Clinical Therapeutics/Volume 42, Number 8, 2020

Original Research
A Phase III, Randomized, Placebo-controlled Trial to
Assess the Efficacy and Safety of Once-daily SPN-812
(Viloxazine Extended-release) in the Treatment of
Attention-deficit/Hyperactivity Disorder in
School-age Children
Azmi Nasser 1; Tesfaye Liranso 1; Toyin Adewole 1; Nicholas Fry 1;
Joseph T. Hull 1; Fatima Chowdhry 1; Gregory D. Busse 1; Andrew J. Cutler 2;
Nandita Joshi Jones 3; Robert L. Findling 4; and Stefan Schwabe 1
1
Supernus Pharmaceuticals, Inc, Rockville, MD, USA; 2SUNY Upstate Medical University,
and Neuroscience Education Institute, Lakewood Ranch, FL, USA; 3CNS Healthcare, Jack-
sonville, FL, USA; and 4Virginia Commonwealth University School of Medicine, Richmond,
VA, USA

ABSTRACT score and the Weiss Functional Impairment Rating

ScaleeParent (WFIRSeP) Total average score. Safety
Purpose: The limitations of current US Food and
assessments included adverse events (AEs), laboratory
Drug Administration (FDA)eapproved medications
tests, vital signs, physical examinations, ECGs, and
for the treatment of attention-deficit/hyperactivity
the Columbia-Suicide Severity Rating Scale. The
disorder (ADHD) set the need for the development of
primary efficacy endpoint was analyzed by using a
novel, effective, and tolerable medications to treat
mixed model for repeated measures; all secondary
this disorder. The purpose of this study was to
measures were analyzed by using an ANCOVA model.
evaluate whether treatment with SPN-812 (viloxazine
Results: A total of 477 subjects were randomized to
extended-release) significantly reduces symptoms of
treatment (intent-to-treat population, n ¼ 460). The
ADHD in children.
majority of subjects were male (63%) and either White
Methods: This study was a randomized, double-
(51.3%) or African American (43.7%). The
blind, placebo-controlled 6-week trial to assess the
demographic and baseline characteristics between the
efficacy and safety of once-daily 100- and 200-mg
groups were similar. Statistically significant
SPN-812 in the treatment of ADHD in male and
improvements in ADHD-RS-5 Total score were
female children 6e11 years of age. Inclusion criteria
observed in both the 100- and 200-mg/day SPN-812
required subjects to have a confirmed Diagnostic and
treatment groups compared to placebo at week 1 of
Statistical Manual of Mental Disorders, Fifth Edition,
treatment (P ¼ 0.0004 and P ¼ 0.0244, respectively),
ADHD diagnosis, an ADHD-Rating Scale-5 (ADHD-
which was maintained through EOS (P ¼ 0.0004 and
RS-5) score
28, a Clinical Global Impression-
P < 0.0001). Significant improvements were also
Severity score
4, and for subjects to be free of
observed at EOS in the CGI-I scale (P ¼ 0.0020 and
ADHD medication
1 week before randomization.
P < 0.0001), Conners 3ePS Composite T-score
The primary efficacy endpoint was the change from
baseline (CFB) at end of study (EOS) in ADHD-RS-5
Accepted for publication May 29, 2020
Total score. Key secondary endpoints included
https://doi.org/10.1016/j.clinthera.2020.05.021
Clinical Global Impression-Improvement (CGI-I) 0149-2918/$ - see front matter
scores at EOS and CFB at EOS in the Conners © 2020 The Authors. Published by Elsevier Inc. This is an open access
3eParent Short Form (Conners 3ePS) Composite T- article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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 A. Nasser et al.

(P ¼ 0.0003 and P ¼ 0.0002), and WFIRSeP Total of upper abdominal pain, increased blood pressure or
average score (P ¼ 0.0019 and P ¼ 0.0002) versus heart rate, decreased appetite, or trouble sleeping.14 In
placebo. Treatment-related AEs reported in
5% of addition to these potential adverse events (AEs),
subjects included somnolence, decreased appetite, and stimulants carry a Warning and Precaution section in
headache. The discontinuation rate due to AEs was <5%. their label for serious cardiovascular events, including
Implications: SPN-812 significantly reduced ADHD sudden death in children and adolescents with cardiac
symptoms in children and was well tolerated. SPN-812 issues or structural abnormalities.14,15 Furthermore,
may prove to be an effective treatment for children overuse and misuse of methylphenidate and
with ADHD. ClinicalTrials.gov identifier: amphetamines can result in addiction/dependence and,
NCT03247530. (Clin Ther. 2020;42:1452e1466) © in rare cases, even acute psychosis.16,17 Considering
2020 The Authors. Published by Elsevier Inc. This is an these risks and concerns, many parents prefer to avoid
open access article under the CC BY-NC-ND license stimulant use in their children.18 Given these
(http://creativecommons.org/licenses/by-nc-nd/4.0/). limitations, the use of prescription stimulants to treat
Key words: ADHD, ADHD-RS-5, Conners 3, SPN- ADHD is not ubiquitous.
812, viloxazine, WFIRS. The availability of prescription nonstimulant
medications (eg, atomoxetine, guanfacine extended
release, clonidine extended release) provides an
alternative treatment for many children and
INTRODUCTION adolescents diagnosed with ADHD for whom
It is estimated that ~5.4 million children and prescription stimulant treatment is undesirable,
adolescents are currently living with attention-deficit/ precluded, or not effective or tolerated. However, for
hyperactivity disorder (ADHD) in the United States some patients, current FDAeapproved nonstimulant
(~10% of all children and adolescents in the United medications are neither more efficacious than
States), making this disorder a substantial public stimulants,19 nor are they devoid of their own
health concern.1 ADHD is characterized by a pattern limitations, risks, and/or drawbacks. For instance,
of age-inappropriate inattentiveness, hyperactivity, despite being generally efficacious, in a recent meta-
and/or impulsivity that usually persists into analysis comparing the efficacy of ADHD
adulthood.2,3 If left untreated, symptoms of ADHD medications, both atomoxetine and guanfacine
can be detrimental to an individual's academic, extended release were found to provide less
social, familial, and occupational trajectories.4e6 improvement in ADHD symptoms than stimulant
Current guidelines for the treatment of ADHD in treatment.20 The use of atomoxetine may also be
school-age children and adolescents recommend that accompanied by nausea, vomiting, fatigue, decreased
clinicians prescribe US Food and Drug Administration appetite, abdominal pain, and somnolence,21 and it is
(FDA)eapproved pharmacotherapy and/or implement contraindicated in patients with severe cardiovascular
behavioral intervention/therapy.7,8 Prescription or hepatic disorders. There is also a potential for
stimulant medications, including various formulations drugedrug interactions with atomoxetine due to
of methylphenidate and amphetamine, have been the cytochrome P450 2D6emediated metabolism.
primary medicinal treatment of ADHD for several Similarly, side effects such as somnolence, fatigue,
decades.9,10 Despite their effectiveness in reducing nausea, lethargy, abdominal pain, insomnia, or
ADHD symptoms for most children and adolescents hypotension can occur with monotherapy or
diagnosed with ADHD, prescription stimulants may adjunctive therapy with the nonstimulants guanfacine
have certain limitations, risks, and/or drawbacks extended release and clonidine extended release.22,23
associated with them that preclude their use for a As such, effective and tolerable alternative
significant proportion of these patients. For instance, medications are needed for those patients for whom
although methylphenidate is one of the most widely current prescription stimulant and/or nonstimulant
prescribed medications for ADHD,11 ~20% of use is not an option.
children and adolescents have an inadequate response SPN-812 (viloxazine extended-release) is a
to treatment.12,13 Daily use of methylphenidate can multimodal serotonergic and noradrenergic
also be associated with an increased incidence or risk modulating agent (SNMA) with reported activity at

