFDs) in pediatric subjects (6-17 years of age) with attention-deficit/hyperactivity disorder (ADHD). Methods Data from four phase III placebo-controlled trials of 100-600 mg/day viloxazine ER (6-8 weeks of treatment) were used to evaluate the change from baseline (CFB) in the Conners 3rd Edition Parent Short Form-Executive Function (C3PS-EF) content scale T-score. Subjects were defined as EFD responders if they had C3PS-EF T-score > 70 at baseline and < 65 at end of study. ADHD symptoms were assessed with ADHD Rating Scale 5th Edition (ADHD-RS-5). Subjects were defined as ADHD symptom responders if they had a ≥ 50% reduction in CFB ADHD-RS-5 Total score at Week 6. The number needed to treat (NNT) and Cohen's d effect sizes were estimated for EFD and ADHD symptoms. Results A total of 1154 subjects were included in the analysis. Statistically significant improvements in EFDs were observed with viloxazine ER versus placebo (p = 0.0002). There were 52.5% of EFD or ADHD symptom responders in the viloxazine ER treatment group and 35.4% in the placebo group (p < 0.0001). The NNT was 5.8. The Cohen's d effect size for EFD and ADHD symptoms was 0.31. Conclusion Consistent with the efficacy of viloxazine ER demonstrated in pivotal trials, viloxazine ER significantly reduced EFDs in subjects with ADHD. Moreover, a substantial proportion of subjects treated with viloxazine ER had large improvements in EFDs, ADHD symptoms, or both.

A post hoc analysis of the effect of viloxazine extended-release capsules on learning and school problems in children and adolescents with attention-deficit/hyperactivity disorder

“…The responder analyses and NNT estimates in this population indicate that a substantial number of children and adolescents with ADHD treated with viloxazine ER can be expected to achieve improvements in clinically assessed LSPs. The results of this analysis are consistent with the data from two other post hoc analyses demonstrating improvement in executive function deficits (measured with C3PS) [22] and improved clinician-rated functional impairments associated with ADHD (measured with the functional impairment scale of the ADHD-RS-5) [26]. Taken together with primary data reported for viloxazine ER, which demonstrated efficacy in reducing ADHD symptoms and a favorable tolerability profile [18][19][20], these studies suggest viloxazine ER treatment can lead to clinically meaningful improvements in ADHD symptoms and functional behavior in children and adolescents with ADHD.…”

“…Recently, completed Phase 3 clinical trials have demonstrated efficacy of viloxazine ER in improving ADHD symptoms vs. placebo in children (6-11 years of age) and adolescents (12-17 years of age) with ADHD [18][19][20][21]. In a post hoc analysis of these four Phase 3 pediatric trials, viloxazine ER treatment was also associated with statistically significant improvements in executive function [22]; deficits in executive function have long been associated with poor learning and school related outcomes in ADHD [1,[23][24][25]. In another post hoc analysis evaluating the effect of viloxazine ER on inattention and hyperactivity/impulsivity-associated functional impairments, the improvements in mean change from baseline (CFB) were observed in all three learning and school related impairment items of ADHD Rating Scale 5th Edition (ADHD-RS-5): completing/returning homework, performing academically at school, and controlling behavior at school [26].…”

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder

“…Viloxazine ER improved scores on the Global Executive Composite (the composite of all nine scales) and the Metacognitive Index statistically significantly more than placebo. These data are consistent with a recent post-hoc analysis in pediatric subjects (6-17 years of age), where subjects treated with viloxazine ER demonstrated statistically significant improvements in executive function over placebo, as assessed by the Conners Third Edition Parent Short Form Executive Function content scale [47]. Improvement in the BRIEF-A Behavioral Regulation Index was not statistically significant in adult subjects in this study.…”

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021

“…Viloxazine is a non-stimulant medication, administered as extended-release capsules, which was approved for attention deficit hyperactivity disorder in children 6 to 17 years of age (Faraone et al 2021 ); it had been available in the past in Europe as a treatment for depression. Its mechanism of action is not fully understood.…”