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.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40263-025-01209-0.
Key Points
| In this open-label extension trial of viloxazine ER safety and efficacy in children (aged 6–11 years) and adolescents (aged 12–18 years) with ADHD, no new safety concerns emerged, and ADHD symptoms and clinical global impression assessments showed continued and sustained improvement. |
| These results support viloxazine ER as a long-term treatment option for children and adolescents with ADHD. |
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is among the most commonly diagnosed neurobehavioral disorders in children and adolescents, with an estimated US prevalence of up to 9.8% [1–3]. Behavioral manifestations of ADHD, including inattention, impulsivity, and hyperactivity, can interfere with multiple areas of a child’s life, impacting self-esteem, academic performance, social and family relationships, and later occupational attainment, as well as increasing the risk of accidents, substance use disorders, obesity, and criminality [4–10]. Long-term studies suggest that proper ADHD treatment can help mitigate these detrimental effects [7–13].
For children with ADHD (≥ 6 years of age), the American Academy of Pediatrics Clinical Practice guidelines recommend the use of US Food and Drug Administration (FDA)-approved medications (CNS stimulants, alpha-2 agonists, atomoxetine, or viloxazine extended-release [ER]), along with interventions such as parent training in behavior management and/or behavioral classroom intervention. For adolescents with ADHD, the guidelines recommend an FDA-approved medication (with the adolescent’s assent), and evidence-based behavioral and educational interventions as individually appropriate [14]. Although stimulants (methylphenidate and amphetamines) are often initiated as first-line therapy, these medications are classified as controlled substances with potential risk for abuse [15], and their limited duration of efficacy and access restrictions may present challenges for practical use in some patients [14, 16, 17]. In 2023, concern regarding potential misuse of stimulants, particularly among adolescents and young adults, prompted the FDA to require that stimulant manufacturers update product prescribing information to more clearly inform of the risks for misuse, addiction, overdose, and diversion associated with these medications [18]. Alternatively, nonstimulants offer medication options with low potential for misuse that can provide effective and consistent ADHD symptom control throughout the day.
Viloxazine ER (viloxazine extended-release capsules; Qelbree®) was initially granted US FDA-approval on 2 April 2021, for the treatment of pediatric (≥ 6 years of age) ADHD, followed by approval for adult ADHD on 29 April 2022. Formulated as pellet-filled capsules that can be taken whole or sprinkled on soft food, the ER technology releases viloxazine at a sufficiently sustained rate to allow for once-daily dosing [19]. Although recommended for morning use based on phase 3 trial conduct, a recent pediatric open-label trial showed similar ADHD symptom reduction regardless of a.m. or p.m. administration (NCT04786990) [20]. Like CNS stimulants, viloxazine ER increases norepinephrine and dopamine prefrontally through its actions as a selective norepinephrine transporter (NET) inhibitor; however, it has low abuse potential and is not a controlled substance. At therapeutic doses, viloxazine ER also has relevant activity at serotonin receptors as a 5-HT2c partial agonist, and 5-HT2b and 5HT-7 antagonist [21, 22]. Although the contributions of 5-HT receptor effects to viloxazine ER efficacy are not fully understood, ADHD has been linked to dysfunction in serotonin pathways, and serotonin plays a modulatory role in behaviors central to ADHD, such as emotional and behavioral impulsivity [23–25].
The safety and efficacy of viloxazine ER for pediatric ADHD were demonstrated in a clinical trial program that included a phase 2 double-blind, placebo-controlled, dose selection trial (NCT02633527) [26] conducted in children (aged 6–12 years), and four phase 3, double-blind, placebo-controlled fixed-dose trials, two in children (aged 6–11 years; NCT03247530 and NCT03247543) and two in adolescents (aged 12–17 years; NCT03247517 and NCT03247556) [27–30]. Here we report results for the ensuing open-label extension (OLE) to these double-blind trials, that evaluated long-term safety (primary endpoint) and efficacy (secondary endpoint) of viloxazine ER.
Methods
Trial Design
This was a phase 3, open-label, flexible-dose, multicenter, long-term extension trial (NCT02736656) enrolling pediatric participants who completed one of the prior viloxazine ER phase 2 or 3 clinical trials [26–30]. This trial ran from 15 April 2016 (first participant dose) to 22 December 2021 (last participant visit) at 68 US sites.
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). Prior to enrollment, the study received institutional review board (IRB) approval and 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.
Regardless of double-blind treatment assignment, viloxazine ER was started in the OLE at 100 mg/day for children (6–11 years) or 200 mg/day for adolescents (≥ 12 years), with weekly adjustments of 100 mg/day (children), or 100 or 200 mg/day (adolescents), on the basis of tolerability and clinical response. The allowed dose range was 100–400 mg/day for children and 100–600 mg/day for adolescents, administered once each morning as a single oral dose. Concomitant medications were not allowed except for nutritional supplements (e.g., multivitamins), over-the-counter medications for minor ailments, or to treat adverse events (AEs) (e.g., acetaminophen or ibuprofen for fever or pain). As viloxazine ER has been shown to be a strong inhibitor of CYP1A2 [31], known CYP1A2 substrates (e.g., theophylline, melatonin, etc.) were prohibited, except caffeine.