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 Clinical Therapeutics

serotonin receptors and the norepinephrine AEs included somnolence, decreased appetite,
transporter.24 In vivo, viloxazine has been shown to headache, fatigue, nausea, and irritability. A low
increase serotonin, norepinephrine, and dopamine,25 discontinuation rate due to AEs was also observed
although the mechanism of action of SPN-812 (n ¼ 13 [6.7%]). Most AEs reported were considered
remains to be fully elucidated. mild to moderate in severity, and each resolved
A previous Phase IIb, randomized, double-blind, following discontinuation of the study medication.
placebo-controlled trial assessed the efficacy and The present study reports the efficacy and safety
safety of once-daily SPN-812 100-, 200-, 300-, and results of once-daily 100-mg and 200-mg SPN-812
400-mg for the treatment of ADHD in children 6e12 for the treatment of children (6e11 years of age)
years of age (N ¼ 222; 1:2:2:2:2 ratio).26 ADHD diagnosed with ADHD from the recent Phase III trial.
symptoms and global illness improvement as
measured by the ADHD-Rating Scale-IV and Clinical PATIENTS AND METHODS
Global ImpressioneSeverity scale (CGI-S), Study Design
respectively, were markedly reduced (improved) after A randomized, double-blind, placebo-controlled, 3-
8 weeks of SPN-812 treatment in the 200-, 300- and arm, parallel-group (100-mg/day and 200-mg/day)
400-mg SPN-812 treatment groups (but not in the trial was conducted at 34 sites in the United States
100-mg group) compared to placebo. In addition, the between October 19, 2017 and September 19, 2018
most commonly reported SPN-812 treatment-related (Figure 1) (ClinicalTrials.gov identifier:

Figure 1. Disposition of subjects. ITT ¼ intent-to-treat.

a
Number of subjects in the safety population is used as denominator for this section.

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 A. Nasser et al.

NCT03247530). After a screening phase (up to 28 were administered at baseline (randomization; visit 2)
days), eligible subjects were randomized on day 1 and again at the end of study (EOS; visit 8/week 6).
(baseline) in a 1:1:1 ratio to placebo or either 100 or The study protocol was approved by the Advarra
200 mg/day of SPN-812. All subjects, regardless of Institutional Review Board (IRB) and conducted in
treatment group assignment, were instructed to take accordance with the Helsinki Declaration and the
2 capsules daily by mouth in the morning, with or International Council for Harmonisation (ICH) Note
without food, throughout the 6-week treatment for Guidance on Good Clinical Practice. The
phase. Group assignments were as follows: (1) the parent(s) or legal guardian(s) of each subject
placebo group took 2 placebo capsules daily for 6 provided written informed consent to allow their
weeks; (2) the 100-mg SPN-812 treatment group child's participation before performing any initial or
took one placebo and one 100-mg SPN-812 capsule new study-related procedures at screening or
daily for 6 weeks; and (3) the 200-mg SPN-812 following any protocol amendments, respectively. All
treatment group took one placebo and one 100-mg versions of the informed consent form were reviewed
SPN-812 capsule daily during week 1, followed by and approved by the IRB. Subjects who completed
two 100-mg capsules daily for the remaining 5 the 6-week treatment phase and continued to meet all
weeks. If necessary, the subject's parent(s) or legal inclusion/exclusion criteria were eligible to participate
guardian(s) was allowed to open the capsules and in a long-term, open-label extension safety clinical
sprinkle the contents over a spoon of soft food (eg, trial (NCT02736656).
apple sauce) for consumption.
The placebo capsule product was formulated to Subjects
visually match the SPN-812 capsules by using the Male and female children (6e11 years of age at
exact same hard gelatin capsule shells as the active screening) were eligible to participate in the study if he
drug product. The placebo capsules contained the or she had a primary diagnosis of ADHD as defined
same inactive ingredients in the same physical form according to the Diagnostic and Statistical Manual of
as contained in the SPN-812 capsules. Taste, smell, Mental Disorders, Fifth Edition (DSM-5), which was
and feel of the placebo capsule and its contents confirmed by the Mini International Neuropsychiatric
matched those of the SPN-812. Thus, the placebo Interview for Children and Adolescents (MINI-KID),
drug product was formulated to make it highly an ADHD-RS-5 Total score
28 at screening (visit 1)
unlikely for subjects/patients or evaluating/rating and baseline (visit 2), and a CGI-S score
4 (ie,
clinicians to predict treatment assigned to subjects. moderate or greater overall illness severity) at
The parent(s) or legal guardian(s) was asked to screening (visit 1). Subjects were required to refrain
incorporate study medication dosing into the family's from taking ADHD medications (other than the study
daily morning routine and make every attempt to keep medication) starting at least 1 week before
the daily dosing time consistent throughout the 6 randomization and throughout the study until EOS.
weeks of treatment; however, some day-to-day Subjects were not eligible to participate if they had a
variability in the timing of the daily dose was current diagnosis of a major psychiatric/neurologic
acceptable, especially if an AE precluded or delayed disorder other than ADHD (excluding oppositional
dosing. Investigator-rated efficacy assessments (ADHD defiant disorder, or major depressive disorder if the
Rating Scale-5 [ADHD-RS-5] and Clinical Global subject was free of major depressive episodes both
Impression-Improvement [CGI-I]) were completed and currently and for the 6 months before screening),
safety assessments were performed at weekly significant systemic disease, a history of allergic
outpatient study visits. Self-rated efficacy assessments reaction to viloxazine or its excipients, any food
completed by the subject's parent or legal guardian allergy or intolerance that contraindicated trial
(Conners 3eParent Short Form [Conners 3ePS], participation, and/or evidence of suicidality within 6
Weiss Functional Impairment Rating ScaleeParent months of screening.
Form [WFIRSeP], and the Parenting Stress Index
Fourth Edition, Short Form [PSI-4-SF]) or by the Assessments
subject (Conners 3eSelf-Report Short Form [Conners The primary efficacy endpoint of this trial was the
3eSRS; only subjects who were 8e11 years of age]) change from baseline (CFB) in the ADHD-RS-5 Total

