Viloxazine Extended-Release Administered With Psychostimulants in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: A Phase 4, Open-Label Trial.

Introduction: Viloxazine extended-release (VLX-ER) is effective as monotherapy for attention-deficit/hyperactivity disorder (ADHD), and is often tried as an add-on treatment when psychostimulant therapy fails to provide an adequate treatment response. This phase 4, open-label study evaluated safety, tolerability, and efficacy of VLX-ER with optimized psychostimulants in pediatric participants with ADHD. Morning versus evening VLX-ER use was also evaluated. Methods: Children and adolescents (6-17 years) experiencing inadequate psychostimulant response (investigator-assessed ADHD Rating Scale-5 [ADHD-RS-5] score ≥24 and Clinical Global Impression-Severity of Illness [CGI-S] scores ≥3) during a 4-week screening period received flexibly-dosed VLX-ER, taken once daily in the morning (weeks 14) or evening (weeks 5-8), concomitantly with a psychostimulant. Safety (primary outcome) and efficacy were evaluated relative to baseline. Results: Fifty-six participants (26 children; 30 adolescents) enrolled, and 48 (85.7%) completed the study. Combination therapy was well tolerated, with only two participants (3.6%) withdrawing due to adverse events (AEs). The most commonly reported AEs were headache (17.9%), decreased appetite (12.5%), and upper respiratory tract infection (10.7%). Mean ± standard deviation investigator-assessed ADHD-RS-5 scores (baseline: 37.2 ± 8.4) improved progressively by -13.5 ± 9.7 points at week 4 and -18.2 ± 10.0 points at week 8 (p < 0.0001 each). Likewise, CGI-S scores (baseline: 4.4 ± 0.6) improved by -0.9 ± 0.9 at week 4 and -1.4 ± 1.1 at week 8 (p < 0.0001 each). Parent-assessed scales, including ratings of morning and evening ADHD behaviors and sleep disturbances, showed significant improvement relative to baseline regardless of morning (week 4) or evening (week 8) VLX-ER dosing. Conclusion: Combined treatment with VLX-ER and psychostimulant therapy showed acceptable safety and tolerability, with improvement in morning and evening ADHD behaviors and sleep disturbances relative to stimulant monotherapy. Timing of VLX-ER administration (morning or evening) did not appear to affect safety, drug response, or sleep improvement.