An Open-Label Extension Study Assessing the Long-Term Safety and Efficacy of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder

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 attention-deficit/hyperactivity disorder (ADHD) in children (> 6 years old) and adults. This phase 3 open-label extension to a pivotal phase 3, double-blind trial evaluated the long-term safety and continued efficacy of viloxazine ER in adults with ADHD.

Methods

This was a multicenter, flexible-dose, open-label extension to a phase III, double-blind, placebo-controlled trial (NCT04016779). Viloxazine ER was initiated at 200 mg/day and adjusted (between 200 and 600 mg/day) to achieve optimal efficacy and tolerability. Trial enrollment was halted temporarily (24 March 2020 to 23 July 2020) due to the coronavirus disease 2019 (COVID-19) pandemic. Participants completing double-blind treatment during that time were offered delayed enrollment upon trial requalification. Safety outcomes were the primary objectives. Secondary objectives were efficacy outcomes, including the ADHD Investigator Symptom Rating Scale (AISRS), and were assessed relative to double-blind baseline (or trial re-entry baseline for those whose enrollment was delayed by the COVID-19 pandemic).

Results

Overall, 159 participants (133 immediate and 26 delayed rollover) received viloxazine ER, with a mean exposure of 265 ± 254.9 days. Adverse events (AEs) included (> 10% incidence) insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%). AEs led to discontinuation for 17.6% of participants [most commonly insomnia (2.5%), nausea (2.5%), and fatigue (1.9%)]. AISRS total score [baseline mean ± standard deviation (SD): 37.9 ± 6.3] improved by the first follow-up visit (−11.4 ± 9.5; week 2) with continued improvement at subsequent visits (last on-study visit: −18.2 ± 11.54). Similar patterns of improvement were seen for other measures of efficacy, including quality of life and executive function. Following initial dose optimization, most participants (73%) used viloxazine ER doses ≥ 400 mg/day, with 36% using doses of 600 mg/day.

Conclusions

Long-term viloxazine ER use was well tolerated, with no new long-term safety findings. Improvements in ADHD symptoms and associated measures were sustained throughout trial participation. In total, 73% percent of adult participants in this long-term study used viloxazine ER doses of 400 mg or more during maintenance treatment.

Clinical Trial Registration

Clinicaltrials.gov Identifier: NCT04143217.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40263-024-01120-0.

Plain Language Summary

Attention-deficit/hyperactivity disorder (ADHD) is common in children and adults and characterized by inattention, impulsivity, and hyperactivity that can substantially interfere with everyday life. On the basis of positive efficacy and safety results from clinical studies in children, adolescents, and adults, viloxazine ER (viloxazine extended-release capsules) received US Food and Drug Administration (FDA) approval as a new treatment for ADHD and is marketed under the brand name Qelbree® (Supernus Pharmaceuticals, Inc). Adults who participated in the short-term (6 weeks) double-blind study that eventually led to the FDA approval of viloxazine ER were invited to enroll in this open-label extension trial to monitor the medication’s long-term safety and continued efficacy. This study also provided a pathway for study participants to continue receiving viloxazine ER until its FDA approval and commercial availability. Participants in the study received viloxazine ER at dosages between 200 and 600 mg/day on the basis of symptom response and side effects (most used at least 400 mg/day). Viloxazine ER was demonstrated to have a good safety and tolerability profile. The most common side effects were insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%). Long-term treatment led to continued improvement in ADHD symptoms, quality of life, and executive function (executive function includes cognitive skills such as organizing and following through with tasks). The study results further support the continued use of viloxazine ER as a long-term treatment option for adults with ADHD.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40263-024-01120-0.

Key Points

For adults taking viloxazine ER (200–600 mg/day) in this open-label extension to a double-blind pivotal trial, ADHD symptoms, quality of life, executive function, and clinical global impression assessments showed further improvement relative to that seen during double-blind treatment, and these were maintained with continued use.

These results support viloxazine ER as a long-term treatment option for adults with ADHD.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and hyperactivity, as well as other associated features (low frustration tolerance, irritability, or mood liability) and may substantially interfere with many aspects of an individual’s life, including academic and educational achievements, work-related performance, and interpersonal relationships [1–4]. ADHD is a highly heritable condition [5, 6] and typically manifests during childhood and persists into adulthood. While many individuals experience partial improvement over time or periods of remission, longitudinal analysis suggests that fewer than 10% experience complete and sustained symptom remission [7]. Therefore, because pharmacologic treatments for ADHD are likely to be taken for many years, it is essential to demonstrate long-term safety and continued response with these medications [8, 9].

A recent global meta-analysis reported prevalence of symptomatic adult ADHD at ~ 7%, making it one of the most common neurobehavioral disorders in adults [10]. Although clinical awareness of adult ADHD is increasing, fewer treatment options are specifically approved for adults than for children, and the majority of these are stimulant medications, which are controlled substances. Though effective, stimulant medications have substantial safety and tolerability issues, pose risk for misuse and diversion, may exacerbate some comorbid conditions associated with ADHD, can be difficult to obtain, and are associated with stigma, making them undesirable for many patients [11, 12]. Concern for potential misuse and addiction are reflected in a recent report on reasons for medication changes in adults with ADHD, where physicians cited medications with lower risk of abuse as a chief unmet need in ADHD care [13]. In 2023, the US Food and Drug Administration (FDA) officially addressed the growing concerns of prescription stimulant medication misuse, abuse, addiction, and overdose and has required updated labeling to the boxed warnings on all stimulant medications to add stronger language regarding misuse and abuse potential and cautions against medication sharing or diversion [14]. These concerns are in response to the growing rate of stimulant prescription fills, which according to prescription claims data (MarketScan commercial databases), increased from 2016 to 2020 (3.6–3.8% of patients), and especially from 2020 to 2021 (to 4.1% of patients) during the COVID-19 pandemic, when many prescription stimulants became available via telehealth [14, 15].

Viloxazine ER (viloxazine extended release capsules; Qelbree^®, Supernus Pharmaceuticals, Inc.) is the first nonstimulant medication to receive FDA approval for the treatment of adult ADHD in more than 20 years [16]. Viloxazine was initially approved in Europe as an immediate-release formulation given three times a day for the treatment of depression, and during its more than 30-year history of use was not associated with major safety issues nor abuse liability [17]. Now reformulated, the ER product allows for once daily dosing to provide adequate plasma concentrations over the 24-h dosing interval [16]. The pharmacologic mechanism of action underlying the therapeutic effect of viloxazine ER for ADHD is presumed to be through norepinephrine (NE) reuptake inhibition [16]. Still, viloxazine shows notable pharmacologic differences from atomoxetine (Strattera^®, Eli Lilly and Company), a potent NE reuptake inhibitor [18], including more moderate affinity for the NE transporter and potentially relevant activity at certain serotonin (5-HT) receptors [19]. Namely, in vitro experiments have shown viloxazine to have partial agonist activity at 5-HT_2C receptors, antagonist activity at 5-HT_2B receptors, and antagonist activity at 5-HT₇ receptors [19]. Rat microdialysis experiments have additionally shown that viloxazine increases NE, dopamine (DA), and 5-HT concentrations in the prefrontal cortex (PFC) at clinically relevant concentrations [20]. The increase in 5-HT at clinically used doses may be unique to viloxazine compared with other NRIs, such as atomoxetine and reboxetine, which have not been reported to significantly alter PFC 5-HT concentrations [21]. Consistent with its lack of abuse potential, viloxazine ER does not bind to DA receptors and transporters in the nucleus accumbens, and increases in DA in this brain region were modest and short-lived in preclinical studies. [19]. These observed effects on PFC NE and DA concentrations in microdialysis experiments are likely due to NE reuptake inhibition, which could be enhanced by the activity at 5-HT receptors, whereas (because viloxazine does not appreciably block 5-HT reuptake transporters) the increased PFC 5-HT concentrations are presumed to result from a direct effect at certain 5-HT receptors [19]. Whether 5-HT modulatory effects meaningfully contribute to viloxazine ER treatment efficacy for ADHD is not fully understood; however, 5-HT deficiencies have been associated with hyperactivity and impulsivity in ADHD [22], and other FDA-approved pharmacotherapies for ADHD, namely amphetamines, are also known to increase prefrontal 5-HT concentrations [23].