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 Clinical Therapeutics

score at EOS (week 6). The ADHD-RS-5 consists of 18 considered treatment-emergent (TEAE); all AEs were
items designed to reflect current symptomatology of recorded following the first administration and are
ADHD based on DSM-5 criteria.3,27 The ADHD-RS-5 thus all considered to be TEAEs (henceforth referred
was administered by a trained rater at each study visit to as AEs). The relationship to treatment, seriousness,
from baseline through EOS. and severity of all AEs were evaluated by the site
There were 3 key secondary endpoints: CGI-I investigator. AEs were determined to be mild if the
score28 at EOS, CFB in the Conners 3ePS Composite subject's symptoms were easily tolerated, moderate if
T-score29 at EOS, and CFB in the WFIRSeP Total discomfort was enough to interfere with usual daily
average score30,31 at EOS. The CGI-I was completed activities and may have warranted intervention, and
at each postbaseline visit through EOS. The Conners severe if the event was incapacitating to the subject's
3ePS also contains 6 content scales, 2 related to core daily activity or significantly affected their clinical
ADHD symptoms (inattention and hyperactivity), status and warranted intervention.
and 4 related to ADHD-associated impairments
(learning problems, executive functioning, defiance/ Statistical Analysis
aggression, and peer relations). The WFIRSeP Sample size calculations indicated that 104 subjects
evaluates functional impairment related to ADHD per treatment group in the intent-to-treat (ITT)
across 6 domains, including family, school, life skills, population would yield 90% power at a significance
child's self-concept, social activity, and risky activity. level of 0.05 (two-sided) using a 2-sample t test with
The Conners 3ePS and WFIRSeP were administered equal allocation across treatment groups; they were
at baseline and EOS visits. based on an effect size of 0.453 obtained in a
Additional secondary endpoints included the CFB at previous Phase IIb trial.26 Based on these
EOS in each ADHD-RS-5 subscale (Inattention and calculations, a total of 432 subjects (144 per
Hyperactivity/Impulsivity); the 50% responder rate per treatment arm) were projected to be randomized to
the ADHD-RS-5 (defined as the proportion of subjects treatment, to account for anticipated dropout rates of
who exhibit a
50% reduction [improvement] in CFB 27.9% in the randomized population.
ADHD-RS-5 Total score); responder rate per the CGI-I The ITT population included all randomized
(or categorical CGI-I; proportion of subjects categorized subjects administered at least 1 dose of study
as “improved,” which is defined as a subject who had a medication, who also had a baseline and at least 1
CGI-I score of 1 [“very much improved”] or 2 [“much post-baseline ADHD-RS-5 assessment. The safety
improved”]) by visit; the CFB in the PSI-4-SF Total population included all randomized subjects
score32 at EOS; and the CFB in the Conners 3eSRS administered at least 1 dose of study medication.
Composite T-score29 at EOS. Other endpoints included The primary efficacy endpoint was analyzed by
individual CFB at EOS in the content scale T-score for using a mixed model for repeated measures
both the Conners 3ePS and Conners 3eSRS and CFB (MMRM); the model included fixed-effect terms for
at EOS in the domain average score for WFIRSeP. baseline ADHD-RS-5 Total score, age group,
Safety and tolerability were assessed by monitoring treatment, visit, and treatment-by-visit interaction as
AEs, results of clinical laboratory tests (including independent variables. All secondary measures were
hepatic enzymes), vital signs, physical examinations, analyzed by using analysis of covariance (ANCOVA)
ECGs, and the Columbia-Suicide Severity Rating with treatment as fixed-effect terms and baseline as a
Scale (C-SSRS). AEs were defined as any unfavorable covariate, except for the CGI-I, which was analyzed
or unintended sign/symptom or laboratory finding, by using baseline CGI-S as a covariate. The family-
including: new disease or injury, clinically significant wise error rate was controlled under 5% by using the
deviation of blood and urinary laboratory test sequential testing procedure.33 For all analyses, P
results, vital signs, or clinical tests; or recurrence of a values, least squares (LS) of treatment means, and
medical condition that was not present at screening differences between the LS treatment means and
or baseline (ie, the AEs described were recorded after placebo were computed. LS mean CFB values are
the first drug administration). Any AE beginning after reported henceforth unless otherwise noted. Statistical
or upon first treatment administration, or that analyses were performed by using SAS version 9.4
worsened following the first administration, was (SAS Institute, Inc, Cary, North Carolina).

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 A. Nasser et al.

