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
. 2025 Nov;39(11):1157-1172.
doi: 10.1007/s40263-025-01209-0. Epub 2025 Aug 13.

Viloxazine Extended-Release Capsules in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Results of a Long-Term, Phase 3, Open-Label Extension Trial

Robert L Findling  1 , Alain Katic  2 , Michael Liebowitz  3 , James Waxmonsky  4 , Nicholas Fry  5 , Peibing Qin  5 , Ilmiya Yarullina  5 , Zulane Maldonado-Cruz  5 , V Rose Lieberman  5 , Jonathan Rubin  6
Affiliations
Clinical Trial

Viloxazine Extended-Release Capsules in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Results of a Long-Term, Phase 3, Open-Label Extension Trial

Robert L Findling et al. CNS Drugs. 2025 Nov.

Abstract

Background and objective: Viloxazine ER (extended-release capsules; Qelbree®) is a nonstimulant medication that has been approved by the United States Food and Drug Administration (FDA) for treatment of pediatric and adult attention-deficit/hyperactivity disorder (ADHD). This phase 3, open-label extension (OLE) trial evaluated the long-term safety and efficacy of viloxazine ER in children and adolescents with ADHD.

Methods: Participants completing the phase 2 or one of the four phase 3 double-blind, placebo-controlled clinical trials were eligible for the OLE trial. Upon entering the OLE, double-blind treatment was discontinued and participants were administered viloxazine ER 100 mg/day (children, aged 6-11 years) or 200 mg/day, (adolescents, aged 12-18 years), with dosage titration as needed over a 12-week dose-optimization period (up to 400 mg/day [children] or 600 mg/day [adolescents]). Participants then entered a maintenance period that continued through US FDA-approval (up to 72 months). Safety (primary objective) was assessed relative to OLE baseline using adverse event (AE), clinical laboratory tests, vital sign, ECG, and Columbia Suicide Severity-Rating Scale (C-SSRS) monitoring. Efficacy was assessed relative to double-blind baseline using the ADHD Rating Scale (ADHD-RS-IV/5) and the Clinical Global Impression-Improvement (CGI-I) scale. Study visits for these assessments occurred every ~ 3 months throughout maintenance treatment.

Results: Participants (N = 1100) included 646 children and 454 adolescents (66.5% male/33.5% female). Median (range) exposure to viloxazine ER in the OLE was 260 (1-1896) days, and the median modal (most frequently used) viloxazine ER doses were 300 mg/day for children and 400 mg/day for adolescents. AEs included (≥ 5% incidence) nasopharyngitis (9.7%), somnolence (9.5%), headache (8.9%), decreased appetite (6.0%), and fatigue (5.7%). AEs were mostly mild or moderate in severity (3.9% reported any severe AE); AEs led to discontinuation in 8.2% of participants. The mean ± SD changes from double-blind baseline in ADHD-RS IV/5 total score were -24.3 ± 12.0 at Month 3, -26.1 ± 11.5 at Month 12, and -22.4 ± 13.6 at participants' last OLE study visit.

Conclusions: The results of this large-scale safety trial support the long-term use of viloxazine ER as a generally well-tolerated and effective treatment option for pediatric ADHD. No new safety concerns emerged, and efficacy results suggest the potential for continued improvement over that seen during double-blind treatment.

Clinical trial registration: Clinicaltrials.gov identifier: NCT02736656.

PubMed Disclaimer

Conflict of interest statement

Declarations. Funding: This work and its open access publication were funded by Supernus Pharmaceuticals, Inc. Conflicts of Interest: R.L.F. receives or has received research support, acted as a consultant and/or has received honoraria from Abbvie, Ajna, Akili, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Bioprojet, BioXcel, Bristol Myers Squibb,Corium, Elsevier, Intra-Cellular Therapies, Iqvia, Karuna, Lundbeck, Maplight, Merck, MJH Life Sciences, NIH, Novartis, Otsuka, Oxford University Press, PaxMedica, PCORI, Pfizer, Radius, Sage, Signant Health, Sumitomo Pharma, Sunovion, Supernus Pharmaceuticals, Takeda, Tris, Viatris, and Xenon. Over the past 3 years, J.W. has received research support from Supernus and served as a consultant for Iron Shore and Adlon Pharmaceuticals. M.L. is a consultant for Vistagen Therapeutics and Newleos Pharma, and in the past 3 years has conducted clinical trials for Supernus, Alto, Biohaven, Janssen, Otsuka, Compass, Abbvie, and Relmada. A.K. has received honoraria from Supernus and in the past 3 years has conducted clinical research for Abbvie, Axsome, Boehringer Ingelheim, Cingulate, Corium, Janssen, Otsuka, Pfizer, Relmada, and Supernus. N.F., P.Q., I.Y., Z.M-C., V.R.L., and J.R. are employees of Supernus Pharmaceuticals, Inc. Ethics Approval: The trial was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation (ICH) Good Clinical Practice Guidelines for biomedical research, and the United States (US) Code of Federal Regulations (21 CFR). The central IRB (Advarra) approved the trial protocol under Pro00026366. Consent to Participate: Each participant’s parent or legal guardian signed an informed consent form (ICF); participants signed an informed assent form, and those turning 18 years of age during the trial also signed an ICF. Consent for Publication: Not applicable. Availability of Data and Materials: The data are not available in a repository, but data will be made available upon reasonable request directed to jrubin@supernus.com. Code Availability: Not applicable. Author Contributions: Conceptualization and design: R.L.F. Methodology and data collection: R.L.F., J.W., A.K., N.F., and M.L. Analysis and interpretation: R.L.F., J.W., I.Y., Z.M.C., V.R.L., P.Q., and J.R. Writing, review, and editing: R.L.F., M.L., J.W., I.Y., Z.M.C., V.R.L., P.Q., and J.R. All authors read and approved the final submitted manuscript and agree to be accountable for this work.