The trial duration was extended every 6 months (up to 72 months) to allow participants to remain on viloxazine ER until market availability. All participants described here (schedule A) have now completed treatment; however, at the time of publication, the trial remains open to pre-school age children (4–5 years) enrolling from a subsequently conducted double-blind trial (NCT04781140; schedule B); results for these participants will be reported separately.
Participants
Participants completing one of the five phase 2 or 3, randomized, double-blind, placebo-controlled trials of viloxazine ER in pediatric ADHD [26–30] were eligible to continue directly into the open-label extension provided they were medically healthy; had normal laboratory assessments, vital signs, and electrocardiograms (ECGs); had body weights ≥ 20 kg (children) and ≥ 35 kg (adolescents); and, for females of child-bearing potential, were either sexually inactive or using acceptable birth control methods (Supplementary Table 1). Double-blind trial eligibility required participants to have a diagnosis of ADHD according to DSM-IV/5, a Clinical Global Impression-Severity (CGI-S) score ≥ 4, and a baseline ADHD-Rating Scale (ADHD-RS) score ≥ 26 if using the 4th edition of the scale (ADHD-RS-IV, phase 2 trial) or ≥ 28 if using the 5th edition (ADHD-RS-5, phase 3 trials) (Fig. 1).
Fig. 1.
Trial participants. VLX-ER viloxazine extended-release, PBO placebo
Participants were excluded for current significant medical, neurological or psychiatric disorders, current suicidal ideation or behaviors as assessed via the Columbia Suicide Severity Rating Scale (C-SSRS), body mass index (BMI) > 95th percentile for age and sex, or current substance or alcohol use.
Assessments
Safety Assessments
Safety assessments included AE monitoring (including severity, seriousness, and treatment relationship), laboratory tests, vital signs, height, weight, BMI, physical examinations, 12-lead ECGs, and suicidality monitoring using the C-SSRS. AEs were coded and summarized according to the Medical Dictionary for Regulatory Activities (MedDRA®) version 20.1. On the basis of concerns for possible ictogenic potential in humans [32, 33], seizure or events that might represent a seizure were considered AEs of special interest for the trial.
Safety outcomes were assessed relative to open-label baseline, defined as the values observed at the last visit of the blinded trial or the most recent value obtained prior to the first dose in the open-label extension trial (visit 1).
Efficacy Assessments
Efficacy assessments included the ADHD Rating Scale (ADHD-RS) total (range 0–54) and subscale (inattention and hyperactivity/impulsivity) scores and Clinical Global Impression – Improvement (CGI-I) scores. The version of ADHD-RS scale used was consistent with that used in each participant’s double-blind lead-in trial: ADHD-RS-IV for the phase 2 trial, and ADHD-RS-5 for the phase 3 trials. The following response thresholds were also assessed: 30% and 50% ADHD-RS-IV/5 responder rates (percentage of participants with ≥ 30% or ≥ 50% reduction from double-blind baseline in total score); and CGI-I responder rate (percentage of participants with a score of 1 [very much improved] or 2 [much improved]).
Efficacy measures were assessed by visit, and for participants’ last study visit, relative to their double-blind baseline score. Safety and efficacy assessments were obtained 1–3 times (based on actual visit number) during initial dose optimization (weeks 1–12, with visits at least 1–3 weeks apart), and then every 3 months thereafter.
Statistical Analyses
Safety analyses (primary outcome) included all participants who received ≥ 1 dose of viloxazine ER in the OLE. Efficacy analyses were based on observed data (no imputation for missing data). Results were summarized descriptively with change from baseline (CFB) and percentages calculated using all participants with non-missing data for that visit. Descriptive statistics were analyzed using SAS® version 9.4.
Results
Patient Disposition and Baseline Characteristics
A total of 1100 participants (646 children, 454 adolescents) received at least one dose of viloxazine ER in the OLE. Of these, 1080 participants (635 children, 445 adolescents) had at least one efficacy assessment during OLE treatment (Table 1). The mean exposure to viloxazine ER in the OLE was 428 days, and the median (range) exposure was 260 (1–1896) days. Notably, 641 (58.3%) participants remained on treatment for at least 6 months, 447 (40.6%) for at least 12 months, and 275 (25.0%) for at least 24 months. The mean participant age was 10.8 years, and 66.5% were male (Table 2).
Table 1.