RESULTS treatment group were similar. Previous ADHD

Demographic and Baseline Characteristics medication use reported at screening (safety
A total of 477 subjects were randomized into the population) was as follows: 89.9% of patients in the
trial, with the ITT population consisting of 460 placebo group, 89.6% in the 100-mg/day SPN-812
subjects (placebo, n ¼ 155; 100-mg/day SPN-812, group, and 84.5% in the 200-mg/day SPN-812 group
n ¼ 147; 200-mg/day SPN-812, n ¼ 158). The safety were not taking any ADHD medication; 6.9%, 6.5%,
population consisted of 474 subjects (placebo, and 10.6% were taking stimulants; and 3.1%, 3.9%,
n ¼ 159; 100-mg/day SPN-812, n ¼ 154; 200-mg/day and 5.0% were taking nonstimulants, respectively.
SPN-812, n ¼ 161); all reasons for discontinuation
are noted in Figure 1. Approximately 19% of subjects ADHD-RS-5
who were screened discontinued from the trial before The mean ADHD-RS-5 Total score and subscale
randomization. The majority of subjects were male scores at baseline were similar among treatment groups
(63%), and either White (51.3%) or African American (Table I). The CFB in ADHD-RS-5 Total score at EOS
(43.7%) (Table I). The demographic (eg, distribution was significantly reduced (improved) with both the
of male subjects vs female subjects and ethnicity/race) 100-mg/day SPN-812 (P ¼ 0.0004) and 200mg/day
and baseline characteristics (eg, age, weight, body SPN-812 (P < 0.0001) compared to placebo (Table II).
mass index, ADHD-RS-5 Total score, and CGI-S Moreover, the CFB in ADHD-RS-5 Total score was
score) between the placebo group and either SPN-812 significantly reduced in the first week of treatment with

Table I. Demographic and baseline characteristics in the intent-to-treat (ITT) population.

Characteristic Placebo SPN-812 Overall

100 mg/day 200 mg/day

N (ITT) 155 147 158 460

Age, mean (SD), y 8.5 (1.7) 8.5 (1.7) 8.5 (1.7) 8.5 (1.7)
Sex, n (%)
Male 97 (62.6) 94 (63.9) 99 (62.7) 290 (63.0)
Female 58 (37.4) 53 (36.1) 59 (37.3) 170 (37.0)
Ethnicity, n (%)
Hispanic or Latino 32 (20.6) 38 (25.9) 51 (32.3) 121 (26.3)
Not Hispanic or Latino 123 (79.4) 108 (73.5) 107 (67.7) 338 (73.5)
Race, n (%)
American-Indian or Alaska Native 1 (0.6) 1 (0.7) 0 2 (0.4)
Asian 1 (0.6) 0 0 1 (0.2)
Black or African American 69 (44.5) 63 (42.9) 69 (43.7) 201 (43.7)
Multiple 7 (4.5) 7 (4.8) 6 (3.8) 20 (4.3)
White 77 (49.7) 76 (51.7) 83 (52.5) 236 (51.3)
Weight, mean (SD), kg 31.1 (8.0) 31.7 (8.9) 31.8 (8.4) 31.5 (8.4)
Body mass index, mean (SD), kg/m2 16.9 (2.2) 17.3 (2.2) 17.2 (2.4) 17.1 (2.3)
ADHD-RS-5, mean (SD)
Total score 43.6 (7.1) 45.0 (6.5) 44.0 (6.8) 44.2 (6.8)
Inattention 22.5 (3.8) 22.8 (3.2) 22.9 (3.5) 22.7 (3.5)
Hyperactivity/Impulsivity 21.1 (4.9) 22.2 (4.7) 21.1 (5.2) 21.5 (4.9)
CGI-S score, mean (SD) 4.8 (0.7) 4.8 (0.8) 4.8 (0.7) ND

ADHD-RS-5 ¼ ADHD Rating Scale-5; CGI-S ¼ Clinical Global ImpressioneSeverity of Illness; ND ¼ not determined; SD ¼
standard deviation.

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 Clinical Therapeutics

daily SPN-812 in both SPN-812 treatment groups, improvement began at week 1 in the 100-mg/day
exhibiting a fast onset of action. This significant effect SPN-812 treatment group (24% vs 9%; P ¼ 0.0005)
was observed at each subsequent week through EOS at and at week 2 in the 200-mg/day SPN-812 treatment
target dose in both the 100-mg/day SPN-812 and group (32% vs 19%; P ¼ 0.0099).
200-mg/day SPN-812 treatment groups compared to
placebo (Figure 2). The CFB in both the ADHD-RS-5 Conners 3−PS
Inattention and Hyperactivity/Impulsivity subscale The mean Conners 3−PS Composite T-score and
scores at EOS was significantly reduced in the content scales T-scores at baseline were similar among
100-mg/day SPN-812(P ¼ 0.0006 and P ¼ 0.0026, treatment groups. The CFB in the Conners 3−PS
respectively) and 200-mg/day (P < 0.0001 and Composite T-score at EOS was significantly reduced
P < 0.0001) SPN-812 treatment groups compared to (improved) in the 100-mg/day (P ¼ 0.0003) and 200-
placebo. Furthermore, there was a significantly higher mg/day (P ¼ 0.0002) SPN-812 treatment groups
50% responder rate in ADHD-RS-5 Total score at compared to placebo (Table III). The CFB in the T-
EOS in the 100-mg/day (P ¼ 0.0063) and 200-mg/day score for 5 of 6 Conners 3−PS content scales at EOS
(P < 0.0001) SPN-812 treatment groups compared to was significantly reduced (improved) in the 100-mg/day
placebo (Figure 3). and 200-mg/day SPN-812 treatment groups compared
to placebo, including inattention (P ¼ 0.0028 and
CGI-I P ¼ 0.0025, respectively), hyperactivity (P ¼ 0.0076
The mean CGI-S score at baseline was similar among and P ¼ 0.0013), learning problems (P ¼ 0.0154 and
treatment groups (Table I). The CGI-I score at EOS was P ¼ 0.0158), executive functioning (P ¼ 0.0002 and
significantly lower in the 100-mg/day (P ¼ 0.0020) and P ¼ 0.0024), and peer relations (P ¼ 0.0003 and
200-mg/day (P < 0.0001) SPN-812 treatment groups P ¼ 0.0023). The CFB in the T-score for the Conners
compared to placebo (Figure 4). Furthermore, the 3−PS defiance/aggression content scale at EOS was
responder rate per the CGI-I score (ie, percentage of significantly reduced only in the 200-mg/day SPN-812
subjects with a CGI-I score of 1 [very much (P ¼ 0.0245) treatment group compared to placebo.
improved] or 2 [much improved]) was also
significantly higher at EOS in the 100-mg/day and WFIRSeP
200-mg/day SPN-812 treatment groups compared to The CFB in WFIRSeP Total average score at EOS was
placebo (45% and 51% vs 30%, respectively; significantly reduced (improved) in the 100-mg/day
P ¼ 0.0065 and P ¼ 0.0002). The significant (P ¼ 0.0019) and 200-mg/day (P ¼ 0.0002) SPN-812
differences in percentage of subjects with clinical treatment groups compared to placebo (Table III). The

Table II. ADHD Rating Scale-5 (ADHD-RS-5) results in the intent-to-treat population at end of study by
treatment group.