Viloxazine ER was initially approved in the USA for the treatment of pediatric ADHD in 2021 on the basis of a robust clinical development program, including four phase III, double-blind, placebo-controlled trials in children and adolescents (6–17 years of age) [16, 24–28]. FDA approval was expanded to include adults with ADHD in 2022 on the basis of demonstrated efficacy and safety in a phase III, double-blind, placebo-controlled, 6-week clinical trial (NCT04016779) [16, 29]. In this double-blind trial, viloxazine ER significantly improved ADHD symptoms and Clinical Global Impression after only 2 weeks of treatment, with executive function also improved by the study endpoint (week 6) [16, 29]. Participants completing the double-blind trial were eligible to receive viloxazine ER in the open-label extension trial presented here. The extension trial was designed to evaluate long-term safety (primary objective) and efficacy (secondary objective) of viloxazine ER as a treatment for adult ADHD, as well as providing participants who volunteered for the trial an avenue to continue viloxazine ER treatment until it was commercially available to them.

Methods

Study Design

This was a phase III, open-label extension, multicenter, flexible-dose clinical trial (NCT04143217) to evaluate the long-term safety and efficacy of viloxazine ER 200–600 mg/day in adults with ADHD. The trial was conducted from January 2020 through July 2022, with trial enrollment suspended between 24 March 2020 and 23 July 2020 due to the coronavirus disease 2019 (COVID-19) pandemic. Remote visits, at the discretion of the individual clinical sites and participants, were permitted during the approximate 5-month shutdown due to the COVID-19 pandemic. Participants who completed the double-blind trial during this period were offered delayed entry into the open-label extension trial once enrollment reopened, provided they completed a screening visit and were able to meet the specified qualification criteria for trial re-entry (refer to Section 2.2.).

Per the initial protocol design, participants took viloxazine ER 200 mg/day during week 1 and 400 mg/day during week 2 (similar to the double-blind trial), after which the dose could be adjusted (at the investigator’s discretion) in weekly increments of up to 200 mg/day to achieve optimal clinical response and tolerability within the range of 200–600 mg/day. The protocol was later amended to have participants take viloxazine ER 200 mg/day for weeks 1 and 2 (until the first return clinic visit), at which time the clinician could further adjust the dose as outlined above. This protocol amendment was intended to reflect clinical practice, where dose adjustments occur following clinician evaluation. If after study week 12 the optimized dose was not providing adequate response, supplementation with an FDA-approved stimulant medication was allowed at the investigator’s discretion. Safety and efficacy assessment visits were conducted at weeks 2 and 4 and then approximately every 8 weeks thereafter, as well as a phone call at the 4-week point between each 8-week visit interval for additional safety and tolerability monitoring.

Participants

Participants who completed the previous double-blind trial were eligible to continue directly into the open-label extension following their end-of-study (EOS; week 6) clinic assessment. If the participant started the open-label extension trial within 7 days (immediate rollover) of completing the double-blind trial (schedule A), safety and efficacy assessments performed at the double-blind EOS visit served as visit 1 assessments in the open-label trial. For participants who started the open-label trial more than 7 days (delayed rollover) after completing the double-blind trial (schedule B), an additional screening visit was conducted within 28 days of open-label trial entry to establish continued eligibility. These assessments were then repeated at visit 1 (study day 1) to confirm eligibility and to serve as baseline safety and efficacy assessments for the open-label trial. Schedule A and B study designs are depicted in Supplementary Fig. 1. Delayed rollover participants were also required to discontinue use of any ADHD medications started in the interim at least 7 days prior to the first dose of viloxazine and have an ADHD Investigator Symptom Rating Scale (AISRS) total score of ≥ 24 and Clinical Global Impression-Severity of Illness (CGI-S) score of ≥ 4 (moderately ill or worse) at the screening visit.

Assessments

Safety Assessments

The primary safety assessments included adverse events (AEs), clinical laboratory evaluations, vital signs, weight, electrocardiograms (ECGs), physical examination, and the Columbia Suicide Severity Rating Scale (C-SSRS). AEs were classified by severity (as determined by the site investigator), seriousness, and relationship to treatment. Adverse events of special interest (AESIs) were defined a priori as seizure or AEs that might represent a seizure (e.g., syncope/syncopal episode, psychogenic nonepileptic seizures, myoclonus, and severe muscle spasms). AEs were summarized according to the Medical Dictionary for Regulatory Activities (MedDRA^®) version 22.1 on the basis of system organ class and preferred term. Because viloxazine ER is a cytochrome P450 (CYP) 1A2 inhibitor, which can inhibit caffeine (a CYP1A2 substrate) metabolism [16], additional safety assessments included monitoring of concomitant medications and participant self-reported caffeine consumption (volume and type of caffeinated beverage/s consumed) over the previous 7 days. For all safety assessments, baseline was defined as the last non-missing value prior to viloxazine ER dosing in the open-label extension.

Efficacy Assessments

Efficacy assessments included AISRS total and subscale (Inattention and Hyperactivity/Impulsivity) scores; CGI-Severity (CGI-S) and CGI-Improvement (CGI-I) scores; Behavioral Rating Inventory of Executive Function-Adult Version (BRIEF-A), including Global Executive Composite (GEC), Behavioral Regulation Index (BRI), Metacognitive Index (MI), and subscales; the Generalized Anxiety Disorder 7-Item (GAD-7) total score; the Symptoms of Depression Questionnaire (SDQ) total score; and the Adult ADHD Quality of Life (AAQoL) total and subscale scores. The BRIEF-A scale scores were converted to T-scores for reporting, as is customary and consistent with the previous double-blind trial analysis [29].

Secondary efficacy assessments also included several predefined responder rates for the AISRS and CGI-S. For the AISRS 30% and 50% response rates, these were defined, respectively, as the percentages of participants who experienced a ≥ 30% or ≥ 50% improvement from baseline in AISRS total score; CGI-S responders were defined as the percentage of participants who were rated as CGI-S score of 1 (normal, not at all ill) or 2 (borderline ill); and CGI-I responders were defined as the percentage of participants rated as CGI-I score of 1 (very much improved) or 2 (much improved). For efficacy assessments, baseline was defined differently for immediate rollover (schedule A) and delayed rollover (schedule B) participants. For immediate rollover participants, baseline was defined as the baseline assessed during the previous double-blind trial; for delayed rollover participants, baseline was defined as the assessment completed just prior to the first dose of viloxazine ER in the open-label extension trial (visit 1). All efficacy assessments were selected to align with those in the double-blind trial, which were evaluated as change from baseline.

