Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2022 Aug;36(8):897-915.
doi: 10.1007/s40263-022-00938-w. Epub 2022 Jul 27.

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

Azmi Nasser  1 , Joseph T Hull  2 , Soumya A Chaturvedi  3 , Tesfaye Liranso  2 , Oyinkansola Odebo  3 , Alisa R Kosheleff  3 , Nicholas Fry  2 , Andrew J Cutler  4 , Jonathan Rubin  2 , Stefan Schwabe  3 , Ann Childress  5
Affiliations
Clinical Trial

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

Azmi Nasser et al. CNS Drugs. 2022 Aug.

Abstract

Background and objective: Attention-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.

Methods: This 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.

Results: A 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.

Conclusions: Treatment 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 registration: Clinicaltrials.gov identifier: NCT04016779.

Plain language summary

Attention-deficit/hyperactivity disorder (ADHD) is a condition characterized by inattention (difficulty maintaining focus), and/or impulsiveness/hyperactivity. In 2021, a nonstimulant medication called viloxazine ER (brand name: Qelbree®) received US FDA-approval for ADHD in children and adolescents (aged 6 to 17 years), based on efficacy and safety demonstrated in clinical trials. Here we present results of a phase 3, randomized, double-blind, placebo-controlled, clinical trial that enrolled 374 adults with ADHD. In this trial, half the patients received viloxazine ER, and half received placebo (identical capsule without active ingredient). Medication doses ranged from 200–600 mg/day, based on symptom response and presence of side effects. To reduce bias, patients and investigators did not know which medication the patient was receiving. The primary measure of efficacy was the Adult ADHD Investigator Symptom Rating Scale (AISRS), a standardized questionnaire rating presence and severity of patient-reported ADHD symptoms. At the end of the 6-week trial, participants receiving viloxazine ER showed greater improvement in ADHD symptoms according to AISRS than those receiving placebo. Improvement was seen in both the Inattentive and Impulsive/Hyperactive components of ADHD and in other study measures, including a measure of behaviors called Executive Function. Viloxazine ER was generally safe and well-tolerated in the trial. The most common side effects were insomnia (14.8%), fatigue (11.6%), and nausea (10.1%). Overall, 9.0% of patients receiving viloxazine and 5% receiving placebo left the trial because of side effects. Due to these positive results, the US FDA recently approved viloxazine ER to treat adults with ADHD.

PubMed Disclaimer

Conflict of interest statement

AN, JTH, TL, NF, and JR, are employees of Supernus Pharmaceuticals, Inc. SAC, OO, ARK, and SS were employees of Supernus Pharmaceuticals, Inc. at the time of this work. AJC has received research support from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore Pharmaceuticals, Janssen, KemPharm, Lundbeck, Neos Therapeutics (now Aytu BioPharma), Neurovance, Noven, Otsuka, Purdue Canada, Rhodes Pharmaceuticals, Shire, Sunovion, Supernus Pharmaceuticals, Inc., Takeda, and Tris Pharma. He has received fees for consulting, advisory boards, and promotional speaking from Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Atentiv, Cingulate Therapeutics, Corium, Ironshore Pharmaceuticals, Janssen, Lundbeck, MedAvante-ProPhase, Neos Therapeutics (now Aytu BioPharma), NLS Pharmaceutics, Noven, Otsuka, Shire, Sunovion, Supernus Pharmaceuticals, Inc., Takeda, and Tris Pharma. He is an employee and board member of the Neuroscience Education Institute. AC has received research support from, served as a consultant or speaker for, or served on an advisory board for Allergan, Takeda (Shire), Emalex, Pearson, Akili, Arbor, Cingulate Therapeutics, Ironshore, Lumos, Aevi Genomic Medicine, Neos Therapeutics, Neurovance, Noven, Otsuka, Pfizer, Purdue, Adlon, Rhodes, Sunovion, Tris, KemPharm, Supernus Pharmaceuticals, Inc., US Food and Drug Administration, NLS Pharma, and Jazz.

