A Phase 3, Placebo-Controlled Trial of Once-Daily Viloxazine Extended-Release Capsules in Adolescents With Attention-Deficit/Hyperactivity Disorder

Nasser, Azmi; Liranso, Tesfaye; Adewole, Toyin; Fry, Nicholas; Hull, Joseph T.; Busse, Gregory D.; Chowdhry, Fatima; Cutler, Andrew J.; Jones, Nandita Joshi; Findling, Robert L.; Schwabe, Stefan

doi:10.1097/jcp.0000000000001404

Cited by 34 publications

(73 citation statements)

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“…The average effects of viloxazine ER on EFDs appeared to be clinically relevant as a substantial proportion of subjects had significant improvements in EFDs. This work extends the previous findings [ 18 – 21 ] of viloxazine ER demonstrating improved ADHD symptoms, and may have implications for clinicians when planning treatment of children and adolescents with ADHD and EFD.…”

Section: Discussionsupporting

confidence: 84%

“…We used data from four double-blind, three-arm, parallel-group, placebo-controlled, phase III clinical trials of viloxazine ER in children and adolescents (6–17 years of age) with ADHD (Table 1 ) [ 18 – 21 ].…”

Section: Methodsmentioning

confidence: 99%

“…Viloxazine has demonstrated activity at the norepinephrine transporter and has been shown to increase prefrontal cortex serotonin levels in preclinical studies, although how these latter changes in serotonin neurotransmitter levels translate into humans remains to be fully elucidated [ 17 ]. In phase III clinical trials in children and adolescents (6–17 years of age) with ADHD, viloxazine ER reduced ADHD symptoms [ 18 – 21 ]. There were also low discontinuation rates during the course of the trials, suggesting a tolerable and safe profile [ 18 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…In phase III clinical trials in children and adolescents (6–17 years of age) with ADHD, viloxazine ER reduced ADHD symptoms [ 18 – 21 ]. There were also low discontinuation rates during the course of the trials, suggesting a tolerable and safe profile [ 18 – 21 ]. The objective of this post-hoc analysis was to evaluate the effects of viloxazine ER on EFD, which was measured in four pediatric phase III clinical trials using the Executive Function content scale of Conners 3rd Edition Parent Short Form (C3PS-EF).…”

Section: Introductionmentioning

confidence: 99%

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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

Faraone

Goméni²,

Hull

et al. 2021

Pediatr Drugs

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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.

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Section: Discussionsupporting

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Faraone

Goméni²,

Hull

et al. 2021

Pediatr Drugs

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“…1 A novel extended‐release version of viloxazine, SPN‐812, has recently been approved by the U.S. Food and Drug Administration as a nonstimulant treatment for attention deficit/hyperactivity disorder (ADHD) in children and adolescents. 2 , 3 , 4 , 5 , 6 Recent in vitro and in vivo animal studies have elucidated a multimodal mechanism of action, with demonstrated activity on norepinephrine and serotonin. 7 …”

mentioning

confidence: 99%

Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN‐812 (Viloxazine Extended‐Release) Pharmacokinetics in Healthy Adults

Wang

Kosheleff

Adeojo

et al. 2021

Clinical Pharm in Drug Dev

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SPN-812 (viloxazine extended-release) is a novel nonstimulant recently approved as a treatment for attentiondeficit/hyperactivity disorder in children and adolescents. Given that SPN-812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN-812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single-sequence, 3-treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN-812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN-812 and paroxetine (period 3). Blood samples were collected for 72 hours post-SPN-812 dosing and analyzed for viloxazine and its primary metabolite, 5-HVLX-gluc. Twenty-two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN-812 and paroxetine was assessed using analysis of variance on the log-transformed pharmacokinetic parameters C max , AUC 0-t , and AUC inf . The least-squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN-812 alone) C max , 116.04%; 90%CI, 109.49%-122.99%; AUC 0-t , 134.65%; 90%CI, 127.65-142.03; and AUC inf , 134.80%; 90%CI, 127.94%-142.03%. CYP2D6 inhibition resulted in a modest change (<35%) on viloxazine AUCs with no change in C max . All adverse events were mild in severity.

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Response Trajectories and Temporal Trends of Viloxazine Treatment for Young People With ADHD

Yu,

Kao,

Thompson

et al. 2024

JAMA Netw Open

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ImportanceViloxazine is a novel nonstimulant medication approved for the treatment of attention-deficit/hyperactivity disorder (ADHD).ObjectivesTo investigate the whether viloxazine is associated with effective and acceptable outcomes when treating children and adolescents with ADHD and to evaluate these outcomes’ associations with viloxazine doses and duration of treatment.Data SourcesThe MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycINFO, and ClinicalTrial.gov databases were searched from database inception to June 23, 2024.Study SelectionTwo reviewers independently screened for double-blind, fixed-dose randomized clinical trials (RCTs) that compared viloxazine with placebo for pediatric patients with ADHD.Data Extraction and SynthesisThe study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Data extraction was completed independently by 2 authors and cross-checked for errors. Random-effects pairwise and dose-response meta-analyses were conducted.Main Outcomes and MeasuresThe primary outcome was the improvement of ADHD symptoms (measured by ADHD Rating Scale–5), and the secondary outcomes were all-cause discontinuation, dropout due to adverse effects, and serious adverse effects.ResultsA total of 5 dose-response RCTs were included, with 1560 participants (1011 [64.8%] male; mean [SD] age, 10.6 [6.7] years). Viloxazine was associated with better outcomes in ADHD treatment compared with placebo (mean difference, 5.47 points; 95% CI, 4.03-6.91 points). The dose-response curve was bell-shaped, suggesting that doses greater than 400 mg or greater than 7 mg/kg might not be associated with more efficacy. The temporal trends analysis showed ascent curves tapering off at approximately weeks 4 to 6. The curve for 100 mg/d declined more rapidly, while the curves for 200 mg/d and 400 mg/d declined more gradually. The overall discontinuation rate due to adverse effects was 4.15% in the viloxazine group (45 of 1084), while viloxazine compared with placebo was associated with 2.48-fold higher risk of discontinuation due to adverse effects (risk ratio, 2.48; 95% CI, 1.26-4.88).Conclusions and relevanceIn this meta-analysis, viloxazine was associated with better efficacy in treating children and adolescents with ADHD than placebo. A moderate dose (200-400 mg or 6-8 mg/kg) may provide optimal treatment outcomes. Future studies are warranted to assess the long-term effect of viloxazine. Viloxazine was relatively well tolerated for children and adolescents with ADHD.

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A Phase 3, Placebo-Controlled Trial of Once-Daily Viloxazine Extended-Release Capsules in Adolescents With Attention-Deficit/Hyperactivity Disorder

Abstract: Supplemental digital content is available in the text.

Cited by 34 publications

References 55 publications

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

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

Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN‐812 (Viloxazine Extended‐Release) Pharmacokinetics in Healthy Adults

Response Trajectories and Temporal Trends of Viloxazine Treatment for Young People With ADHD

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