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/).

1452 Volume 42 Number 8


(P ¼ 0.0003 and P ¼ 0.0002), and WFIRSeP Total
average score (P ¼ 0.0019 and P ¼ 0.0002) versus
placebo. Treatment-related AEs reported in
5% of
subjects included somnolence, decreased appetite, and
headache. The discontinuation rate due to AEs was <5%.
Implications: SPN-812 significantly reduced ADHD
symptoms in children and was well tolerated. SPN-812
may prove to be an effective treatment for children
with ADHD. ClinicalTrials.gov identifier:
NCT03247530. (Clin Ther. 2020;42:1452e1466) ©
2020 The Authors. Published by Elsevier Inc. This is an
open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Key words: ADHD, ADHD-RS-5, Conners 3, SPN-
812, viloxazine, WFIRS.
INTRODUCTION
It is estimated that ~5.4 million children and
adolescents are currently living with attention-deficit/
hyperactivity disorder (ADHD) in the United States
(~10% of all children and adolescents in the United
States), making this disorder a substantial public
health concern.1 ADHD is characterized by a pattern
of age-inappropriate inattentiveness, hyperactivity,
and/or impulsivity that usually persists into
adulthood.2,3 If left untreated, symptoms of ADHD
can be detrimental to an individual's academic,
social, familial, and occupational trajectories.4e6
Current guidelines for the treatment of ADHD in
school-age children and adolescents recommend that
clinicians prescribe US Food and Drug Administration
(FDA)eapproved pharmacotherapy and/or implement
behavioral intervention/therapy.7,8 Prescription
stimulant medications, including various formulations
of methylphenidate and amphetamine, have been the
primary medicinal treatment of ADHD for several
decades.9,10 Despite their effectiveness in reducing
ADHD symptoms for most children and adolescents
diagnosed with ADHD, prescription stimulants may
have certain limitations, risks, and/or drawbacks
associated with them that preclude their use for a
significant proportion of these patients. For instance,
although methylphenidate is one of the most widely
prescribed medications for ADHD,11 ~20% of
children and adolescents have an inadequate response
to treatment.12,13 Daily use of methylphenidate can
also be associated with an increased incidence or risk
August 2020
A. Nasser et al.
of upper abdominal pain, increased blood pressure or
heart rate, decreased appetite, or trouble sleeping.14 In
addition to these potential adverse events (AEs),
stimulants carry a Warning and Precaution section in
their label for serious cardiovascular events, including
sudden death in children and adolescents with cardiac
issues or structural abnormalities.14,15 Furthermore,
overuse and misuse of methylphenidate and
amphetamines can result in addiction/dependence and,
in rare cases, even acute psychosis.16,17 Considering
these risks and concerns, many parents prefer to avoid
stimulant use in their children.18 Given these
limitations, the use of prescription stimulants to treat
ADHD is not ubiquitous.
The availability of prescription nonstimulant
medications (eg, atomoxetine, guanfacine extended
release, clonidine extended release) provides an
alternative treatment for many children and
adolescents diagnosed with ADHD for whom
prescription stimulant treatment is undesirable,
precluded, or not effective or tolerated. However, for
some patients, current FDAeapproved nonstimulant
medications are neither more efficacious than
stimulants,19 nor are they devoid of their own
limitations, risks, and/or drawbacks. For instance,
despite being generally efficacious, in a recent meta-
analysis comparing the efficacy of ADHD
medications, both atomoxetine and guanfacine
extended release were found to provide less
improvement in ADHD symptoms than stimulant
treatment.20 The use of atomoxetine may also be
accompanied by nausea, vomiting, fatigue, decreased
appetite, abdominal pain, and somnolence,21 and it is
contraindicated in patients with severe cardiovascular
or hepatic disorders. There is also a potential for
drugedrug interactions with atomoxetine due to
cytochrome P450 2D6emediated metabolism.