Statistical Analyses

All safety and efficacy statistical analyses were based on the safety population, which included participants who received ≥ 1 dose of viloxazine ER. Results were summarized using descriptive statistics for continuous variables and using counts and percentages for categorical variables. Percentages are based on the total number of participants with non-missing data. No imputations were made for missing data points. All statistical analyses were performed using SAS^® version 9.4.

Results

Participant Disposition and Baseline Characteristics

Overall, 159 participants (n = 133, immediate rollover; n = 26, delayed rollover) received ≥ 1 dose of viloxazine ER and were included in safety and efficacy assessments (Table 1). The mean ± standard deviation (SD) exposure to viloxazine ER in the open-label extension was 265 ± 254.9 days (median 191 days; range 1–887 days). Notably, 81 participants (50.9%) received treatment for at least 6 months, 50 (31.4%) received treatment at least 12 months, and 9 (5.7%) received treatment for longer than 24 months (Fig. 1). Mean ± SD participant age was 36.3 ± 10.3 years, with enrollment balanced between male (51.6%) and female (48.4%; Table 2) participants. Overall, 108 (67.9%) participants reported taking concomitant medications during the study. The most common (> 5%) medications were vitamins; contraceptives; viral vaccines; and single doses or short courses of analgesics (e.g., ibuprofen, acetaminophen), antihistamines (e.g., cetirizine, loratadine, diphenhydramine), or antibiotics. Additionally, ten participants (6.3%) were prescribed a stimulant medication (methylphenidate or amphetamine product) concomitantly at some point during the trial. Nearly all participants (90%) reported caffeine consumption while taking viloxazine ER, with 29.6% consuming ≥ 1000 mg of caffeine weekly.

Table 1.

Participant disposition

Participant disposition, n	Immediate rollover		Delayed rollover		Total
Prior treatment	Placebo	Viloxazine ER	Placebo	Viloxazine ER
Enrolled	74	60	18	12	164
Not dosed	0	1	3	1	5
Received viloxazine ER (safety set)	74	59	15	11	159
Reason for early discontinuation
Withdrew consent	15	20	5	2	42
Adverse event	19	5	2	3	29
Lost to follow-up	17	10	2	0	29
Lack of efficacy	8	6	0	1	15
Noncompliance with study drug	4	2	0	0	6
Physician decision	0	1	0	0	1
Othera	3	6	2	0	11
Remaining in study at time of final closure by sponsorb	8	9	4	5	26

An “immediate rollover” participant was defined as a participant who enrolled in the study at or ≤ 7 days after their last clinical trial visit during the previous double-blind trial. A “delayed rollover” participant was defined as a participant who enrolled in the study > 7 days after their last clinical trial visit during the previous double-blind trial. The safety set included all enrolled participants that received ≥ 1 dose of viloxazine ER.

ER, extended-release; FDA, US Food and Drug Administration

^aOther reasons for early discontinuation included: (1) conflict with new work schedule (n = 1); (2) participants did not want to continue in extension trial (n = 2); (3) pregnancy (n = 1); (4) participant did not return (n = 1); (5) following enrollment in the OLE, it was discovered that elevations in ALT and/or AST levels at the end of double-blind study visit should have disqualified participants (n = 2), in the viloxazine ER treatment group, from entry into the OLE, therefore these participants were discontinued, and these ALT and/or AST elevations were not considered by investigators to be AEs; (6) participant used prohibited medication and had new onset of depression (n = 1); (7) use of amphetamines (with or without cannabis) (n = 2); and (8) unable to comply with study procedures (n = 1).

^bThe trial was closed (last patient visit 26 July 2022) following FDA approval and viloxazine ER becoming commercially available for adults.

Fig. 1.

Exposure duration to viloxazine ER.

Table 2.

Demographics and baseline characteristics

	Overall (N = 159)
Age (years), mean ± SD	36.3 ± 10.3
Median (range)	35 (18–58)
Age group (years), n (%)
18–44	119 (74.8)
45–65	40 (25.2)
Sex, n (%)
Male	82 (51.6)
Female	77 (48.4)
Ethnicity, n (%)
Hispanic or Latino	31 (19.5)
Not Hispanic or Latino	128 (80.5)
Race, n (%)
White	133 (83.6)
Black or African American	16 (10.1)
Othera	10 (6.3)
Weight (kg), mean ± SD	80.7 ± 17.0
BMI (kg/m2), mean ± SD	27.3 ± 4.7
Weekly caffeine consumption (mg), n (%)
None	4 (2.5)
< 1000	96 (60.4)
≥ 1000	47 (29.6)
Unknown	12 (7.5)
AISRS total score, mean ± SD	37.9 ± 6.3
Inattention subscale	21.6 ± 3.4
Hyperactivity/impulsivity subscale	16.2 ± 4.9
AAQoL score, mean ± SDb	54.9 ± 15.0
BRIEF-A T-score, mean ± SD
BRIc	63.0 ± 11.2
GECd	70.4 ± 10.9
MId	73.4 ± 11.6
CGI-S score, mean ± SD	4.6 ± 0.6
% Moderately ill  % Markedly ill  % Severely ill	45.3% 48.4% 6.3%
GAD-7 total score, mean ± SDe	5.9 ± 4.5
SDQ score, mean ± SDe	105.9 ± 17.2

AAQoL, Adult Attention-Deficit Hyperactivity Disorder Quality of Life; ADHD, attention-deficit/hyperactivity disorder; AISRS, ADHD Investigator Symptom Rating Scale; BMI, body mass index; BRI, Behavioral Regulation Index; BRIEF-A, Behavior Rating Inventory of Executive Function-Adult; CGI-I, Clinical Global Impression-Improvement; CGI-S, Clinical Global Impression-Severity of Illness; GAD-7, Generalized Anxiety Disorder 7-Item Scale; GEC, Global Executive Composite; MI, Metacognitive Index; SD, standard deviation; SDQ, Symptoms of Depression Questionnaire

^aOther includes Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander; participants who were reported as > 1 race; and participants who did not report their race.

^bn = 128

^cn = 157

^dn = 156

^en = 158

Participants were started at 200 mg/day viloxazine ER; after week 1 (start of week 2), 103 participants received at least 400 mg/day of viloxazine ER. Following initial dose optimization (≥ week 13), the most frequently used dose was between 400 and 600 mg/day for most participants (73%), with 36% using 600 mg/day (Fig. 2, Supplementary Fig. 2).

Fig. 2.

Modal dose used following optimization (≥ week 13).