Participant disposition
| Children 6–11 years |
Adolescents 12–18 years |
Total | |
|---|---|---|---|
| Enrolled, n (%) | 646 (100.0) | 454 (100.0) | 1100 (100.0) |
| Safety analysis set, n (%) | 646 (100.0) | 454 (100.0) | 1100 (100.0) |
| Efficacy analysis set, n (%) | 635 (98.3) | 445 (98.0) | 1080 (98.2) |
| Completed triala, n (%) | 103 (15.9) | 66 (14.5) | 169 (15.4) |
| Did not complete trial, n (%) | 543 (84.1) | 388 (85.5) | 931 (84.6) |
| Primary reason for early discontinuation, n (%) | |||
| Withdrawal by parent/guardian | 179 (27.7) | 110 (24.2) | 289 (26.3) |
| Withdrawal by subject | 86 (13.3) | 65 (14.3) | 151 (13.7) |
| Lost to follow-up | 143 (22.1) | 122 (26.9) | 265 (24.1) |
| Adverse event | 56 (8.7) | 28 (6.2) | 84 (7.6) |
| Patient non-compliant | 21 (3.3) | 19 (4.2) | 40 (3.6) |
| Non-compliance with study drug | 6 (0.9) | 7 (1.5) | 13 (1.2) |
| Investigator’s decision | 1 (0.2) | 0 | 1 (0.1) |
| Patient did not meet all eligibility criteria | 0 | 1 (0.2) | 1 (0.1) |
| Other | 51 (7.9) | 36 (7.9) | 87 (7.9) |
| Lack of efficacy | 18 (2.8) | 11 (2.4) | 29 (2.6) |
| Site closure | 10 (1.5) | 3 (0.7) | 13 (1.2) |
| Due to COVID-19 | 2 (0.3) | 1 (0.2) | 3 (0.3) |
| Positive urine drug screening | 1 (0.2) | 3 (0.7) | 4 (0.4) |
| Prohibited concomitant medication | 3 (0.5) | 0 | 3 (0.3) |
| Misuse/overuse of study medication | 1 (0.2) | 0 | 1 (0.1) |
| Pregnancy | 0 | 1 (0.2) | 1 (0.1) |
| Trial terminated by sponsor | 0 | 1 (0.2) | 1 (0.1) |
| Lost to follow-up | 0 | 1 (0.2) | 1 (0.1) |
| Investigator’s decision | 4 (0.6) | 4 (0.9) | 8 (0.7) |
| Patient non-compliant | 3 (0.5) | 1 (0.2) | 4 (0.4) |
| Withdrawal by parent/guardian | 9 (1.4) | 9 (2.0) | 18 (1.6) |
| Withdrawal by patient | 0 | 1 (0.2) | 1 (0.1) |
aParticipants remaining at trial termination by sponsor
Table 2.
Baseline demographic and clinical characteristics
| Children (n = 646) | Adolescents (n = 454) | Total (N = 1100) | |
|---|---|---|---|
| Age, years | |||
| Mean (SD) | 8.6 (1.6) | 13.9 (1.7) | 10.8 (3.1) |
| Median (range) | 9 (6–11) | 14 (12–18) | 11 (6–18) |
| Weight, kga | |||
| Mean (SD) | 31.9 (8.3) | 56.5 (12.9) | 42.0 (16.0) |
| Z-score, mean (SD) | 0.2 (0.9) | 0.3 (0.9) | 0.3 (0.9) |
| Height, cma | |||
| Mean (SD) | 135.1 (11.0) | 163.1 (10.2) | 146.7 (17.5) |
| Z-score, mean (SD) | 0.2 (1.0) | 0.1 (1.0) | 0.2 (1.0) |
| BMI, kg/m2a, mean (SD) | 17.2 (2.3) | 21.1 (3.5) | 18.8 (3.4) |
| Sex, n (%) | |||
| Male | 423 (65.5) | 308 (67.8) | 731 (66.5) |
| Female | 223 (34.5) | 146 (32.2) | 369 (33.5) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 169 (26.2) | 151 (33.3) | 320 (29.1) |
| Not Hispanic or Latino | 477 (73.8) | 303 (66.7) | 780 (70.9) |
| Race, n (%) | |||
| White | 357 (55.3) | 304 (67.0) | 661 (60.1) |
| Black/African American | 250 (38.7) | 134 (29.5) | 384 (34.9) |
| American Indian/Alaska Native | 5 (0.8) | 2 (0.4) | 7 (0.6) |
| Asian | 4 (0.6) | 1 (0.2) | 5 (0.5) |
| > 1 race | 30 (4.6) | 13 (2.9) | 43 (3.9) |
| ADHD-RS-IV/5 total scoreb, mean (SD) | 42.4 (7.3) | ||
| Inattention subscale | 22.4 (3.6) | ||
| Hyperactivity/impulsivity subscale | 19.9 (5.4) |
Height and weight were compared to US Centers for Disease Control and Prevention (CDC) child and adolescent growth charts to calculate Z-scores
ADHD attention-deficit/hyperactivity disorder, ADHD-RS ADHD Rating Scale, BMI body mass index, SD standard deviation
an = 645 children and N = 1099 total patients
bN = 1080 at double-blind baseline
Fewer than 10% of children and 20% of adolescents remained on the starting doses of 100 mg/day and 200 mg/day, respectively. Following initial optimization visits, the median modal (most frequently used) viloxazine ER doses during long-term treatment were 300 mg/day in children and 400 mg/day in adolescents, with 38.3% of children and 72.6% of adolescents using modal doses ≥ 400 mg/day (Supplementary Table 2).