ADHD-RS-5 Measure Placebo SPN-812

(n ¼ 155)
100 mg/day (n ¼ 147) 200 mg/day (n ¼ 158)

CFB, LS mean (SE)

Total score −10.9 (1.14) −16.6 (1.16)* −17.7 (1.12)y
Inattention subscalez −5.7 (0.60) −8.6 (0.62)* −9.2 (0.60)y
Hyperactivity/Impulsivity subscalez −5.5 (0.59) −8.0 (0.60)* −8.7 (0.58)y
50% responder ratex 31 (19.8%) 50 (34.2%)* 65 (41.2%)y

*P < 0.05 versus placebo.

y
P < 0.0001 versus placebo.
z
P values derived from ANCOVA model.
x
P values derived from logistic regression.

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 A. Nasser et al.

Figure 2. Analysis of change from baseline in ADHD-Rating Scale-5 (ADHD-RS-5) Total score in the intent-to-
treat population. LS ¼ least squares; SE ¼ standard error. *P < 0.05. yP < 0.0001.

CFB in the average score for 4 of 6 WFIRSeP domains at WFIRSeP self-concept and life skills domains at EOS
EOS was significantly reduced (improved) in the 100-mg/ was not significantly reduced for either SPN-812
day and 200 mg/day SPN-812 treatment groups treatment group compared with placebo.
compared to placebo, including the family (P ¼ 0.0276
and P ¼ 0.0003, respectively), school (P ¼ 0.0022 and Conners 3−SRS and PSI-4-SF
P ¼ 0.0009), social activities (P ¼ 0.0222 and The CFB in Conners 3−SRS Composite T-score or
P ¼ 0.0052), and risky activities (P ¼ 0.0294 and the PSI-4-SF Total score at EOS was not significantly
P ¼ 0.0036) domains. The CFB in the average score for reduced for either the 100-mg/day or 200-mg/day

Figure 3. Analysis of ADHD-Rating Scale-5 50% responder rate at end of study in the intent-to-treat popula-
tion. *P < 0.05. yP < 0.0001.

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Figure 4. Improvement in Clinical Global ImpressioneImprovement scale (CGI-I) scores by week in the intent-
to-treat population. Improvement was defined as a score of 1 (very much improved) or 2 (much
improved). *P < 0.05.

SPN-812 treatment groups compared with placebo Overall, discontinuations due to AEs were
(P ¼ 0.1292 and P ¼ 0.3447; P ¼ 0.9974 and infrequent, with 7 subjects receiving SPN-812 and 2
P ¼ 0.4557, respectively). subjects in the placebo group discontinuing the trial
(placebo, n ¼ 2 [1.3%]; 100-mg/day SPN-812, n ¼ 5
Safety and Tolerability [3.2%]; 200-mg/day SPN-812, n ¼ 2 [1.2%]). AEs
Safety assessments were performed during weekly, leading to discontinuation in the SPN-812 treatment
postbaseline outpatient study visits. The majority of AEs groups included tachycardia (0.3%), fatigue (0.3%),
reported were mild to moderate in severity (Table IV). ECG T-wave inversion (0.3%), dizziness (0.3%),
The most common TEAEs that were considered related aggression (0.3%), conduct disorder (0.3%),
to treatment occurring in
5% of subjects in any SPN- pyromania (0.3% [noted earlier]), sleep terror
812 treatment group and greater in percentage than (0.3%), and decreased appetite (0.3%), although
placebo were somnolence (8.9%), decreased appetite each occurred in no more than 1 subject (Table IV).
(6.0%), and headache (5.4%). Four subjects receiving No clinically significant trends were found in clinical
SPN-812 reported one or more AEs that were laboratory test results. The majority of subjects had
considered severe. One subject (200-mg/day group) normal hematology values at baseline, and these
experienced abdominal pain, nausea, vomiting, and remained normal at EOS. Decreases in neutrophil
acute appendicitis considered unrelated to treatment, levels were most common, observed in 19 (13.7%), 10
which resolved without sequelae. One subject (100-mg/ (7.4%), and 18 (13.0%) subjects in the placebo, 100-
day group) experienced severe somnolence, while mg/day SPN-812, and 200-mg/day SPN-812 groups,
another subject (100-mg/day group) reported severe respectively. In addition, a total of 42 subjects had a
initial insomnia, both of which were considered possibly post-baseline neutrophil count that was <1500 cells/
related to treatment but resolved without requiring mL, including 33 African-American or Black subjects
treatment interruption. The fourth subject (100-mg/day (11 subjects in each of the 3 treatment arms). All 33 of
group) reported severe pyromania considered unrelated these subjects had neutrophil counts <1500 cells/mL at
to treatment and discontinued the trial. baseline. No subjects had a neutrophil count that was

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 A. Nasser et al.

Table III. Conners 3eParent Short Form (Conners 3ePS) and Weiss Functional Impairment Rating
ScaleeParent Form (WFIRSeP) results by treatment group. Values indicate change from baseline
and are given as least squares mean (SE); P values are derived from an ANCOVA model.

