Dataset Information

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

ABSTRACT:

Purpose

This phase 3 clinical trial evaluated the efficacy and safety of viloxazine extended-release capsules (VLX-ER) as a monotherapy for attention-deficit/hyperactivity disorder (ADHD) in adolescents (12-17 years).

Methods

Eligible subjects (n = 310) were randomized to receive once-daily 200 and 400 mg VLX-ER, or placebo for 6 weeks. The primary efficacy end point was change from baseline (CFB) at the end of study (EOS) in ADHD Rating Scale-5 Total score. Key secondary end points were Clinical Global Impression-Improvement score at EOS, CFB at EOS in Conners 3-Parent Short Form Composite T-score, and CFB at EOS in Weiss Functional Impairment Rating Scale-Parent Total average score.

Results

In the 200-mg/d and 400-mg/d VLX-ER treatment groups, a significant improvement was found in the CFB at EOS in ADHD Rating Scale-5 Total (P = 0.0232, P = 0.0091) and Inattention (P = 0.0424, P = 0.0390) and Hyperactivity/Impulsivity (P = 0.0069, P = 0.0005) subscale scores versus placebo. The Clinical Global Impression-Improvement score was significantly improved at EOS in the 200-mg/d and 400-mg/d VLX-ER groups versus placebo (P = 0.0042, P = 0.0003). The Conners 3-Parent Short Form composite T-score and Weiss Functional Impairment Rating Scale-Parent Total average score exhibited improvement in both VLX-ER groups; however, the difference versus placebo was not statistically significant. The most common treatment-related adverse events were somnolence, headache, decreased appetite, nausea, and fatigue. The adverse event-related discontinuation rates were <5% in all groups.

Conclusions

Viloxazine extended-release demonstrated statistically significant and clinically meaningful improvement in ADHD symptoms in adolescents and was generally well tolerated.

SUBMITTER: Nasser A

PROVIDER: S-EPMC8244935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectiveAttention-deficit/hyperactivity disorder is a neurodevelopmental disorder that typically begins in childhood and often persists into adulthood. Recent phase III trials have demonstrated the efficacy and safety of viloxazine extended-release capsules (viloxazine ER; Qelbree®) in pediatrics (6-17 years of age). The aim of this study was to evaluate the efficacy and safety of viloxazine ER in adults with attention-deficit/hyperactivity disorder.MethodsThis was a phase III, randomized, double-blind, placebo-controlled, two-arm trial in adults (18-65 years of age) with attention-deficit/hyperactivity disorder. Eligible subjects were randomized 1:1 to viloxazine ER (flexible dose of 200-600 mg/day) or matched placebo. The primary efficacy endpoint was the change from baseline at end of study (week 6) in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. The key secondary endpoint was the change from baseline at end of study in the Clinical Global Impressions-Severity of Illness (CGI-S) score. Additional secondary outcome measures included the AISRS Inattention and Hyperactivity/Impulsivity subscales, the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the Generalized Anxiety Disorder-7 Item (GAD-7), and the Clinical Global Impressions-Improvement (CGI-I); each was analyzed at end of study. Responder rates on CGI scales and the AISRS were also assessed.ResultsA total of 374 subjects were randomized. At end of study, the mean viloxazine ER dose was 504 mg. The reduction in the change from baseline at end of study AISRS total score (least-square means ± standard error) was significantly greater in subjects treated with viloxazine ER (-15.5 ± 0.91) compared with placebo (-11.7 ± 0.90), p = 0.0040. The reduction in the CGI-S score was also significantly greater in subjects treated with viloxazine ER (-1.4 ± 0.10) compared with placebo (-1.0 ± 0.10), p = 0.0023. The viloxazine ER group demonstrated significantly greater improvements in the AISRS Inattention (p = 0.0015) and Hyperactivity/Impulsivity (p = 0.0380) subscales, the CGI-I (p = 0.0076), and the BRIEF-A Global Executive Composite (p = 0.0468) and Metacognition Index (p = 0.0100). Analysis of categorical secondary endpoints revealed that the viloxazine ER group had a significantly higher AISRS 30% response rate compared with placebo (p = 0.0395); all other comparisons were not significant. Many treatment effects (including the primary and key secondary endpoints) were significant by week 2. The most common treatment-related adverse events that occurred in ≥5% of subjects receiving viloxazine ER were insomnia (14.8%), fatigue (11.6%), nausea (10.1%), decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). Viloxazine ER was well tolerated, with a 9.0% discontinuation rate due to adverse events compared with 4.9% in the placebo group.ConclusionsTreatment with viloxazine ER resulted in a statistically significant improvement in primary and key secondary endpoints, indicating improvements in attention-deficit/hyperactivity disorder symptomology, executive function, and overall clinical illness severity in adults. Viloxazine ER was well tolerated at the tested doses in adults with attention-deficit/hyperactivity disorder.Clinical trial registrationClinicaltrials.gov identifier: NCT04016779.