Safety Outcomes (Primary Endpoints)
Adverse Events
Given the long-term nature of the trial and its occurrence during the coronavirus disease 2019 (COVID-19) pandemic, AE rates (Table 3) were noteworthy for being generally low. No single AE occurred in more than 10% of participants, and over 40% of participants reported no AEs during open-label treatment (57.3% in each age group reported at least one AE).
Table 3.
Summary of treatment-emergent adverse events by age group in the open-label extension
| Children (n = 646) | Adolescents (n = 454) | Total (N = 1100) | |
|---|---|---|---|
| Patients with ≥ 1 TEAE | 370 (57.3) | 260 (57.3) | 630 (57.3) |
| Most common (≥ 3% of patients) TEAEs by PT, n (%) | |||
| Nasopharyngitis | 54 (8.4) | 53 (11.7) | 107 (9.7) |
| Somnolence | 60 (9.3) | 45 (9.9) | 105 (9.5) |
| Headache | 58 (9.0) | 40 (8.8) | 98 (8.9) |
| Decreased appetite | 45 (7.0) | 21 (4.6) | 66 (6.0) |
| Fatigue | 40 (6.2) | 23 (5.1) | 63 (5.7) |
| Irritability | 26 (4.0) | 12 (2.6) | 38 (3.5) |
| Nausea | 19 (2.9) | 16 (3.5) | 35 (3.2) |
| Weight increased | 23 (3.6) | 12 (2.6) | 35 (3.2) |
| TEAEs by maximum severity, n (%) | |||
| Mild | 159 (24.6) | 132 (29.1) | 291 (26.5) |
| Moderate | 184 (28.5) | 112 (24.7) | 296 (26.9) |
| Severe | 27 (4.2) | 16 (3.5) | 43 (3.9) |
| ≥ 1 treatment-related TEAE, n (%) | 235 (36.4) | 138 (30.4) | 373 (33.9) |
| ≥ 1 TEAE of special interesta, n (%) | 4 (0.6) | 4 (0.9) | 8 (0.7) |
| ≥ 1 TESAE, n (%) | 17 (2.6) | 19 (4.2) | 36 (3.3) |
| ≥ 1 treatment-related TESAE, n (%) | 3 (0.5) | 3 (0.7) | 6 (0.5) |
| TEAEs leading to treatment discontinuation by PT (≥ 0.5% of patients), n (%) | 61 (9.4) | 29 (6.4) | 90 (8.2) |
| Somnolence | 4 (0.6) | 7 (1.5) | 11 (1.0) |
| Suicidal ideation | 5 (0.8) | 5 (1.1) | 10 (0.9) |
| Fatigue | 6 (0.9) | 1 (0.2) | 7 (0.6) |
| Decreased appetite | 4 (0.6) | 1 (0.2) | 5 (0.5) |
PT preferred term, TEAE treatment-emergent adverse event, TESAE treatment-emergent serious adverse event
aTEAEs of special interest included seizures or TEAEs that might represent a seizure (e.g., syncope/syncopal episode, pseudo-seizure, myoclonus, severe muscle spasms)
The most commonly reported AEs (≥ 5% of participants) included nasopharyngitis (9.7%), somnolence (9.5%), headache (8.9%), decreased appetite (6.0%), and fatigue (5.7%) (Table 3). AE frequency was only slightly higher in those who previously received placebo versus viloxazine ER as double-blind treatment (60% versus 56%, respectively, reported ≥ 1 AE), with somnolence (13.3% versus 7.8%), and headache (10.7% versus 8.1%) being the only AEs reported by ≥ 10% of former placebo users (Supplementary Table 3).