Figures

Fig. 1
Fig. 1
Trial participants. VLX-ER viloxazine extended-release, PBO placebo
Fig. 2
Fig. 2
Weight and height changes by month of treatment. (Top) weight: mean absolute z-score by month of treatment. (Bottom) height: mean absolute z-score by month of treatment. BL baseline, LOSV last on-study visit, SD standard deviation
Fig. 3
Fig. 3
Change from double-blind baseline in mean ADHD-RS-IV/5 total score. Double-blind baseline scores (mean ± SD) were 41.9 ± 7.4 (received placebo; n = 476) and 42.5 ± 7.5 (received viloxazine ER; n = 1084). For the subset of participants who entered the open-label extension, mean double-blind baseline scores were 41.7 ± 7.4 (received placebo in DB; n = 338) and 42.7 ± 7.3 (received viloxazine ER in DB; n = 742). ADHD-RS ADHD Rating Scale, BL baseline, CFB change from baseline, DB double blind, OLE open-label extension, SD standard deviation
Fig. 4
Fig. 4
Change from double-blind baseline in mean ADHD-RS-IV/5 hyperactivity/impulsivity subscore. Double-blind baseline scores (mean ± SD) were 19.5 ± 5.6 (received placebo; n = 476) and 20.1 ± 5.5 (received viloxazine ER; n = 1084). For the subset of participants who entered the open-label extension, mean double-blind baseline scores were 19.4 ± 5.6 (received placebo in DB; n = 338) and 20.2 ± 5.3 (received viloxazine ER in DB; n = 742). ADHD-RS ADHD Rating Scale, BL baseline, CFB change from baseline, DB double blind, HI hyperactivity/impulsivity, OLE open-label extension, SD standard deviation, Wk week
Fig. 5
Fig. 5
Change from double-blind baseline in mean ADHD-RS-IV/5 inattention subscore. Double-blind baseline scores (mean ± SD) were 22.4 ± 3.7 (received placebo; n = 476) and 22.4 ± 3.6 (received viloxazine ER; n = 1084). For the subset of participants who entered the open-label extension, mean double-blind baseline scores were 22.4 ± 3.7 (received placebo in DB; n = 338) and 22.5 ± 3.5 (received viloxazine ER in DB; n = 742). ADHD-RS ADHD Rating Scale, BL baseline, CFB change from baseline, DB double blind, OLE open-label extension, SD standard deviation, Wk week
Fig. 6
Fig. 6
CGI-I score. CGI-I Clinical Global Impression-Improvement, DB double-blind, OLE open-label extension, LOSV last on-study visit, SD standard deviation
Fig. 7
Fig. 7
ADHD-RS-IV/5 50% responders. ADHD-RS-IV/5 50% responder rate is defined as the percentage of participants at each visit who had a ≥ 50% reduction from double-blind baseline in total score. ADHD-RS ADHD Rating Scale, DB double blind, OLE open-label extension
Fig. 8
Fig. 8
CGI-I responders. CGI-I responder rate is defined as the percentage of participants at each visit who had a CGI-I score of 1 [very much improved] or 2 [much improved]. CGI-I Clinical Global Impression-Improvement, DB double blind, OLE open-label extension
See this image and copyright information in PMC

References

    1. Holbrook JR, Cuffe SP, Cai B, Visser SN, Forthofer MS, Bottai M, et al. Persistence of parent-reported ADHD symptoms from childhood through adolescence in a community sample. J Atten Disord. 2016;20(1):11–20. - PMC - PubMed
    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):142–51. - PMC - PubMed
    1. Bitsko RH, Claussen AH, Lichstein J, Black LI, Jones SE, Danielson ML, et al. Mental health surveillance among children-United States, 2013–2019. MMWR Suppl. 2022;71(2):1–42. - PMC - PubMed
    1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychiatric Association; 2013.
    1. Altfas JR. Prevalence of attention deficit/hyperactivity disorder among adults in obesity treatment. BMC Psychiatry. 2002;2:9. - PMC - PubMed

Publication types

Associated data