Similarly, side effects such as somnolence, fatigue,
nausea, lethargy, abdominal pain, insomnia, or
hypotension can occur with monotherapy or
adjunctive therapy with the nonstimulants guanfacine
extended release and clonidine extended release.22,23
As such, effective and tolerable alternative
medications are needed for those patients for whom
current prescription stimulant and/or nonstimulant
use is not an option.
SPN-812 (viloxazine extended-release) is a
multimodal serotonergic and noradrenergic
modulating agent (SNMA) with reported activity at
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 Clinical Therapeutics
serotonin receptors and the norepinephrine
transporter.24 In vivo, viloxazine has been shown to
increase serotonin, norepinephrine, and dopamine,25
although the mechanism of action of SPN-812
remains to be fully elucidated.
A previous Phase IIb, randomized, double-blind,
placebo-controlled trial assessed the efficacy and
safety of once-daily SPN-812 100-, 200-, 300-, and
400-mg for the treatment of ADHD in children 6e12
years of age (N ¼ 222; 1:2:2:2:2 ratio).26 ADHD
symptoms and global illness improvement as
measured by the ADHD-Rating Scale-IV and Clinical
Global ImpressioneSeverity scale (CGI-S),
respectively, were markedly reduced (improved) after
8 weeks of SPN-812 treatment in the 200-, 300- and
400-mg SPN-812 treatment groups (but not in the
100-mg group) compared to placebo. In addition, the
most commonly reported SPN-812 treatment-related
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.
1454
AEs included somnolence, decreased appetite,
headache, fatigue, nausea, and irritability. A low
discontinuation rate due to AEs was also observed
(n ¼ 13 [6.7%]). Most AEs reported were considered
mild to moderate in severity, and each resolved
following discontinuation of the study medication.
The present study reports the efficacy and safety
results of once-daily 100-mg and 200-mg SPN-812
for the treatment of children (6e11 years of age)
diagnosed with ADHD from the recent Phase III trial.
PATIENTS AND METHODS
Study Design
A randomized, double-blind, placebo-controlled, 3-
arm, parallel-group (100-mg/day and 200-mg/day)
trial was conducted at 34 sites in the United States
between October 19, 2017 and September 19, 2018
(Figure 1) (ClinicalTrials.gov identifier:
Volume 42 Number 8

NCT03247530). After a screening phase (up to 28
days), eligible subjects were randomized on day 1
(baseline) in a 1:1:1 ratio to placebo or either 100 or
200 mg/day of SPN-812. All subjects, regardless of
treatment group assignment, were instructed to take
2 capsules daily by mouth in the morning, with or
without food, throughout the 6-week treatment
phase. Group assignments were as follows: (1) the
placebo group took 2 placebo capsules daily for 6
weeks; (2) the 100-mg SPN-812 treatment group
took one placebo and one 100-mg SPN-812 capsule
daily for 6 weeks; and (3) the 200-mg SPN-812
treatment group took one placebo and one 100-mg
SPN-812 capsule daily during week 1, followed by
two 100-mg capsules daily for the remaining 5
weeks. If necessary, the subject's parent(s) or legal
guardian(s) was allowed to open the capsules and
sprinkle the contents over a spoon of soft food (eg,
apple sauce) for consumption.
The placebo capsule product was formulated to
visually match the SPN-812 capsules by using the
exact same hard gelatin capsule shells as the active
drug product. The placebo capsules contained the
same inactive ingredients in the same physical form
as contained in the SPN-812 capsules. Taste, smell,
and feel of the placebo capsule and its contents
matched those of the SPN-812. Thus, the placebo
drug product was formulated to make it highly
unlikely for subjects/patients or evaluating/rating
clinicians to predict treatment assigned to subjects.