For 33.9% of participants (36.4% children; 30.4% adolescents), ≥ 1 AEs were considered to be related to viloxazine ER treatment, most commonly somnolence, 9.3% (children, 8.8%; adolescents, 9.9%); decreased appetite, 5.8% (children, 6.7%; adolescents, 4.6%); fatigue, 5.3% (children, 5.6%; adolescents, 4.8%); and headache, 4.5% (children, 4.6%; adolescents, 4.4%). These generally abated with continued treatment, with post hoc analysis of treatment-emergent AEs (both treatment related and unrelated), showing the longest median duration for decreased appetite (68 days), followed by fatigue (49.5 days), somnolence (32 days), and headache (8 days). Evaluation of the 350 (31.8%) participants who experienced at least one of these four AEs showed that approximately half [168 (15.3%) participants] required additional management, including concomitant medical treatment (9.4%; most commonly acetaminophen [3.2%] and ibuprofen [3.2%]), dose reduction (4.5%), drug interruption (0.1%), and/or discontinuation of drug (1.9%).
AEs were largely mild (26.5%) or moderate (26.9%) in severity. Of the 3.9% who reported any severe AE, none occurred in > 1% of participants (suicidal ideation, detailed below, was rated as severe for seven participants [0.6%], followed by somnolence for four participants [0.4%]). Seizures and events that might represent a seizure (e.g., syncope, pseudoseizure, myoclonus, severe muscle spasms) were designated a priori as AEs of special interest for the study, and were reported by eight participants (0.7%), including four participants (three children [0.5%] and one adolescent [0.2%]) with reported AEs of seizures/epilepsy.
Overall, 24 participants (2.2%) reported any AE related to suicidality, including 19 with suicidal ideation (n = 4 considered treatment related), 1 with suicidal behavior and ideation, and 4 with a reported suicide attempt (one of whom also had an AE of suicidal ideation). None of the cases of suicidal behavior or attempt was considered treatment related. These AEs were considered serious for 13 of the participants with suicidal ideation only, and for all of the participants with suicidal behavior or attempt. Overall, 11 participants (1.1%), including 9 reporting suicidal ideation only and 2 participants reporting a suicide attempt (including the one who also had ideation) withdrew from the study because of these AEs. The participant with suicidal behavior and ideation temporarily interrupted treatment but remained in the trial.
In total, 36 (3.3%) participants reported one or more serious AEs, which were considered treatment-related for 6 participants: 1 with syncope (moderate, day 81) that resolved the same day and did not result in change to study medication, 1 with new onset “petit mal epilepsy” (moderate, day 390) that resulted in discontinuation, 1 with depression (moderate, day 976) and 3 with suicidal ideation (described above) who withdrew from the trial.
In total, AEs led to treatment discontinuation for 90 participants (8.2%), most commonly, somnolence (11 participants; 1.0%), suicidal ideation (10 participants; 0.9%), and fatigue (7 participants; 0.6%) (Table 3).
Clinical Laboratory Evaluations, Vital Signs, Physical Examinations, and Electrocardiograms
There were no remarkable changes in clinical laboratory or hematology values, except for low neutrophil counts in some participants. Overall, 148 (13.5%) participants had neutrophil counts < 1500 per µL at any post baseline assessment, with 52 (35.1%) of these also < 1500 per µL at baseline. Among Black and African American participants, 103 (26.8%) had counts < 1500 per µL at any post-baseline visit, with 44 (42.7%) also < 1500 per µL at baseline. Neutropenia was reported as an AE for three (0.3%) participants, all mild and none leading to treatment discontinuation.
Eight participants had elevated alanine aminotransferase (ALT), one had elevated aspartate transferase (AST), and two had elevations in ALT and AST reported as AEs. All were asymptomatic and did not lead to discontinuation. These elevations resolved while on therapy except for three participants who had elevated ALT through the end of the trial. In addition, two participants had “elevated liver enzymes” reported as AEs that were considered unrelated to treatment and did not lead to discontinuation.
Elevations in heart rate, systolic or diastolic blood pressure were occasionally observed during the trial but were seldom considered AEs (Supplementary Fig. 1). Overall, 150 (15.8%) participants had high seated (resting) systolic blood pressure, and 181 (19.0%) had high seated diastolic blood pressure recorded at any post-baseline visit; however, these were considered AEs for only 11 participants (1.0%). This included five participants with increased diastolic blood pressure, four with increased systolic blood pressure, and four with overall blood pressure increases (two of whom experienced multiple increased blood pressure AEs). These AEs were described as mild for nine participants and moderate for two participants, none led to discontinuation. In addition, although 82 participants (8.6%) had high seated (resting) heart rate at any post-baseline visit, increased heart rate and/or tachycardia (including orthostatic tachycardia) were reported as AEs for only 36 participants (3.6%) all of which were assessed as mild-to-moderate in severity. Tachycardia resulted in discontinuation for only one participant (a 6-year-old child). To further evaluate the potential for sustained elevation in blood pressure and heart rate, we additionally conducted a post hoc analysis to determine the number of participants with elevated systolic blood pressure, diastolic blood pressure, or heart rate at ≥ 3 post-baseline visits including on at least two of the three last on-study visits: 1.4% had elevations in systolic blood pressure, 1.3% had elevations in diastolic blood pressure, 0.4% had elevations in heart rate, and 2.6% had elevations in any blood pressure or heart rate measurement.