Primary Outcome: Safety

Adverse Events

Overall, 72.3% (n = 115) of participants experienced 1 or more AEs during the open-label extension, most commonly insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%) (Table 3). All of these were reported more frequently for participants who had previously received placebo in the prior double-blind trial (Table 3). For 51.6% (n = 82) of participants, ≥ 1 AEs were considered to be related to viloxazine ER treatment, most commonly (≥ 5% occurrence) insomnia (11.3%), fatigue (10.1%), nausea (9.4%), headache (5.7%), and dry mouth (5.0%). For most participants, AEs were mild (26.4%) or moderate (40.3%) in severity. Of the 5.7% reporting any severe AE, the only events reported by more than 1 individual were insomnia (n = 2) and headache (n = 2).

Table 3.

Summary of adverse events

Category, Preferred Term, n (%)	Prior double-blind treatment assignment		Overall (N = 159)
	Placebo (n = 89)	Viloxazine ER (n = 70)
≥ 1 treatment-emergent AE	67 (75.3)	48 (68.6)	115 (72.3)
≥ 1 treatment-related AE	49 (55.1)	33 (47.1)	82 (51.6)
AEs by maximum severity
Mild	19 (21.3)	23 (32.9)	42 (26.4)
Moderate	40 (44.9)	24 (34.3)	64 (40.3)
Severe	8 (9.0)	1 (1.4)	9 (5.7)
≥ 1 AESIa	2 (2.2)	0	2 (1.3)
≥ 1 SAEb	1 (1.1)	1 (1.4)	2 (1.3)
Most common AEs (≥ 2% overall incidence)
Insomniac	16 (18.0)	6 (8.6)	22 (13.8)
Nausea	19 (21.3)	3 (4.3)	22 (13.8)
Headached	11 (12.4)	6 (8.6)	17 (10.7)
Fatigue	12 (13.5)	4 (5.7)	16 (10.1)
Erectile dysfunctione	3 (3.4)	3 (4.3)	6 (7.3)
Coronavirus infection	7 (7.9)	4 (5.7)	11 (6.9)
Anxiety	7 (7.9)	3 (4.3)	10 (6.3)
Dry mouth	5 (5.6)	3 (4.3)	8 (5.0)
Vomiting	4 (4.5)	4 (5.7)	8 (5.0)
Constipation	6 (6.7)	1 (1.4)	7 (4.4)
Decreased appetite	7 (7.9)	0	7 (4.4)
Dizziness	5 (5.6)	2 (2.9)	7 (4.4)
Diarrhea	6 (6.7)	0	6 (3.8)
Dyspepsia	3 (3.4)	2 (2.9)	5 (3.1)
Tachycardia	5 (5.6)	0	5 (3.1)
Apathy	1 (1.1)	3 (4.3)	4 (2.5)
Irritability	2 (2.2)	2 (2.9)	4 (2.5)
Palpitations	3 (3.4)	1 (1.4)	4 (2.5)
Restlessness	3 (3.4)	1 (1.4)	4 (2.5)
Sinusitis	2 (2.2)	2 (2.9)	4 (2.5)
Upper respiratory tract infectionf	3 (3.4)	1 (1.4)	4 (2.5)
Urinary tract infection	3 (3.4)	1 (1.4)	4 (2.5)

Note: Collated percentages are reported in the footnote for insomnia^c, headache^d, and upper respiratory tract infection^f on the basis of combined terms for each AE

AE, adverse event; AESI, adverse events of special interest; ER, extended-release; SAE, serious adverse event

^aAESI were defined as seizure or AEs that might represent a seizure, including, but not limited to, syncope/syncopal episode, psychogenic nonepileptic seizures, myoclonus, and severe muscle spasms

^bSAEs were considered unrelated to viloxazine ER treatment

^cInsomnia (17.6%, respectively): initial insomnia, insomnia, middle insomnia, poor quality sleep, sleep disorder, terminal insomnia

^dHeadache (12.6%, respectively): headache, migraine, migraine with aura, tension headache

^eErectile dysfunction incidence is based on male participants that received ≥ 1 dose of viloxazine ER (n = 82). Of these participants experiencing erectile dysfunction as an AE (n = 6), one discontinued the study and five were noted to be recovered/resolved without a change in dose

^fUpper respiratory tract infection (n = 10; 6.3%): nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, viral sinusitis, viral upper respiratory tract infection. Somnolence (n = 5; 3.1%): somnolence, lethargy, sedation. Abdominal pain-related terms (abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper) were < 2%

Two participants (1.3%) experienced serious AEs (SAEs), all of which were deemed by investigators to be severe, but unrelated to study medication. One of these participants experienced serious adverse events of deep vein thrombosis and pulmonary embolism on study day 97 that resolved but resulted in treatment discontinuation. The second participant experienced serious adverse events of fall, spinal column injury, and syncope on study day 341 but remained in the study without a change in viloxazine ER dose. Syncope was reported as an AESI for two participants (1.3%). These included the participant with the SAE (described above), and a participant who experienced moderate syncope on study day 146 that was also assessed as unrelated to viloxazine ER and did not require a change in dosage.

Overall, AEs led to treatment discontinuation for 28 (17.6%) total participants, including 20 (22.5%) of the 89 who had received placebo during the double-blind trial and 8 (11.4%) of the 70 who had received viloxazine ER during the double-blind trial. The most common AEs leading to treatment discontinuation were insomnia (2.5%), nausea (2.5%), and fatigue (1.9%). Of the ten participants who received supplemental stimulant treatment, three (33.3%) reported onset of any AE during stimulant use (participant 1: anxiety and sinusitis; participant 2: nausea and irritable bowel syndrome; and participant 3: somnolence and an episode of food poisoning). None of these AEs were severe or serious or resulted in viloxazine ER discontinuation.

Clinical Laboratory Evaluations, Vital Signs, Physical Examinations, Electrocardiograms, and Suicidality

Clinical hematology laboratory monitoring showed no new safety signals. A total of four (2.5%) participants had elevations in aspartate aminotransferase (AST; n = 3) and/or alanine aminotransferase (ALT; n = 4) that were reported as AEs. Viloxazine ER was withdrawn for two of these participants (both of whom had received viloxazine ER during double-blind without clinically significant transaminase elevations and were participating in the open-label under the delayed-entry protocol). Elevations were < 3× the upper limits of the reference ranges (female/male: AST 34/39 U/L and ALT 33/44 U/L, respectively) in all but one individual, a 37-year-old man with AST 54 U/L and ALT 151 U/L on study day 91 (considered possibly related to treatment) that led to viloxazine ER discontinuation. The other participant who discontinued was a 55-year-old woman who had ALT and occasional AST elevations prior to both double-blind and open-label treatment; AST/ALT remained elevated during treatment with the highest reported values of 43/84 on day 23 that were reported as an AE of moderate elevated liver enzymes (considered unlikely related to treatment), and the individual was subsequently withdrawn from the study due to this AE. All AST/ALT elevations resolved, including for the 2 participants who continued study medication without interruption, and none were associated with increases in bilirubin or alkaline phosphatase.