Project description:PurposeThe ADHD Rating Scale (ADHD-RS) assesses 18 symptoms of inattention and hyperactivity/impulsivity and has been used in many clinical trials to evaluate the treatment effect of drugs on ADHD. The fifth edition of this scale (ADHD-RS-5) also assesses the impact of inattention and hyperactivity/impulsivity symptoms on six domains of functional impairment (FI): family relationships, peer relationships, completing/returning homework, academic performance at school, controlling behavior at school, and self-esteem. Here, we report the effect of viloxazine extended-release capsules (viloxazine ER), a novel nonstimulant treatment for ADHD in children and adolescents (ages 6-17 years), on FI from a post hoc analysis of four randomized, double-blind, placebo-controlled Phase 3 clinical trials (N=1354).Patients and methodsADHD-RS-5 investigator ratings of ADHD symptoms and FIs were conducted at baseline and weekly post-baseline for 6-8 weeks in the four trials. Change from baseline (CFB) in ADHD-RS-5 FI scores (Total score [sum of 12 FI items] and Inattention and Hyperactivity/Impulsivity subscale scores [sum of 6 corresponding FI items]) and the 30% and 50% Responder Rates (ADHD-RS-5 FI Total score) were compared between viloxazine ER and placebo.ResultsThe reduction (improvement) in ADHD-RS-5 FI scores (Total and subscale scores) and the percentage of responders (30% and 50%) at Week 6 were significantly greater in each viloxazine ER dose group vs placebo. In the 100-400 mg/day viloxazine ER groups, improvements were found as early as Week 1 (100-mg/day) or Week 2 (200-, 400-mg/day) of treatment. Analysis of individual items of ADHD-related FIs demonstrated that the effect of viloxazine ER was observed across all domains of impairment.ConclusionSignificant improvements observed in ADHD-related FIs are consistent with the reduction in inattention and hyperactivity/impulsivity symptoms demonstrated in the viloxazine ER Phase 3 pediatric trials. Therefore, viloxazine ER provides clinically meaningful improvement of ADHD symptoms and functioning in children and adolescents with ADHD, starting as early as Week 1-2 of treatment.

Project description:ObjectiveTo evaluate measures of sleep (exploratory endpoints) in two pivotal studies of a multilayer bead extended-release methylphenidate (MPH-MLR) treatment of attention-deficit/hyperactivity disorder in children.MethodsStudy 1 evaluated the time course of response to MPH-MLR (n = 26) patients in an analog classroom setting through four phases: screening (≤28 days), open label (OL) dose optimization (4 weeks), double-blind (DB) crossover (2 weeks; placebo vs. optimized dose), and follow-up call. Study 2 was a forced-dose parallel evaluation of MPH-MLR (n = 230) in four phases: screening (≤28 days), DB (1 week; placebo or MPH-MLR 10, 15, 20, or 40 mg/day), OL dose optimization (11 weeks), and follow-up call. Sleep was evaluated by parents using the Children's or Adolescent Sleep Habits Questionnaire (CSHQ or ASHQ) during the DB and OL phases. DB analysis: Study 1 (crossover), analysis of variance; Study 2, analysis of covariance. OL analysis: paired t-test.ResultsDB: treatments were significantly different in Study 1 only for CSHQ Sleep Onset Delay (MPH-MLR, 1.90 vs. placebo, 1.34; p = 0.0046, placebo was better), and Study 2 for CSHQ Parasomnias (treatment, p = 0.0295), but no MPH-MLR treatment was different from placebo (pairwise MPH-MLR treatment to placebo, all p ≥ 0.170). OL: CSHQ total and Bedtime Resistance, Sleep Duration, Sleep Anxiety, Night Wakings, Parasomnias, and Sleep-disordered Breathing subscales decreased (improved, Study 1) significant only for CSHQ Night Wakings (p < 0.05); in Study 2 CSHQ total and Bedtime Resistance, Sleep Duration, Night Wakings, Parasomnias, and Daytime Sleepiness, and ASHQ total, Bedtime, Sleep Behavior, and Morning Waking all significantly improved (p < 0.05).ConclusionsIn both studies, there was minimal negative impact of MPH-MLR on sleep during the brief DB phase and none during the longer duration OL phase. Some measures of sleep improved with optimized MPH-MLR dose.

Project description:ObjectiveThe purpose of this study was to assess the time of onset and time course of efficacy over 12.0 hours of extended-release multilayer bead formulation of methylphenidate (MPH-MLR) compared with placebo in children 6-12 years of age with attention-deficit/hyperactivity disorder (ADHD) in a laboratory school setting.MethodsThis randomized double-blind placebo-controlled study included children 6-12 years of age with ADHD. Enrolled children went through four study phases: 1) Screening period (≤4 weeks) and a 2 day medication washout period; 2) open-label period with dose initiation of MPH-MLR 15 mg daily and individual dose optimization treatment period (2-4 weeks); 3) double-blind crossover period in which participants were randomized to sequences (1 week each) of placebo and the optimized MPH-MLR dose given daily; and 4) follow-up safety call. Analog classroom time course evaluations were performed at the end of each double-blind week. The primary efficacy end-point was the mean of the on-treatment/postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)-Total scores over time points collected 1.0-12.0 hours after dosing. End-points were evaluated using a mixed-effects analysis of covariance.ResultsThe evaluable population included 20 participants. The least-squares mean postdose SKAMP-Total score was higher for placebo than for MPH-MLR (2.18 vs. 1.32, respectively; p=0.0001), indicating fewer symptoms with MPH-MLR therapy than with placebo. No difference in SKAMP-Total score between participants who received sequence 1 or sequence 2 was noted. From each of hours 1.0-12.0, least-squares mean SKAMP-Total score was significantly lower for those receiving MPH-MLR than for those receiving placebo (p≤0.0261). Neither serious adverse events nor new or unexpected safety findings were noted during the study.ConclusionsMPH-MLR showed a significant decrease in SKAMP scores compared with placebo in children with ADHD 6-12 years of age, indicating a decrease in ADHD symptoms. The estimated onset was observed within 1.0 hour, and duration was measured to 12.0 hours postdose.Trial registrationClinicalTrials.gov Identifier: NCT01269463.