Overall, participants maintained within age normative weight and height ranges according to Centers for Disease Control and Prevention (CDC) child and adolescent growth charts [34, 35]. The mean ± SD z-scores were 0.3 ± 0.9 for weight and 0.2 ± 1.0 for height at baseline, and 0.2 ± 1.0 for weight and 0.1 ± 1.6 for height at last on-study visit. z-Scores ranged between − 1.0 and 1.0 for all visits (Fig. 2), indicating that growth measures were within a normal range for population values. Consistent with these values, few participants experienced weight decrease (2.7%) or weight increase (3.2%) as AEs. Weight decrease resulted in discontinuation for one adolescent participant.
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
Efficacy Outcomes (Secondary Endpoints)
ADHD symptoms showed sustained improvement during open-label treatment. Figure 3 shows ADHD-RS-IV/5 scores for all patients assessed in double-blind trials (full analysis set n = 1560) as well as scores during the OLE for those who continued into this trial (full analysis set n = 1080). For participants in the OLE, mean ± SD baseline ADHD-RS-IV/5 scores (taken from their prior double-blind trial) were 42.7 ± 7.3 for those who had received viloxazine ER (n = 742) and 41.7 ± 7.4 for those who had received placebo (n = 338). By the end of double-blind participation, these scores had improved to 23.8 ± 14.5 and 30.3 ± 14.0, respectively, representing changes from baseline of − 18.8 ± 13.9 and − 11.4 ± 13.0, respectively. ADHD-RS-IV/5 change scores continued to improve during OLE dose titration, and by the second open-label titration visit already exceeded the magnitude of improvement seen with viloxazine ER at the end of double-blind (Fig. 3). By the end of the OLE dose optimization period (month 3), mean ± SD ADHD-RS-IV/5 score improvement from double-blind baseline was − 24.3 ± 12.0 and was similar regardless of prior double-blind treatment assignment (−24.7 ± 12.2 and − 23.4 ± 11.4, for those who had previously received viloxazine ER or placebo, respectively). Mean ADHD-RS-IV/5 change scores remained consistently below that of the viloxazine ER change score at the end of double-blind (range: − 24.3 to − 32.4 points) at subsequent OLE visits (Fig. 3) with mean ± SD change at participants’ last OLE visit (at either drop-out or end of study) of − 22.4 ± 13.6.
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
Both ADHD hyperactive/impulsive and inattention symptoms improved, as assessed using ADHD-RS-IV/5 subscales. Respective changes from double-blind baseline to OLE visit 2, OLE month 3, and OLE last on-study visit were (mean ± SD) − 6.8 ± 6.6, − 11.8 ± 6.7, and − 10.9 ± 7.4 for hyperactivity/impulsivity (Fig. 4), and − 7.6 ± 6.7, − 12.5 ± 6.4, and − 11.5 ± 7.3 for inattention (Fig. 5). Mean ± SD CGI-I scores were 3.2 ± 1.3 at OLE visit 2, 2.1 ± 1.1 at month 3, and 2.4 ± 1.3 at last on-study visit, consistent with ADHD-RS-IV/5 score improvements (Fig. 6).
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.
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.
CGI-I score. CGI-I Clinical Global Impression-Improvement, DB double-blind, OLE open-label extension, LOSV last on-study visit, SD standard deviation
By OLE visit 2, 52.4% and 32.2% of participants had met the 30% and 50% ADHD-RS-IV/5 responder rate thresholds, respectively (Fig. 7). These improvements continued during the OLE, with 84.2% and 65.0% of participants meeting the 30% and 50% thresholds after dose optimization (month 3). At the last on-study visit, 75.5% and 56.7% of participants met the 30% and 50% responder rate thresholds, respectively (Fig. 7). Similarly, by OLE visit 2, month 3, and the last on-study visit, 32.6%, 70.6%, and 59.2% of patients, respectively, had met CGI-I responder criteria (score of 1 or 2) (Fig. 8). These responder rates were higher than those seen for viloxazine ER following double-blind treatment (50% ADHD-RS-IV/5 and CGI-I responder rates of 41.6% and 49.8%, respectively) and remained above these thresholds throughout open-label maintenance dosing (month 3 through end of study; Figs. 7 and 8).
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.
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
Discussion
Findings from this OLE trial support the safety and sustained efficacy of viloxazine ER for the extended treatment of pediatric ADHD. Safety outcomes were consistent with those observed during double-blind trials, and no new safety signals were observed. Overall, AE incidence was low for the > 5-year duration of the trial, which overlapped with the onset of the COVID-19 pandemic. Nasopharyngitis, somnolence, headache, decreased appetite, and fatigue were the only AEs reported in > 5% of participants, and no AE was reported in ≥ 10% of participants. Most AEs were mild or moderate in severity and none resulted in treatment discontinuation in > 1.0% of participants.