Measure Placebo (n ¼ 155) SPN-812

100 mg 200 mg
(n ¼ 147) (n ¼ 158)

Conners 3ePS (T-score)

Composite −4.8 (0.81) −9.1 (0.83)* −9.2 (0.82)*
Content Scales
Inattention −6.6 (1.06) −11.1 (1.09)* −11.1 (1.06)*
Hyperactivity −6.0 (1.06) −10.0 (1.08)* −10.8 (1.06)*
Learning problems −3.2 (0.91) −6.4 (0.94)* −6.3 (0.91)*
Executive functioning −6.5 (0.99) −11.9 (1.03)* −10.8 (0.99)*
Defiance/aggression −4.3 (1.12) −6.0 (1.13) −7.9 (1.11)*
Peer relations −2.7 (1.19) −8.8 (1.21)* −7.8 (1.18)*
WFIRSeP (average score)
Total −0.22 (0.033) −0.36 (0.033)* −0.39 (0.032)*
Domains
Family −0.26 (0.048) −0.41 (0.048)* −0.51 (0.047)*
Self-concept −0.21 (0.044) −0.25 (0.045) −0.27 (0.043)
School −0.28 (0.051) −0.51 (0.052)* −0.52 (0.051)*
Life skills −0.27 (0.038) −0.36 (0.038) −0.34 (0.037)
Social activities −0.20 (0.043) −0.34 (0.044)* −0.37 (0.043)*
Risky activities −0.12 (0.028) −0.21 (0.028)* −0.24 (0.028)*

*P < 0.05 versus placebo. SE ¼ standard error.

<500 cells/mL. Decreased neutrophil count was reported as an AE. In each case, the subject's ALT and AST
as an AE in only 2 instances (100-mg/day SPN-812 and levels were within the normal range at screening; the
200 mg/day SPN-812); the event was considered not event was considered not related and unlikely related
related to treatment in each case, and it was considered to treatment, respectively, and it was considered mild
moderate or mild in severity, respectively. Incidents of in severity in each case. Overall, clinical laboratory
hepatic enzyme abnormalities included above-normal abnormalities were reported as AEs in 0 subjects in the
alanine aminotransferase (ALT; placebo, n ¼ 4 placebo group, 2 subjects (1.3%) in the 100-mg/day
[2.9%]; 100-mg/day SPN-812, n ¼ 5 [3.7%]; 200-mg/ SPN-812 treatment group, and 2 subjects (1.2%) in
day SPN-812, n ¼ 7 [5.1%]), below-normal alkaline the 200-mg/day SPN-812 treatment group;
phosphatase (ALP; placebo, n ¼ 4 [2.9%]; 100-mg/ abnormalities included decreased neutrophil count,
day SPN-812, n ¼ 3 [2.2%]; 200-mg/day SPN-812, decreased leukocytes and monocytes, and the incidents
n ¼ 4 [2.9%]); and above-normal aspartate of increased ALT and AST levels noted earlier (both of
aminotransferase (AST; placebo, n ¼ 3 [2.2%]; 100- which were considered mild in severity and unlikely
mg/day SPN-812, n ¼ 3 [2.2%]; 200-mg/day SPN- related to the study treatment).
812, n ¼ 3 [2.2%]). There were only 2 subjects (one Individual clinically relevant changes in vital signs
each taking SPN-812 100 mg/day and SPN- were infrequent, with the exception of respiratory rate
812 200 mg/day) in whom elevated hepatic enzyme below normal (reported in >10% of subjects, with no
levels post-baseline (both ALT and AST) were reported meaningful difference found vs placebo). Abnormal

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Table IV. Summary of adverse events (AEs) using the safety population. Values are given as n (%).

Safety Measure (Preferred Term) Placebo (n ¼ 159) SPN-812

100 mg/day 200 mg/day Overall
(n ¼ 154) (n ¼ 161) (n ¼ 315)

At least 1 AE 47 (29.6) 74 (48.1) 77 (47.8) 151 (47.9)

Treatment-related AEs
5%
Somnolence 3 (1.9) 14 (9.1) 14 (8.7) 28 (8.9)
Decreased appetite 0 7 (4.5) 12 (7.5) 19 (6.0)
Headache 3 (1.9) 7 (4.5) 10 (6.2) 17 (5.4)
AEs leading to discontinuation
Total 2 (1.3) 5 (3.2) 2 (1.2) 7 (2.2)
Tachycardia 0 1 (0.6) 0 1 (0.3)
Fatigue 0 1 (0.6) 0 1 (0.3)
ECG T-wave inversion 0 1 (0.6) 0 1 (0.3)
Decreased appetite 0 0 1 (0.6) 1 (0.3)
Dizziness 0 1 (0.6) 0 1 (0.3)
Aggression 1 (0.6) 1 (0.6) 0 1 (0.3)
Agitation 1 (0.6) 0 0 0
Conduct disorder 0 1 (0.6) 0 1 (0.3)
Pyromania 0 1 (0.6) 0 1 (0.3)
Sleep terror 0 0 1 (0.6) 1 (0.3)

vital signs were reported in <10% of subjects in any placebo group, 2 patients in the 200-mg/day SPN-812
SPN-812 treatment group, and all were considered group, and no patients in the 100-mg/day SPN-812
mild in severity. Hypotension was reported as a mild group. No suicidal ideation or behaviors were reported
AE in 1 subject in the 200-mg/day group, and as an AE for either SPN-812 treatment group, nor
increased blood pressure was reported as a mild AE in were they recorded per the C-SSRS; however, an
2 subjects in the 200-mg/day group. Cardiovascular- incident of suicidal ideation was reported at week 5 in
related AEs were infrequent, with one case of 1 subject (0.7%) in the placebo group. No subject
tachycardia reported in the 100-mg/day SPN-812 deaths occurred during this trial.
treatment group (0.6%) leading to trial
discontinuation, and 3 cases (1.9%) reported in the
200-mg/day SPN-812 treatment group (one case of DISCUSSION
which was concurrent with the incident of increased In this Phase III trial, both the 100-mg/day and 200-mg/
blood pressure noted earlier). These latter cases did day doses of SPN-812 were effective in reducing ADHD
not lead to trial discontinuation. No cases of symptoms in children. The primary efficacy endpoint,
tachycardia occurred with placebo treatment. One case the CFB in ADHD-RS-5 Total score at EOS, met
of palpitations was reported in the 200 mg/day SPN- statistical significance in both SPN-812 treatment arms
812 treatment group (0.6%), whereas none was (100-mg/day and 200-mg/day) compared to placebo.
reported with placebo treatment. Lastly, one case of Moreover, statistical significance for the CFB in
ECG T-wave inversion occurred in the 100-mg/day ADHD-RS-5 Total score was observed as early as
SPN-812 treatment group (0.6%), which led to week 1 for both SPN-812 treatment arms, suggesting
discontinuation; the subject was lost to follow-up in an early onset of action. The results of this current
terms of AE follow-up. Phase III trial are consistent with a previous Phase II
Weight decrease at least possibly related to the study trial investigating SPN-81226 and suggest that SPN-
medication in >1 subject was observed in 1 patient in the 812 treatment may result in a clinically meaningful