Figures

Fig. 1
Fig. 1
Study design. Clinical trial design illustrating timing of study visits, efficacy assessments, and dose titration. Fixed doses were used during weeks 1 and 2; flexible doses of viloxazine extended release (ER) were used during weeks 3–6. Efficacy assessments were conducted at screening, baseline, and the end of weeks 1, 2, 3, 4, and 6. No study visit was scheduled at the end of week 5. AISRS Adult ADHD Investigator Symptom Rating Scale, BRIEF-A Behavior Rating Inventory of Executive Function-Adult Version, CGI Clinical Global Impressions scale, CGI-I CGI-Improvement, CGI-S CGI-Severity, EOS end of study, GAD-7 General Anxiety Disorder-7 scale
Fig. 2
Fig. 2
Disposition of subjects. Asterisk: One patient randomized to placebo was randomized in error and discontinued prior to receiving treatment with study medication; one subject randomized to viloxazine extended release (ER) had a positive pregnancy test and was withdrawn from the study prior to receiving treatment with study medication. N number of subjects
Fig. 3
Fig. 3
Adult ADHD Investigator Symptom Rating Scale (AISRS). Results from the AISRS demonstrate significant symptomatic improvements within 2 or 3 weeks following initiation of viloxazine extended release (ER) treatment and continuing through end of study (EOS). This was true for the changes from baseline in the AISRS total score (a), the Inattention subscale (b), and the Hyperactivity/Impulsivity subscale (c) (baseline plotted as 0 for reference). Significantly more subjects treated with viloxazine ER responded to treatment as assessed by an AISRS reduction of 30% (d) and 50% (e) response criteria from baseline. No study visit was scheduled for week 5. a–c Shown as least-squares means ± standard error; d, e are percent of subjects. *p < 0.05; **p < 0.01; ***p < 0.001 (relative to placebo). ADHD attention-deficit/hyperactivity disorder
Fig. 4
Fig. 4
Clinical Global Impressions (CGI) scales. Results from the CGI scales demonstrate significant overall improvements beginning within 2 weeks of treatment with viloxazine extended release (ER) and continuing through end of study (EOS) on the Clinical Global Impressions-Severity of Illness scale (CGI-S) change from baseline (a) and Clinical Global Impressions-Improvement (CGI-I) scale raw scores (b). Significantly more subjects treated with viloxazine ER responded to treatment (i.e., score of 1 or 2) as assessed by CGI-S (c) and CGI-I (d) response criteria on weeks 2, 3, and 4. No study visit was scheduled for week 5. a, b Shown as least-squares means ± standard error; c, d are percent of subjects. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 (relative to placebo)
See this image and copyright information in PMC

Comment in

References

    1. American Psychiatric Association . Diagnostic and statistical manual of mental disorders. 5. Washington, DC: American Psychiatric Publishing; 2013.
    1. Sibley MH, Arnold LE, Swanson JM, Hechtman LT, Kennedy TM, Owens E, et al. Variable patterns of remission from ADHD in the multimodal treatment study of ADHD. Am J Psychiatry. 2022;179(2):142–151. - PMC - PubMed
    1. Weiss G, Hechtman LT. Hyperactive children grown up: ADHD in children, adolescents, and adults. 2. New York: Guilford Press; 1993.
    1. Biederman J, Mick E, Faraone SV. Age-dependent decline of symptoms of attention deficit hyperactivity disorder: impact of remission definition and symptom type. Am J Psychiatry. 2000;157(5):816–818. - PubMed
    1. Turgay A, Goodman DW, Asherson P, Lasser RA, Babcock TF, Pucci ML, et al. Lifespan persistence of ADHD: the life transition model and its application. J Clin Psychiatry. 2012;73(2):192–201. - PubMed

Publication types

MeSH terms

Associated data