Once-Daily SPN-812 200 and 400 mg in the treatment of ADHD in School-aged Children: A Phase III Randomized, Controlled Trial

Abstract

Purpose: SPN-812 (viloxazine extended-release) is under investigation for the treatment of attentiondeficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase III study evaluated the efficacy and tolerability of SPN-812 200 and 400 mg once daily in children 6e11 years of age with ADHD. Methods: Patients were randomly assigned to receive SPN-812 200 mg, SPN-812 400 mg, or placebo, once daily for 8 weeks (including 3 weeks titration period). The primary efficacy endpoint was the change from baseline (CFB) in ADHD Rating Scale (RS)-5 Total score at end of study (EOS). Key secondary endpoints included Clinical Global ImpressioneImprovement (CGI-I) score at EOS, CFB in Conners 3eParent Short Form (PS) composite Tscore at EOS, and CFB in Weiss Functional Impairment Rating ScaleeParent (WFIRS-P) Total average score at EOS. Findings: A total of 313 patients were enrolled, with 301 in the intent-to-treat population (194 boys, 107 girls; mean age [SD], 8.4 [1.7] years). At EOS, the CFBs in ADHD-RS-5 Total score and CGI-I score were significantly improved with both 200-and 400mg/d SPN-812 versus placebo (ADHD-RS-5, P ¼ 0.0038 and 0.0063, respectively; CGI-I, P ¼ 0.0028 and 0.0099). At EOS, the CFB in Conners 3-PS composite T-score was significantly improved with 200-(P ¼ 0.0064), but not 400-mg/ d (P ¼ 0.0917), SPN-812 compared to placebo. No significant difference between the groups was found in WFIRS-P Total average score. The rate of discontinuations due to adverse events in both SPN-812 treatment groups combined was <5%. Implications: SPN-812 200 and 400 mg once daily was associated with improvements in ADHD symptoms in school-aged children and was generally well tolerated. ClinicalTrials.gov identifier: NCT03247543.

Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status

“…Viloxazine was found to be effective for ADHD symptoms and generally well tolerated, as demonstrated in several recent randomized, double-blind, placebo-controlled, phase II and III clinical trials [36][37][38][39]68]. In a recent phase II trial in children aged 6-12 years with ADHD (n = 222), treatment-emergent AEs (TEAEs) were generally mild or moderate, with only three severe TEAEs reported (tearfulness, irritability, and decreased appetite) [68].…”

“…The typical target dose for depression was 300-400 mg/day in adults or 100-200 mg/day in elderly patients, generally administered twice or three times daily [4]. Contemporary studies in the treatment of ADHD have administered viloxazine ER at daily doses of 100-400 mg in children (aged 6-11 years), and 200-600 mg in adolescents (aged 12-17 years) and 200-600 mg in adults (aged 18-65 years) [36][37][38][39][40].…”

“…Ongoing research has considered whether an ER formulation of viloxazine may help mitigate some of the aforementioned gastrointestinal side effects. Recent phase III [36][37][38][39] studies investigating the ER formulation at 100-600 mg/day in pediatric patients (i.e., children and adolescents, aged 6-17 years) diagnosed with ADHD found the incidence of nausea and vomiting for viloxazine to be 9.8%, vs 4.1% for placebo.…”

“…In a recent phase II trial in children aged 6-12 years with ADHD (n = 222), treatment-emergent AEs (TEAEs) were generally mild or moderate, with only three severe TEAEs reported (tearfulness, irritability, and decreased appetite) [68]. In four subsequent phase III trials in children aged 6-11 years [36,37] and adolescents aged 12-17 years [38,39], viloxazine ER was well-tolerated over 6-8 weeks of treatment (pooled N = 1117). The most frequently reported AEs were somnolence (14.5%), headache (10.8%), and decreased appetite (8.1%), with low discontinuation rates because of TEAEs (4% averaged across all trials), less than 1% of subjects reporting a serious TEAE, and no deaths [36][37][38][39].…”

“…In three of these four phase III trials, statistically significant improvements in ADHD-Rating Scale, Fifth Edition total scores (the primary endpoint) were reported as soon as 1 week following the onset of once-daily treatment with viloxazine ER 100 mg, 200 mg, and 400 mg, relative to placebo [36][37][38]. In the fourth phase III trial (adolescents, N = 292), the primary efficacy endpoint (improvement on ADHD-Rating Scale, Fifth Edition total scores) did not reach statistical significance for once-daily viloxazine ER 600 mg, despite being statistically significant for patients treated with the 400-mg dose [39].…”