During short-term (6–8 week) double-blind trials of viloxazine ER in pediatric ADHD, the most-commonly reported AEs were somnolence (14.5%), headache (10.8%), decreased appetite (8.1%), fatigue (6.5%), and nausea (5.1%). Despite the long-term, multi-year length of the trial, the incidence of each of these AEs was lower during this open-label trial, including for the subset of participants previously treated with placebo during double-blind treatment (except for fatigue [7.5%]).
Overall, suicidal ideation, behavior, and attempts were uncommonly reported as AEs (2.2%), even though these symptoms were prospectively monitored using the validated C-SSRS. Most cases of suicidal ideation and all cases of suicidal behavior/attempts were assessed as unrelated to viloxazine ER treatment, and AEs of suicidal behavior/attempts occurred months after the initiation of viloxazine ER use (range: days 118–898 of trial). The low incidence of suicidality in this trial is notable considering recent studies have shown an upward trend in suicidality among US adolescents in the past 10 years [36], particularly during the COVID-19 pandemic [37]. For example, in the 2021 Youth Behavior Risk Survey conducted by the CDC, 22% of high school students reported seriously considering suicide, 10% said they attempted suicide, and 3% reported being treated for a suicide attempt [36]. A study of US preteens (ages 8–12 years) also found that suicide rates increased 8.2% annually from 2008 to 2022 [38]. Individuals with ADHD may be at greater risk for suicidal ideation and behavior due to impulsivity that is an inherent feature of ADHD [39]. Compared with the CDC statistics [36], the rates of suicidality reported in our trial (2.2%) are low. This may be due to the exclusion of patients with current or recent suicidality or psychiatric comorbidities in our ADHD studies [26–30], a potential monitoring or observation bias, or other unknown reasons.
In combination with double-blind trial data, these long-term observations provide a more informative assessment of suicidality risk with viloxazine ER. In the short-term double-blind trials (n = 1019) of viloxazine ER in children and adolescents, suicidal ideation and behavior were also found to be uncommon (0.9%), but because these rates were higher than for the placebo group (0.4%), viloxazine ER prescribing information includes a boxed warning for suicidality.
In addition, while some studies suggest that stimulants may be associated with lower risk of suicidality compared with nonstimulants, demographic factors indicate that individuals typically prescribed nonstimulants are more likely to be undergoing psychotherapy, have psychiatric comorbidities, and be using other psychotropic medications than individuals prescribed stimulants [39–41]. This may explain the observed differences in suicidality risk.
While there were no remarkable patterns of change seen in clinical laboratory or hematology values during the OLE trial, 13.5% of participants had neutrophil counts < 1500 per μL at any post-baseline assessment (of these participants, approximately one-third (n = 52) had neutrophil counts < 1500 per μL at baseline). These observations were not considered clinically meaningful, were not frequently reported as AEs (0.3% neutropenia, 0.4% low neutrophil count), and did not result in discontinuation. Low neutrophil counts were reported by similar numbers of patients taking placebo (8.8%) and viloxazine ER (8.8%) during the pediatric double-blind trials and were not reported in the adult double-blind ADHD trial. Because most participants with low neutrophil counts were Black or African American it was thought that the observations may be largely explained by presence of benign ethnic neutropenia or presence of a bacterial/viral infection combined with chance finding given the higher number of observations obtained post-baseline relative to baseline. Eleven participants had elevated AST and/or ALT as AEs, which were largely transient and did not result in treatment discontinuation. Minor elevations in transaminases were also observed in the short-term double-blind trials [27–30]. In both short-term and long-term viloxazine ER trials in children and adults to date, which involved 1461 participants, no participant has fulfilled the criteria for drug-induced liver injury (increases of > 3× ULN for ALT or AST with a total bilirubin > 2× ULN).
Consistent with the clinical recommendations to monitor for blood pressure and heart rate changes while initiating and titrating viloxazine ER [19], abnormal blood pressure measurements were observed occasionally, but were typically not clinically meaningful, with few being reported as AEs. No participant discontinued treatment owing to changes in blood pressure, and one participant discontinued treatment owing to tachycardia. No blood pressure or heart rate AEs were considered serious or severe. These results are consistent with current labeling for viloxazine ER [19] and observations in short-term studies [26–30].
The labels for many ADHD medications contain FDA warnings regarding the potential for suppression of growth (weight and height) in children [42–47]. In the pediatric double-blind studies of viloxazine ER, children receiving the viloxazine ER did not gain as much weight as those receiving placebo, and adolescents receiving viloxazine ER lost weight while those receiving placebo gained weight. Results from this long-term trial show that, while some experienced decreased appetite, participants maintained normal weight and height relative to the CDC growth charts [34, 35].