Elevations in systolic blood pressure, diastolic blood pressure, and heart rate were also observed during the study, with mean ± SD elevations (measured while sitting) at participants’ last on-study visit (LOSV) of 2.5 ± 11.2 mmHg, 1.5 ± 8.3 mmHg, and 4.8 ± 11.9 beats/min, respectively. Of the 153 participants for whom measurements were available, 30.7% (n = 47) and 14.4% (n = 22) had any sitting systolic or diastolic blood pressure increase of ≥ 15 mmHg, and 24.8% (n = 38) had any post-baseline heart rate increase of ≥ 20 beats/min at any time during the open-label extension trial. However, these increases may not have been sufficiently high nor persistent to meet a definition of hypertension. In fact, blood pressure or heart rate increases were not commonly reported as AEs, and only seven participants (4.4%) reported any AE related to elevated blood pressure [hypertension (n = 3), increased diastolic blood pressure (n = 3), or increased blood pressure (n = 1)], and five total participants (3.1%) reported AEs of increased heart rate and/or tachycardia (including two participants with tachycardia on ECG at a single visit where the AE was considered mild and unlikely/not related to treatment). All AEs of increased blood pressure or heart rate were mild or moderate in severity, and none resulted in dose modifications or treatment discontinuation. Additionally, three participants discontinued for AEs considered cardiac in nature, one for palpitations (moderate, treatment-related), one for irregular heart rate (mild; possibly treatment-related), and one for sinus arrhythmia (moderate, unlikely treatment-related) that was noted on ECG. The specific arrhythmia was not reported for this individual; however, all ECG intervals were within normal ranges and no treatment was administered for the event.

A total of three (1.9%) participants reported bodyweight changes as an AE [weight increased (n = 1), unlikely treatment-related; weight decreased (n = 2), possibly treatment-related] that were mild in severity and did not result in treatment change or discontinuation. Overall, the mean ± SD change from baseline in body weight at participants’ LOSV was – 0.5 ± 4.95 kg. Of 153 participants with available data, 14.4% (n = 22) experienced weight gain of ≥ 5% of their bodyweight, and 27.5% (n = 42) experienced a loss of ≥ 5% at any study visit. At participants’ LOSV, these percentages were 9.8% (n = 15) and 17.0% (n = 26), respectively.

Two participants (1.3%) reported suicidal ideation on C-SSRS, with positive responses to the question, “Have you wished you were dead or wished you could go to sleep and not wake up?” For the first participant, the response was recorded on study day 14 and was not reported as an AE; for the second participant, the response was recorded on study day 644 and was reported as an AE that was assessed as mild and not treatment-related. Neither participant discontinued or had a viloxazine ER dose change as a result of the response, and both continued participation through the end of the study (days 704 and 867, respectively). A third participant recorded a positive response to this same C-SSRS question prior to beginning open-label viloxazine ER treatment (visit 1); this participant subsequently quit taking viloxazine ER on day 8 due to AEs of insomnia, dry mouth, and restless leg syndrome. No suicidal ideation was reported at the early termination visit. There were no other “yes” responses to C-SSRS questions. No participant reported suicidal behavior (neither on C-SSRS nor as an AE).

Secondary Outcome: Efficacy

Overall, ADHD symptoms showed consistent improvement over the course of the trial, beginning at the first clinic assessment (week 2), where the mean ± SD change from baseline (37.9 ± 6.3) in AISRS total score was –11.4 ± 9.5 points (Fig. 3). AISRS scores by this timepoint were similar regardless of prior treatment group or rollover status, with absolute scores of 26.1 ± 10.5 (n = 95) for delayed rollover participants and those treated with placebo in the double-blind trial versus 27.4 ± 12.8 (n = 51) for immediate rollover participants treated with viloxazine ER in double-blind (Fig. 3). Further improvement was seen at subsequent visits, with overall AISRS score reductions at 6 months (week 28), 1 year (week 52), and LOSV of ‒ 19.9 ± 9.9 (n = 81), ‒22.0 ± 10.4 (n = 51), and –18.2 ± 11.5 (n = 146), respectively. Improvement was observed for both AISRS Inattention and Hyperactivity/Impulsivity subscales, which also decreased from baseline scores of 21.6 ± 3.4 and 16.2 ± 4.9, respectively, by week 2 (‒ 6.1 ± 5.6 and – 5.3 ± 5.4), with further reductions (improvement) at subsequent visits (Supplementary Table 1). Improvement in these subscales at 6 months (week 28), 1 year (week 52), and LOSV were, respectively,– 11.2 ± 5.9, – 11.8 ± 6.0, and – 9.9 ± 7.1 for Inattention, and – 8.7 ± 5.3, – 10.2 ± 5.8, and – 8.3 ± 5.9 for Hyperactivity/Impulsivity.

Fig. 3.

AISRS total score change from baseline by visit. For participants who enrolled in the open-label trial within 7 days of completing the previous double-blind trial (immediate rollover), BL was the double-blind BL score; for participants who enrolled in the open-label trial more than 7 days after the previous double-blind clinical trial (delayed rollover), BL was measured immediately prior to the first dose of viloxazine ER in the open-label study. The inset shows the improvements over the first 20 weeks of the open-label extension for immediate rollover participants who received viloxazine ER in the double-blind trial and delayed rollover participants who received viloxazine ER during the double-blind trial or immediate/delayed rollover participants who received placebo. ADHD, attention-deficit/hyperactivity disorder; AISRS, ADHD Investigator Symptom Rating Scale; BL, baseline; CFB, change from baseline; DB, double-blind; ER, extended-release; LOSV, last on-study visit; SD, standard deviation

At the end of the double-blind trial, 60.0% (n = 78/130) and 39.2% (n = 51/130) of participants receiving viloxazine ER had met the AISRS 30% and 50% reduction responder thresholds, respectively. Following dose optimization in the open-label trial (week 12), the percentage of participants meeting these responder thresholds at all subsequent visits was above 70% for the AISRS 30% reduction requirement, and above 50% for the AISRS 50% reduction requirement. The generally high responder rates were not solely the result of dropout among nonresponders, in that 71.9% (n = 105/146) of participants who had any post-baseline data experienced a ≥ 30% reduction in AISRS total score at their LOSV, and that 47.3% (n = 69/146) of participants (Fig. 4) experienced a ≥ 50% reduction at their LOSV.

Fig. 4.

AISRS total score ≥ 50% responder rates by visit. For participants who enrolled in the open-label trial within 7 days of completing the previous double-blind trial (immediate rollover), BL was the double-blind BL score; for participants who enrolled in the open-label trial more than 7 days after the previous double-blind clinical trial (delayed rollover), BL was measured immediately prior to the first dose of viloxazine ER in the open-label study. AISRS 50% responder rate is defined as the percent of participants at each visit who had a ≥ 50% reduction from BL in AISRS total score. ADHD, attention-deficit/hyperactivity disorder; AISRS, ADHD Investigator Symptom Rating Scale; BL, baseline; DB, double-blind; ER, extended-release; LOSV, last on-study visit

CGI-S and CGI-I results mirrored the improvement in AISRS scores. The CGI-S score was 4.6 ± 0.6 at baseline (all participants at least moderately ill), improved by – 1.0 ± 1.0 at week 2, and showed further reductions at subsequent visits. Reductions from baseline at 6 months (week 28), 1 year (week 52), and LOSV were –1.8 ± 1.2, –2.1 ± 1.3, and –1.6 ± 1.3, respectively (Fig. 5). At LOSV (n = 159), 56.6% of participants had improved such that they would be classified as between not at all ill to mildly ill, while 43.4% remained moderately to severely ill. CGI-I ratings also reflected improvement at week 2 (score 2.9 ± 0.96) and decreased (improved) further at subsequent study weeks. Scores at 6 months (week 28), 1 year (week 52), and LOSV were 2.2 ± 0.9, 1.9 ± 1.1, and 2.4 ± 1.1, respectively (Table 4, Supplementary Fig. 3A). At LOSV (n = 152), 23.0% of participants were very much improved, 28.3% were much improved, 27.6% were minimally improved, 18.4% had no change, 2.0% were minimally worse, and 0.7% were much worse.