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 A. Nasser et al.

reduction in ADHD symptoms within 1 week of ADHD symptoms and functionality, there are several
treatment initiation. factors that may have influenced the threshold for
Significant improvements were also found within detecting improvements via these particular scales.
both ADHD-RS-5 Inattention and Hyperactivity/ First, this trial was statistically powered for the
Impulsivity subscale scores for 100-mg/day and 200- primary endpoint and not for secondary endpoints.
mg/day SPN-812 treatment at EOS, which was further As such, the sample size may have been insufficient
supported by the significant improvement in the to detect effects in some of the secondary measures,
responder rate per the ADHD-RS-5 (percentage of including the PSI-4-SF and the Conners 3−SRS.
subjects who had a
50% reduction in the CFB Second, subjects in this trial who were 6e7 years of
ADHD-RS-5 Total score) at EOS. This finding suggests age did not complete the Conners 3−SRS as this
that a significant proportion of subjects in this trial had measure is only validated in children 8e17 years of
a clinically meaningful, global improvement in ADHD age.29 Given that the ITT population ranged from
symptoms. Analyses of the relationship between ages 6e11 years, responses were limited to those
ADHD-RS-5 Total score and the CGI-I score suggest subjects aged
8 years and thus had a reduced
that a substantial improvement on the ADHD-RS-5 sample size, which may have confounded the power
Total score (50%e60% reduction) is in concordance to detect a significant change. Furthermore, older
with CGI-I score of 2 (much improved).34 The subjects may be more cognizant of the extent of their
significantly greater responder rate per the CGI-I score symptoms and experience with ADHD during self-
(ie, percentage of subjects who had a CGI-I score of 1 evaluation. Lastly, although the 6-week duration of
[much improved] or 2 [very much improved]) that was the current trial is typical for pivotal investigations in
also observed in both SPN-812 treatment groups ADHD,35 the impact of a therapeutic agent on
compared to placebo is consistent with the strong overall quality of life may be more discernible after a
concordance between 50% responder rate per the longer duration, or following clinical follow-up that
ADHD-RS-5 Total score and the overall clinical tracks the life trajectory of trial subjects.
impression of subject health.34 These statistically Overall, the majority of participants who received 100-
significant findings are therefore clinically meaningful. mg/day and 200 mg/day SPN-812 completed the trial
In addition to the significant improvements in ADHD (n ¼ 126 [80.3%] and n ¼ 141 [87.6%], respectively).
symptoms that were observed on the investigator-rated Both doses of SPN-812 were generally well tolerated,
ADHD-RS-5 and CGI-I assessments with SPN-812 with most AEs being mild or moderate in severity.
treatment, there were significant improvements in Severe AEs rarely occurred (4 total with SPN-812
ADHD symptoms and ADHD-related deficits in treatment). No cases of suicidal ideation, as measured
functionality and behavior observed on the parental by the C-SSRS, were noted in the subjects receiving 100-
self-rated Conners 3−PS and WFIRS−P with SPN-812 mg/day or 200 mg/day SPN-812. Most abnormalities in
treatment. For instance, on the Conners 3−PS, parents clinical laboratory results were not clinically significant
whose child was treated with SPN-812 reported and were transient. The incidence of clinical laboratory
significantly greater improvements in the areas of abnormalities for hepatic enzymes was low and similar
inattention, hyperactivity, learning problems, across all treatment groups. The cutoff for low
executive functioning, and peer relations compared to neutrophil count was set to <1500 cells/mL. Decreased
the parents whose child received placebo. On the neutrophil count was reported as an AE in only 2
WFIRS−P, parents whose child was treated with SPN- instances (one each taking 100-mg/day SPN-812 and
812 reported significantly greater improvement in the 200-mg/day SPN-812); the event was considered not
domains of family, school, social activities, and risky related to treatment in each case, and it was considered
activities. These parent-reported data support the moderate or mild in severity, respectively. Decreases in
investigator-rated observations, as well as indicate that neutrophil levels were observed in 19 (13.7%), 10
treatment with SPN-812 can improve the deficits in (7.4%), and 18 (13.0%) subjects in the placebo, 100-
daily functioning inherent in ADHD. mg/day, and 200-mg/day groups, respectively. The
Although significant improvements were not majority of these subjects were African American or
observed on parent self-rated PSI-4-SF for parental Black, who usually have lower neutrophil counts at
stress level and subject self-rated Conners 3−SRS for baseline. The overall observations of low neutrophil