The parent(s) or legal guardian(s) was asked to
incorporate study medication dosing into the family's
daily morning routine and make every attempt to keep
the daily dosing time consistent throughout the 6
weeks of treatment; however, some day-to-day
variability in the timing of the daily dose was
acceptable, especially if an AE precluded or delayed
dosing. Investigator-rated efficacy assessments (ADHD
Rating Scale-5 [ADHD-RS-5] and Clinical Global
Impression-Improvement [CGI-I]) were completed and
safety assessments were performed at weekly
outpatient study visits. Self-rated efficacy assessments
completed by the subject's parent or legal guardian
(Conners 3eParent Short Form [Conners 3ePS],
Weiss Functional Impairment Rating ScaleeParent
Form [WFIRSeP], and the Parenting Stress Index
Fourth Edition, Short Form [PSI-4-SF]) or by the
subject (Conners 3eSelf-Report Short Form [Conners
3eSRS; only subjects who were 8e11 years of age])
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A. Nasser et al.
were administered at baseline (randomization; visit 2)
and again at the end of study (EOS; visit 8/week 6).
The study protocol was approved by the Advarra
Institutional Review Board (IRB) and conducted in
accordance with the Helsinki Declaration and the
International Council for Harmonisation (ICH) Note
for Guidance on Good Clinical Practice. The
parent(s) or legal guardian(s) of each subject
provided written informed consent to allow their
child's participation before performing any initial or
new study-related procedures at screening or
following any protocol amendments, respectively. All
versions of the informed consent form were reviewed
and approved by the IRB. Subjects who completed
the 6-week treatment phase and continued to meet all
inclusion/exclusion criteria were eligible to participate
in a long-term, open-label extension safety clinical
trial (NCT02736656).
Subjects
Male and female children (6e11 years of age at
screening) were eligible to participate in the study if he
or she had a primary diagnosis of ADHD as defined
according to the Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5), which was
confirmed by the Mini International Neuropsychiatric
Interview for Children and Adolescents (MINI-KID),
an ADHD-RS-5 Total score
28 at screening (visit 1)
and baseline (visit 2), and a CGI-S score
4 (ie,
moderate or greater overall illness severity) at
screening (visit 1). Subjects were required to refrain
from taking ADHD medications (other than the study
medication) starting at least 1 week before
randomization and throughout the study until EOS.
Subjects were not eligible to participate if they had a
current diagnosis of a major psychiatric/neurologic
disorder other than ADHD (excluding oppositional
defiant disorder, or major depressive disorder if the
subject was free of major depressive episodes both
currently and for the 6 months before screening),
significant systemic disease, a history of allergic
reaction to viloxazine or its excipients, any food
allergy or intolerance that contraindicated trial
participation, and/or evidence of suicidality within 6
months of screening.
Assessments
The primary efficacy endpoint of this trial was the
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
items designed to reflect current symptomatology of
ADHD based on DSM-5 criteria.3,27 The ADHD-RS-5
was administered by a trained rater at each study visit
from baseline through EOS.
There were 3 key secondary endpoints: CGI-I
score28 at EOS, CFB in the Conners 3ePS Composite
T-score29 at EOS, and CFB in the WFIRSeP Total
average score30,31 at EOS. The CGI-I was completed
at each postbaseline visit through EOS. The Conners
3ePS also contains 6 content scales, 2 related to core
ADHD symptoms (inattention and hyperactivity),
and 4 related to ADHD-associated impairments
(learning problems, executive functioning, defiance/
aggression, and peer relations). The WFIRSeP
evaluates functional impairment related to ADHD
across 6 domains, including family, school, life skills,
child's self-concept, social activity, and risky activity.
The Conners 3ePS and WFIRSeP were administered
at baseline and EOS visits.
Additional secondary endpoints included the CFB at
EOS in each ADHD-RS-5 subscale (Inattention and
Hyperactivity/Impulsivity); the 50% responder rate per
the ADHD-RS-5 (defined as the proportion of subjects
who exhibit a
50% reduction [improvement] in CFB
ADHD-RS-5 Total score); responder rate per the CGI-I
(or categorical CGI-I; proportion of subjects categorized
as “improved,” which is defined as a subject who had a
CGI-I score of 1 [“very much improved”] or 2 [“much
improved”]) by visit; the CFB in the PSI-4-SF Total
score32 at EOS; and the CFB in the Conners 3eSRS
Composite T-score29 at EOS. Other endpoints included
individual CFB at EOS in the content scale T-score for
both the Conners 3ePS and Conners 3eSRS and CFB
at EOS in the domain average score for WFIRSeP.