Fig. 5.

CGI-S total score by visit. For participants who enrolled in the open-label trial within 7 days of completing the previous double-blind trial (immediate rollover), BL was the double-blind BL score; for participants who enrolled in the open-label trial more than 7 days after the previous double-blind clinical trial (delayed rollover), BL was measured immediately prior to the first dose of viloxazine ER in the open-label study. The inset shows the improvements over the first 20 weeks of the open-label extension for immediate rollover participants who received viloxazine ER in the DB trial and delayed rollover participants who received viloxazine ER during the double-blind trial or immediate/delayed rollover participants who received placebo. BL, baseline; CGI-S, Clinical Global Impression-Severity of Illness; DB, double-blind; ER, extended-release; LOSV, last on-study visit; SD, standard deviation

Table 4.

Summary of the absolute values at baseline and by visit for CGI-I and AAQoL measures and change from baseline in AISRS and BRIEF-A scales by visit

		BRIEF-A
	AISRS	GEC	BRI	MI	CGI-I	AAQoL
BL	159, 37.9 ± 6.3	156, 70.4 ± 10.9	157, 63.0 ± 11.2	156, 73.4 ± 11.6	146, 2.9 ± 1.0	128, 54.9 ± 15.0
Week 2	146, −11.4 ± 9.50	ND	14, −0.5 ± 5.92	14, −2.4 ± 9.36	146, 2.9 ± 1.0	ND
Week 4	132, −15.0 ± 10.13	117, –9.3 ± 9.9	119, −8.4 ± 9.32	117, −8.9 ± 10.45	132, 2.6 ± 1.0	97, 10.3 ± 14.7
Week 12	112, −17.6 ± 10.69	104, –10.0 ± 11.5	106, −8.7 ± 10.66	104, −10.0 ± 11.80	112, 2.4 ± 1.0	87, 12.2 ± 17.2
Week 20	95, −18.7 ± 11.46	91, –13.0 ± 12.2	94, −10.6 ± 10.70	91, −12.9 ± 13.00	95, 2.2 ± 1.0	73, 13.6 ± 18.9
Week 28	81, −19.9 ± 9.88	78, –14.2 ± 12.8	79, −10.7 ± 11.59	78, −15.0 ± 13.04	81, 2.2 ± 0.9	62, 16.6 ± 17.8
Week 36	67, −20.9 ± 10.39	65, –14.6 ± 12.0	66, −11.7 ± 10.86	65, −15.0 ± 12.46	67, 1.9 ± 0.9	52, 14.7 ± 17.9
Week 44	59, −21.1 ± 10.27	57, –14.2 ± 11.7	58, −11.0 ± 10.61	57, −14.8 ± 12.02	59, 1.9 ± 0.9	43, 17.7 ± 15.8
Week 52	51, −22.0 ± 10.40	50, –15.1 ± 13.8	51, −12.3 ± 12.88	50, −15.3 ± 13.58	51, 1.9 ± 1.1	38, 16.7 ± 17.1
Week 60	39, −22.6 ± 11.34	38, –15.4 ± 14.3	38, −11.6 ± 13.09	38, −16.2 ± 14.24	39, 1.8 ± 0.9	30, 16.6 ± 17.0
Week 68	36, −22.1 ± 11.32	36, –16.3 ± 15.2	36, −12.8 ± 14.04	36, −16.9 ± 15.32	36, 1.8 ± 1.0	26, 16.7 ± 18.1
Week 76	33, −24.3 ± 10.64	33, –16.7 ± 15.1	33, −13.1 ± 13.43	33, −17.2 ± 15.71	33, 1.8 ± 0.9	26, 17.2 ± 14.7
Week 84	29, −22.8 ± 10.86	28, –15.9 ± 12.7	28, −13.1 ± 10.66	28, −15.9 ± 13.93	29, 1.9 ± 0.9	22, 17.3 ± 14.8
Week 92	25, −24.2 ± 11.94	25, –14.8 ± 15.0	25, −12.0 ± 11.82	25, −14.7 ± 16.41	25, 1.8 ± 1.0	18, 18.2 ± 17.1
Week 100	13, −23.7 ± 11.72	13, –16.1 ± 16.3	13, −12.8 ± 12.10	13, −16.7 ± 17.47	13, 1.8 ± 0.9	9, 14.5 ± 14.5
Week 108	9, −26.3 ± 11.29	9, –17.8 ± 20.6	9, −14.8 ± 18.40	9, −18.1 ± 20.59	9, 1.7 ± 0.7	6, 15.8 ± 17.3
Week 116	8, −25.9 ± 12.41	7, –12.9 ± 17.3	7, −12.9 ± 15.69	7, −11.9 ± 18.25	8, 1.8 ± 0.7	5, 14.5 ± 16.2
Week 124	4, −21.5 ± 16.26	3, –13.7 ± 28.5	3, −10.0 ± 24.56	3, −14.7 ± 27.30	4, 2.5 ± 1.3	1, 6.0
LOSV	146, −18.2 ± 11.54	120, –12.9 ± 13.5	121, −10.1 ± 11.73	120, −13.2 ± 14.27	146, 2.4 ± 1.1	99, 11.6 ± 18.2

AAQoL, Adult Attention-Deficit Hyperactivity Disorder Quality of Life; AISRS, ADHD Investigator Symptom Rating Scale; BRI, Behavioral Regulation Index; BRIEF-A, Behavior Rating Inventory of Executive Function-Adult; CGI-I, Clinical Global Impression-Improvement; GEC, Global Executive Composite; LOSV, last on-study visit; MI, metacognitive index; SD, standard deviation

Data are n, mean ± SD.

As with AISRS scores, participants who had received placebo in double-blind and those who returned to the trial as delayed-rollover participants showed rapid improvement upon starting viloxazine ER treatment. By week 2, CGI-S scores for these participants were similar to direct rollover participants who had received viloxazine ER during double-blind treatment (3.6 ± 1.03 and 3.6 ± 1.03, respectively).

CGI-S responder rates and CGI-I responder rates on viloxazine ER treatment reached 30.8% (n = 40/130) and 48.5% (n = 63/130), respectively, at the end of the double-blind trial and continued to increase during open-label treatment. Respective CGI-S and CGI-I responder rates were 29.5% and 61.6% following initial dose optimization (week 12), 42.0% and 70.4% at 6 months (week 28), and 56.9% and 80.4% at 1 year (week 52), and generally remained at or higher than these levels at subsequent visits. At participants’ LOSV (n = 146), 37.0% were classified as CGI-S responders and 71.9% as CGI-I responders (Fig. 6, Supplementary Fig. 3B). A similar pattern of improvement was observed for other secondary efficacy endpoints throughout the open-label extension trial, including BRIEF-A GEC, BRI and MI index T-scores, AAQOL, GAD-7, and SDQ (Table 4, Supplementary Table 1).