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 Clinical Therapeutics

counts could likely be explained by benign ethnic significant, across a variety of behavioral and social
neutropenia.36 Abnormalities in vital signs and ECG domains. These data also indicate functional
results were mild and transient in nature. Few AEs improvement in addition to symptomatic
relating to cardiovascular events or changes in blood improvement. Overall, once-daily SPN-812 (100 mg
pressure were reported. and 200 mg) was well tolerated, as demonstrated by
The positive results of this Phase III trial suggest that the low rate of discontinuation due to TEAEs
SPN-812 may have potential advantages for children observed for either SPN-812 dose. Collectively, the
(6e11 years of age) with ADHD compared with other results of this Phase III clinical trial indicate that
ADHD medications. For instance, it is well documented SPN-812 is an effective and overall well-tolerated
that stimulant therapy provides variable effectiveness pharmacotherapy that could be a future treatment
throughout the day,37 and a subset of patients are not option for children (6e11 years of age) with ADHD.
appropriate candidates for stimulant use due to
contraindications and/or tolerability issues.38e40
Alternatively, currently approved nonstimulants can DISCLOSURES
have variable latencies for patient response, suboptimal Drs. Nasser, Liranso, Adewole, Hull, Chowdhry, Busse,
response, and AE profiles that may also preclude their and Schwabe and Mr. Fry are employees of Supernus
use in certain populations.20e23,41 Long acting forms of Pharmaceuticals, Inc. Dr. Findling receives or has
nonstimulant medication, such as SPN-812 (viloxazine received research support, acted as a consultant, and/
extended-release), may provide more consistent, or has received honoraria from Acadia, Aevi, Akili,
effective, and safe treatment for these patients. This Alcobra, Allergan, Alkermes, Amerex, American
Phase III trial results suggest that the efficacy of SPN- Academy of Child & Adolescent Psychiatry, American
812 for ADHD symptoms can begin as early as week 1 Psychiatric Press, Arbor, Axsome, Daiichi-Sankyo,
of treatment, along with a safe and well-tolerated Genentech, KemPharm, Luminopia, Lundbeck,
clinical profile. MedAvante-ProPhase, Merck, the National Institutes
of Health, Neurim, Noven, Nuvelution, Otsuka,
CONCLUSIONS PCORI, Pfizer, Physicians Postgraduate Press, Purinix,
This Phase III trial met the efficacy objective and Q BioMed, Receptor Life Sciences, Roche, Sage,
showed statistically significant differences between Signant Health, Sunovion, Supernus Pharmaceuticals,
SPN-812 (100-mg/day and 200-mg/day) and placebo Inc., Syneurx, Takeda, Teva, TouchPoint, Tris
in the primary endpoint (CFB in ADHD-RS-5 at Pharma, and Validus. Dr. Cutler is a consultant for
EOS). Statistical improvements in ADHD-RS-5 Total Adlon Therapeutics, Aevi Genomics, Akili Interactive,
score compared to placebo were seen after 1 week of Arbor Pharmaceuticals, Ironshore, KemPharm,
SPN-812 treatment and were maintained throughout Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka,
the 6-week trial, indicating an early and sustained Purdue, Shire, Sunovion, Supernus Pharmaceuticals,
effect. Significantly more improvement per the CGI-I Inc., Takeda, and Tris Pharma; has received speaker/
score at EOS was observed with SPN-812 treatment promotional honoraria from Adlon Therapeutics,
versus placebo. Furthermore, SPN-812 exhibited Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics,
efficacy across both the Inattention and Otsuka, Shire, Sunovion, Takeda, and Tris Pharma;
Hyperactivity/Impulsivity subscales of the ADHD-RS- and has received research grants from Aevi Genomics,
5. Investigator-rated assessments were also supported Akili Interactive, Arbor Pharmaceuticals, Ironshore,
by parent self-rated assessments (Conners 3−PS and KemPharm, Lundbeck, Neos Therapeutics, Otsuka,
WFIRS−P), which indicated improvement not only in Purdue, Shire, Sunovion, Supernus Pharmaceuticals,
their child's ADHD symptoms but also in ADHD- Inc., Takeda, and Tris Pharma. The authors have
associated impairments (learning problems, executive indicated that they have no other conflicts of interest
functioning, defiance/aggression, and peer relations) regarding the content of this article.
and functioning in different settings (family, school, Supernus Pharmaceuticals Inc. employees
social activities, and risky activities). Thus, the participated in study design; in the collection, analysis
benefits of treatment with SPN-812 appear to be and interpretation of data; in the writing of the report;
clinically meaningful, and not just statistically and in the decision to submit the article for publication.

1464 Volume 42 Number 8

 A. Nasser et al.

ACKNOWLEDGMENTS 3. American Psychiatric Association. Diagnostic and Statistical

This work was funded by Supernus Pharmaceuticals, Manual of Mental Disorders. 5th ed. Washington, DC:
Inc. Writing and editorial support was provided by American Psychiatric Publishing; 2013.
Imprint Science. 4. Arnold LE, Hodgkins P, Kahle J, Madhoo M, Kewley G.
Long-term outcomes of ADHD: academic achievement and
Dr. Nasser contributed to study conceptualization;
performance. J Atten Disord. 2020;24:73e85.
oversight of all aspects of the study methods,
5. Deberdt W, Thome J, Lebrec J, et al. Prevalence of ADHD in
analysis, and data interpretation; and writing, nonpsychotic adult psychiatric care (ADPSYC): a
reviewing, and updating the manuscript drafts. Dr. multinational cross-sectional study in Europe. BMC
Liranso contributed to statistical methodology, Psychiatry. 2015;15:242.
statistical analyses, data interpretation support, 6. Treuer T, Chan KLP, Kim BN, et al. Lost in transition: a
critical review of the manuscript, and help with review of the unmet need of patients with attention deficit/
updating the manuscript drafts. Dr. Adewole hyperactivity disorder transitioning to adulthood. Asia Pac
contributed to drug safety, development of the safety Psychiatr. 2017;9.
sections and plans, oversight of the study protocols, 7. Pliszka S. Aacap Work Group on Quality Issues: practice
safety data analyses support, and critical review of parameter for the assessment and treatment of children and
the manuscript. Mr. Fry contributed to project adolescents with attention-deficit/hyperactivity disorder. J Am
Acad Child Adolesc Psychiatr. 2007;46:894e921.
management, implementation of the study protocols,
8. Subcommittee on Attention-Deficit/Hyperactivity Disorder,
execution of the study, and critical review of the
Steering Committee on Quality Improvement Management,
manuscript. Dr. Hull contributed to execution of Wolraich M, Brown L, Brown RT, DuPaul G, et al. ADHD:
study protocols; protocols amendments; analyzing the clinical practice guideline for the diagnosis, evaluation, and
data; interpreting the results; and writing, reviewing, treatment of attention-deficit/hyperactivity disorder in
and updating the manuscript drafts. Dr. Chowdhry children and adolescents. Pediatrics. 2011;128:1007e1022.
contributed to development of study protocols, 9. Arnold LE. Methyiphenidate vs. amphetamine: comparative
analyzing the data, interpreting the results, and review. J Atten Disord. 2000;3:200e211.
critical review of the manuscript drafts. Dr. Busse 10. Raman SR, Man K, Bahmanyar S, et al. Trends in
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Opin Investig Drugs. 2016;25:463e474.
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data interpretation; and critically reviewed the 1991;36:141e155.
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Address correspondence to: Azmi Nasser, PhD, Supernus Pharmaceuticals,

Inc, 9715 Key West Ave, Rockville, MD, 20850, USA. E-mail: anasser@
supernus.com

1466 Volume 42 Number 8