Safety and tolerability were assessed by monitoring
AEs, results of clinical laboratory tests (including
hepatic enzymes), vital signs, physical examinations,
ECGs, and the Columbia-Suicide Severity Rating
Scale (C-SSRS). AEs were defined as any unfavorable
or unintended sign/symptom or laboratory finding,
including: new disease or injury, clinically significant
deviation of blood and urinary laboratory test
results, vital signs, or clinical tests; or recurrence of a
medical condition that was not present at screening
or baseline (ie, the AEs described were recorded after
the first drug administration). Any AE beginning after
or upon first treatment administration, or that
worsened following the first administration, was
1456
considered treatment-emergent (TEAE); all AEs were
recorded following the first administration and are
thus all considered to be TEAEs (henceforth referred
to as AEs). The relationship to treatment, seriousness,
and severity of all AEs were evaluated by the site
investigator. AEs were determined to be mild if the
subject's symptoms were easily tolerated, moderate if
discomfort was enough to interfere with usual daily
activities and may have warranted intervention, and
severe if the event was incapacitating to the subject's
daily activity or significantly affected their clinical
status and warranted intervention.
Statistical Analysis
Sample size calculations indicated that 104 subjects
per treatment group in the intent-to-treat (ITT)
population would yield 90% power at a significance
level of 0.05 (two-sided) using a 2-sample t test with
equal allocation across treatment groups; they were
based on an effect size of 0.453 obtained in a
previous Phase IIb trial.26 Based on these
calculations, a total of 432 subjects (144 per
treatment arm) were projected to be randomized to
treatment, to account for anticipated dropout rates of
27.9% in the randomized population.
The ITT population included all randomized
subjects administered at least 1 dose of study
medication, who also had a baseline and at least 1
post-baseline ADHD-RS-5 assessment. The safety
population included all randomized subjects
administered at least 1 dose of study medication.
The primary efficacy endpoint was analyzed by
using a mixed model for repeated measures
(MMRM); the model included fixed-effect terms for
baseline ADHD-RS-5 Total score, age group,
treatment, visit, and treatment-by-visit interaction as
independent variables. All secondary measures were
analyzed by using analysis of covariance (ANCOVA)
with treatment as fixed-effect terms and baseline as a
covariate, except for the CGI-I, which was analyzed
by using baseline CGI-S as a covariate. The family-
wise error rate was controlled under 5% by using the
sequential testing procedure.33 For all analyses, P
values, least squares (LS) of treatment means, and
differences between the LS treatment means and
placebo were computed. LS mean CFB values are
reported henceforth unless otherwise noted. Statistical
analyses were performed by using SAS version 9.4
(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
A total of 477 subjects were randomized into the
trial, with the ITT population consisting of 460
subjects (placebo, n ¼ 155; 100-mg/day SPN-812,
n ¼ 147; 200-mg/day SPN-812, n ¼ 158). The safety
population consisted of 474 subjects (placebo,
n ¼ 159; 100-mg/day SPN-812, n ¼ 154; 200-mg/day
SPN-812, n ¼ 161); all reasons for discontinuation
are noted in Figure 1. Approximately 19% of subjects
who were screened discontinued from the trial before
randomization. The majority of subjects were male
(63%), and either White (51.3%) or African American
(43.7%) (Table I). The demographic (eg, distribution
of male subjects vs female subjects and ethnicity/race)
and baseline characteristics (eg, age, weight, body
mass index, ADHD-RS-5 Total score, and CGI-S
score) between the placebo group and either SPN-812
medication use reported at screening (safety
population) was as follows: 89.9% of patients in the
placebo group, 89.6% in the 100-mg/day SPN-812
group, and 84.5% in the 200-mg/day SPN-812 group
were not taking any ADHD medication; 6.9%, 6.5%,
and 10.6% were taking stimulants; and 3.1%, 3.9%,
and 5.0% were taking nonstimulants, respectively.