Fig. 6.

CGI-S responder rates by visit. For participants who enrolled in the open-label trial within 7 days of completing the previous double-blind trial (immediate rollover), BL was the double-blind BL score; for participants who enrolled in the open-label trial more than 7 days after the previous double-blind clinical trial (delayed rollover), BL was measured immediately prior to the first dose of viloxazine ER in the open-label study. CGI-S responder rate is defined as the percent of participants at each visit who had a CGI-S score of 1 (normal, not at all ill, asymptomatic) or 2 (borderline ill). BL, baseline; CGI-S, Clinical Global Impression-Severity of Illness; DB, double-blind; ER, extended-release; LOSV, last on-study visit

Discussion

The results from this open-label extension study support the long-term use of viloxazine ER as a well-tolerated and effective nonstimulant treatment option for adults with ADHD. Safety outcomes were consistent with those observed in the double-blind study, and importantly, there were no new safety findings. For the majority of individuals (73%), the most frequently used viloxazine ER dosage, during the maintenance phase, ranged between 400 and 600 mg/day, yet the overall incidence of AEs was low, particularly given the long duration of the study and its conduct during the COVID-19 pandemic. No AE was reported by more than 15% of participants. Insomnia, nausea, headache, and fatigue were the only AEs reported by more than 10% of participants. These appeared generally transient, with a post hoc analysis showing median duration being longest for insomnia [34 days]. Of the 61 participants who experienced any of these four AEs, approximately half (n = 32) required additional management, including one or more of the following: medical treatment (n = 13), dose reduction (n = 9), drug interruption (n = 1), or discontinuation (n = 13). AEs were mostly mild or moderate in severity, including among participants who received concomitant stimulant treatment, and were reflective of the types of AEs seen during short-term treatment [29]. As would be expected, AEs were reported more frequently by participants who had previously received placebo (75.3%) relative to participants who received viloxazine ER (68.6%) in the double-blind trial.

Insomnia and nausea (13.8% of participants for each AE) were the most commonly reported AEs in this trial and were reported with similar frequency for viloxazine ER-treated participants in the 6-week, double-blind lead-in trial (15.9% and 12.2%, respectively) [29]. Conversely, somnolence was less common, reported by 1.9% in this trial and 2.6% in double-blind trial. Interestingly, the opposite pattern was seen with viloxazine ER across the 5 double-blind pediatric ADHD trials (6–17 years of age), where somnolence was the most commonly reported AE (14.5%), and insomnia (2.1%) was less commonly reported [24, 26–28, 30]. The reasons for the difference between age groups are not entirely clear since sleep disorders, including insomnia, are a common comorbidity for individuals with ADHD regardless of age [31, 32]; however, one possibility may be the more widespread use of caffeine among adults in this trial [33, 34].

Approximately 90% of participants reported consuming caffeine in this study, with 29.6% reporting ≥ 1000 mg per week of caffeine use, the equivalent of a cup or more of coffee a day (a standard 8 oz cup of coffee contains 100–150 mg of caffeine). Caffeine is primarily hepatically metabolized by the CYP1A2 enzyme. Although a clinical study conducted to determine the effects of viloxazine ER on CYP substrates did not show an increase in peak caffeine concentrations after a single caffeine dose, its presence in the body was substantially prolonged owing to the inhibitory effect of viloxazine ER on CYP1A2-mediated caffeine metabolism. Consequently, consuming multiple doses of caffeine in a day, or using caffeine later in the day, could potentially lead to insomnia due to slowing of caffeine metabolism [16]. Interestingly, however, atomoxetine, another norepinephrine reuptake inhibitor approved for ADHD, which does not have effects on CYP1A2 or caffeine metabolism, elicits a similar AE pattern with respect to prominence of insomnia in adults compared with children. In adult clinical trials of atomoxetine, insomnia (~ 15%) was more commonly reported than somnolence (~ 8%) [18], whereas in pediatric clinical trials the opposite was seen [somnolence (~ 11%) of participants versus insomnia (< 2%)] [18].Although atomoxetine is not known to inhibit cytochrome P450 isoenzymes (or caffeine metabolism), as it is metabolized by CYP2D6 and therefore strongly influenced by CYP2D6 modulators and genotypic variation, with atomoxetine concentrations as well as side effects (including insomnia) being elevated in CYP2D6 poor metabolizers [18].

Consistent with the clinical recommendations to monitor patients for blood pressure and heart rate changes while initiating and titrating viloxazine ER treatment, elevations in blood pressure or heart rate measurements were occasionally observed (with overall rates similar to the prior 6-week, double-blind trial) but seldom rose to the level of a clinical diagnosis of hypertension (on the basis of AE reporting) and did not result in discontinuation. Although three participants discontinued for cardiac or ECG-related AEs, none were considered serious or severe. These observations are consistent with a phase I study in healthy adult volunteers, in which supratherapeutic doses of viloxazine ER (1800 mg/day × 2 days) had no clinically meaningful impact on cardiac repolarization (QT interval) or other ECG parameters that would suggest a risk for cardiac arrhythmias or ECG abnormalities [35]. Although four participants had elevations in AST and/or ALT reported as AEs, none were considered severe, and none were associated with elevations in alkaline phosphatase or bilirubin that would meet criteria for drug-induced liver injury [36]. These elevations normalized even in those participants who continued treatment. Similar elevations in transaminases (without increases in bilirubin) were also seen across pediatric ADHD trials assessing viloxazine ER [37]. To date, which includes the approximate 30-year span in which viloxazine immediate-release was approved as an antidepressant in Europe [17], there have been no reports of liver injury due to viloxazine treatment, and there are no warnings regarding liver injury in the USA prescribing information for Qelbree [37].

Overall, viloxazine ER did not appear to be associated with a trend for weight gain, and mean patient body weight decreased slightly (0.5 kg weight loss) during the trial. By LOSV, 17% reported losing at least 5% of their body weight compared with 9.8% who reported at least a 5% weight gain. This appears consistent with reports of lower weight gain for age (relative to placebo) in children and adolescents taking viloxazine ER for ADHD reported in the prescribing information. Further evaluation of weight changes by baseline body weight could be considered; however, the low number of AEs related to weight gain (n = 1) or loss (n = 2) suggest weight changes were not viewed as clinically significant.

Overall, efficacy assessments showed continued improvement in the open-label study beyond that seen for viloxazine ER at the end of double-blind treatment, and these changes appeared persistent across visits, although mean scores are more variable at later timepoints due to dwindling sample size. Still, improvement did not appear to be solely due to dropout of nonresponders during the open-label study because the changes at LOSV were also larger in magnitude than those seen at the end of the double-blind trial. Although only limited conclusions can be made regarding efficacy because this was not a placebo-controlled study, and we acknowledge that there is a possible bias because of the lack of any comparison group, efficacy did appear to be sustained over the duration of the trial, as demonstrated by few participants (9.1%) discontinuing the study due to lack of efficacy. Although there are no head-to-head comparison studies between viloxazine ER and other ADHD medications, this finding contrasts with other long-term studies of nonstimulant ADHD medications, such as the OLE study of atomoxetine in adults, in which just over 25% of participants discontinued the study due to lack of efficacy [38, 39]. In addition, few participants (~ 6%, n/N = 10/159) required the addition of a stimulant. Of note, executive function, a prominent source of difficulty for individuals with ADHD, also appeared to show further improvement beyond that seen in the double-blind trial on the basis of the changes in BRIEF-A GEC, BRI, and MI T-scores. These long-term improvements in ADHD symptoms appeared clinically meaningful across maintenance visits on the basis of predefined responder rates, with 50–80% of participants experiencing at least a 50% reduction in AISRS scores and 50–89% rated as “much improved” or “very much improved” on CGI-I.