Measures of ADHD symptoms and global assessments showed continued score reductions during open-label treatment that appeared to persist across visits. As participants who are not responding well may tend to drop out of the study earlier, in addition to CFB in efficacy measures over time, we also report the CFB at participants' last on-study visit, as these include values for the participants who drop out early and may therefore be more reflective of overall trial improvement. While reasons for improvement in an uncontrolled study are uncertain (i.e., time on treatment, drug effect, unblinded nature, etc.), the magnitude of change at participants’ last on-study visit (regardless of time or reason for dropout) exceeded that seen during double-blind treatment, suggesting that the observed improvement during the open-label extension was not merely due to the dropout of nonresponders.
We note that few participants remained in the OLE for over 4 years. This is likely due to the timing of rollovers, as the five participants who remained after month 48 were all rollovers from the phase 2 trial. Since the phase 2 trial occurred before the phase 3 trials, the phase 2 participants began rolling into the open-label extension earlier, hence the additional data points for these participants.
Compared with pediatric OLE studies of lisdexamfetamine dimesylate (a more recently approved stimulant product) and atomoxetine (a nonstimulant), a similar percentage of participants in this trial discontinued because of AEs (viloxazine ER: 7.6%; lisdexamfetamine dismesylate: 6.7%; atomoxetine: 8.5%), suggesting comparable tolerability [48, 49]. Conversely, fewer participants in viloxazine ER and lisdexamfetamine OLE studies discontinued for lack of efficacy (viloxazine ER 2.6%; lisdexamfetamine dimesylate 1.9%) compared with the atomoxetine OLE (26.2%), perhaps reflective of pharmacologic differences between viloxazine ER and atomoxetine [48, 49].
It is important to note that although the 600 mg dose of viloxazine ER was studied in adolescents in this trial, this dosage is not FDA-approved for pediatric use. The 600 mg dose was previously studied in adolescents in a phase 3 double-blind, placebo-controlled trial, where it did not show statistically significant improvement on the primary endpoint. However, because the OLE was already ongoing and allowed the 600 mg/day dose, no changes were made to the protocol. In addition, it was not known at the start of the OLE whether the FDA would approve the 600 mg daily dosage for adolescent use, so the protocol allowed physicians to continue using it when they thought a higher dose was warranted, in order to gather information on long-term safety and efficacy of this dosage.
This trial may have been impacted by the overlap with the COVID-19 pandemic. At the start of the pandemic, approximately 300 of the 1100 total participants remained enrolled in the OLE trial. While there was no significant change in trial dropout noted at the start of the pandemic, three participants cited COVID-19 as a specific reason for dropout and four had documented COVID-19 infections; occult cases of COVID-19 also cannot be ruled out. The impact of the widespread disruptions of school and childcare on ADHD symptoms and function cannot easily be accounted for and may have affected symptom assessment or continued trial participation. These factors may affect the comparability of this trial to similar ADHD medication trials. In addition, the phase 2 trial of viloxazine ER included in this analysis used a different version of the ADHD-RS (IV edition) than that used in the phase 3 trials (5th edition)[26–30]; however, the scale items were considered sufficiently similar to allow the trials to be analyzed together.
We also note that the exclusion of participants with psychiatric comorbidities may be a limitation given that many children and adolescents with ADHD also have co-occurring disorders, such as depression, anxiety, autism spectrum disorder, learning disabilities, behavioral or conduct problems, or developmental delays. We recently conducted a decentralized trial enrolling adults with a primary diagnosis of ADHD as well as depression and/or anxiety symptoms, and observed improvement in both clinician- and patient-rated measures of ADHD, depression, and anxiety symptoms [50]. Further studies will be needed to evaluate the safety and efficacy of viloxazine ER in children and adolescents with ADHD and mood symptoms or other co-occurring disorders.
Conclusions
Viloxazine ER demonstrated good tolerability in this open-label extension trial lasting up to 72 months, and no new safety signals were noted. Continued improvement of ADHD symptoms was observed and appeared sustained with long-term viloxazine ER treatment. 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 children and adolescents with ADHD.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
The authors would like to acknowledge Dr. Joseph T. Hull, PhD, Supernus Pharmaceuticals, Inc., for contributions to protocol development, clinical trial management, data review, and production of the final study report; Dr. Andrea Formella, PharmD, CMPP, Supernus Pharmaceuticals, Inc., for editorial assistance and recommendations and coordination of post hoc data analysis for the manuscript; Dr. Jennifer Koch, PhD, CMPP, Supernus Pharmaceuticals, Inc., for figure creation support; and Dr. Mary Lin, PhD, CMPP, Supernus Pharmaceuticals, Inc., for medical writing and project management support.
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.
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Associated Data
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Supplementary Materials
Data Availability Statement
The data are not available in a repository, but data will be made available upon reasonable request directed to jrubin@supernus.com.