Improvement in AAQoL ratings coincided with improvement in ADHD and executive function measures and also suggests that the level of long-term benefit experienced from viloxazine ER treatment was clinically meaningful to participants. At the end of the double-blind trial, participants using viloxazine ER had a mean ± SD AAQoL improvement of 10.9 ± 14.61 points over baseline [40], which exceeds the 8-point minimum clinically important change for this scale [41]. AAQoL scores showed continued improvement following open-label dose-optimization, with mean increases of 12.2 to 18.2 points over baseline across maintenance visits.Notably, there was no significant correlation between weekly reported caffeine use and efficacy measures (AISRS, CGI-S, or AAQoL scores). This is consistent with a preliminary regression analysis previously conducted using interim data from this study and a prior double-blind trial that suggested caffeine use did not affect efficacy (but did increase risk of insomnia) [42].

A substantial limitation of this trial was that the study period overlapped with the COVID-19 pandemic. Clinical site shutdowns necessitated temporary suspension of enrollment into the open-label extension that affected ~ 168 (~ 62.9%) of the 267 eventual double-blind trial completers. Despite the opportunity for delayed enrollment once the open-label trial reopened, the inevitable combination of hurdles involved with the pandemic, including trying to recontact these individuals, discontinue any disallowed medications, and reestablish sufficient symptom presence to requalify in this study, notably impacted open-label enrollment. Only 90 of the 168 individuals completing the double-blind trial after suspension of open-label enrollment returned and requalified under the delayed entry protocol (enrollment rate 54.2%), compared with 74 of 99 individuals who completed the double-blind trial before the shutdown (enrollment rate of 74.7%). Additionally, the impact and associated stresses of widespread disruptions in work, school, and childcare (particularly during the early months of the pandemic) on participants’ ADHD symptoms, function, and willingness/ability to continue trial participation are not easily accounted for, and hamper the ability to compare our results with those of other medication trials. A move to remote clinic visits was permitted during the temporary shutdown, albeit optional based on individual investigation sites and participants, which could also have affected interpretation of efficacy measures over an approximate 5-month period of the study. Overall, 6.9% (n = 11) of participants contracted documented COVID-19, and others may have had occult cases. The impact of these factors on AEs and safety outcomes are also difficult to measure. Given the uncertainty of possible COVID-19 symptoms, participants may have been under a period of heightened awareness to physical well-being that inadvertently led to potential over-reporting of AEs and a greater willingness to discontinue study participation due to an AE or to concerns about being exposed to COVID-19 by visiting a study site; however, the similarity of AEs types to those seen in the double-blind trial, and lack of new safety signals, is reassuring. Another limitation affecting the generalizability of our findings is the exclusion of participants with comorbid psychiatric conditions commonly reported in adults with ADHD, such as depression, anxiety, or substance use disorders, as well as the exclusion of participants with cardiovascular disorders or other medical conditions that may be more commonly seen in older adults with ADHD [29]. Because viloxazine was originally studied as an antidepressant, it could potentially have utility in persons with ADHD and concomitant depression and anxiety.

Additional studies or analyses to assess the extent to which these results generalize to individuals with these disorders or other common ADHD comorbidities, and to evaluate which participants will be most likely to respond to viloxazine ER, are needed.

Conclusions

Viloxazine ER showed good tolerability in this long-term open-label extension trial in adults with ADHD. There were no new safety findings, and AEs were similar in nature and frequency to those seen during the phase III double-blind trial. Participants maintained on viloxazine ER showed continued improvement in ADHD symptoms, executive function, and quality of life measures. Although the COVID-19 pandemic led to temporary trial enrollment closure, which likely impacted participation and generalizability of trial findings, the present study supports the long-term use of viloxazine ER as a well-tolerated and effective nonstimulant option for treatment of ADHD in adults.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Funding

This research was entirely supported by Supernus Pharmaceutials, Inc. Open acces publication was funded by Supernus Pharmaceutials, In.

Conflict of Interest

A.C. has received research support from, served as a consultant or speaker for, or served on an advisory board for Aardvark, Adlon, Akili Interactive, Allergan, Alora, Arbor, Axsome, Aytu, Cingulate Therapeutics, Corium, Emalex, Ironshore, KemPharm, Lumos, Neurovance, Noven, Otsuka, Purdue, Rhodes, Sunovion, Takeda Pharmaceuticals, Tris, and Supernus Pharmaceuticals, Inc. A.J.C. has received research support from, served as a consultant or speaker for, or served on an advisory board for AbbVie (Allergan), Acadia, Aevi Genomic Medicine, Akili Interactive, Arbor Pharmaceuticals, Atentiv, Axsome, Boehringer Ingelheim, Biogen, BioXcel, Cerevel, Cingulate Therapeutics, Corium, Eli Lilly, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Karuna, KemPharm, LivaNova, Lundbeck, MedAvante-ProPhase, Neos Therapeutics (now Aytu BioPharma), Neumora, Neurocrine, NeuroSigma, Neurovance, NLS Pharma, Noven, Otsuka, Purdue Canada, Rhodes Pharmaceuticals, Relmada Therapeutics, Inc., Sage Therapeutics, Sumitomo (Sunovion), Supernus Pharmaceuticals, Inc., Takeda Pharmaceuticals (Shire), Teva, Thynk Health, Tris Pharma, and VistaGen. L.A.A. has received grant and research support from Otsuka, Takeda Pharmaceuticals, and Corium Pharmaceuticals; has served as a consultant to Bracket, Major League Baseball, the National Football League, Otsuka Pharmaceuticals, Takeda Pharmaceuticals, Supernus Pharmaceuticals, Inc., and SUNY; and has received loyalty payments (as inventor) since 2004 from NYU for the license of adult ADHD scales and training materials. N.F., K.A., Z.M.C., A.E.F., and J.R. are employees of Supernus Pharmaceuticals, Inc.

Ethics Approval

The study was approved by an institutional review board (WCG IRB #20192701) and conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice Guidelines.

Consent to Participate

Each participant provided written informed consent prior to enrollment.

Consent for Publication

Not applicable.

Availability of Data and Material

The data are not available in a repository, but data will be made upon reasonable request directed to jrubin@supernus.com.

Code Availability

Not applicable.

Author Contributions

Conceptualization and design: J.R., A.J.C., and A.C. Methodology and data collection: J.R. Analysis and interpretation: J.R., A.J.C., L.A., A.C., and A.E.F. Final data assurance: K.A., Z.M.C., and A.E.F. Medical writing: A.E.F. All authors have read, reviewed, and approved the original drafts and final submitted version of the manuscript and agree to be held accountable for the work.