ADHD-RS-5
The mean ADHD-RS-5 Total score and subscale
scores at baseline were similar among treatment groups
(Table I). The CFB in ADHD-RS-5 Total score at EOS
was significantly reduced (improved) with both the
100-mg/day SPN-812 (P ¼ 0.0004) and 200mg/day
SPN-812 (P < 0.0001) compared to placebo (Table II).
Moreover, the CFB in ADHD-RS-5 Total score was
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,
exhibiting a fast onset of action. This significant effect
was observed at each subsequent week through EOS at
target dose in both the 100-mg/day SPN-812 and
200-mg/day SPN-812 treatment groups compared to
placebo (Figure 2). The CFB in both the ADHD-RS-5
Inattention and Hyperactivity/Impulsivity subscale
scores at EOS was significantly reduced in the
100-mg/day SPN-812(P ¼ 0.0006 and P ¼ 0.0026,
respectively) and 200-mg/day (P < 0.0001 and
P < 0.0001) SPN-812 treatment groups compared to
placebo. Furthermore, there was a significantly higher
50% responder rate in ADHD-RS-5 Total score at
EOS in the 100-mg/day (P ¼ 0.0063) and 200-mg/day
(P < 0.0001) SPN-812 treatment groups compared to
placebo (Figure 3).
CGI-I
The mean CGI-S score at baseline was similar among
treatment groups (Table I). The CGI-I score at EOS was
significantly lower in the 100-mg/day (P ¼ 0.0020) and
200-mg/day (P < 0.0001) SPN-812 treatment groups
compared to placebo (Figure 4). Furthermore, the
responder rate per the CGI-I score (ie, percentage of
subjects with a CGI-I score of 1 [very much
improved] or 2 [much improved]) was also
significantly higher at EOS in the 100-mg/day and
200-mg/day SPN-812 treatment groups compared to
placebo (45% and 51% vs 30%, respectively;
P ¼ 0.0065 and P ¼ 0.0002). The significant
differences in percentage of subjects with clinical
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
(n ¼ 155)
CFB, LS mean (SE)
Total score −10.9 (1.14)
Inattention subscalez −5.7 (0.60)
Hyperactivity/Impulsivity subscalez −5.5 (0.59)
50% responder ratex 31 (19.8%)
*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.
1458
improvement began at week 1 in the 100-mg/day
SPN-812 treatment group (24% vs 9%; P ¼ 0.0005)
and at week 2 in the 200-mg/day SPN-812 treatment
group (32% vs 19%; P ¼ 0.0099).
Conners 3−PS
The mean Conners 3−PS Composite T-score and
content scales T-scores at baseline were similar among
treatment groups. The CFB in the Conners 3−PS
Composite T-score at EOS was significantly reduced
(improved) in the 100-mg/day (P ¼ 0.0003) and 200-
mg/day (P ¼ 0.0002) SPN-812 treatment groups
compared to placebo (Table III). The CFB in the T-
score for 5 of 6 Conners 3−PS content scales at EOS
was significantly reduced (improved) in the 100-mg/day
and 200-mg/day SPN-812 treatment groups compared
to placebo, including inattention (P ¼ 0.0028 and
P ¼ 0.0025, respectively), hyperactivity (P ¼ 0.0076
and P ¼ 0.0013), learning problems (P ¼ 0.0154 and
P ¼ 0.0158), executive functioning (P ¼ 0.0002 and
P ¼ 0.0024), and peer relations (P ¼ 0.0003 and
P ¼ 0.0023). The CFB in the T-score for the Conners
3−PS defiance/aggression content scale at EOS was
significantly reduced only in the 200-mg/day SPN-812
(P ¼ 0.0245) treatment group compared to placebo.
WFIRSeP
The CFB in WFIRSeP Total average score at EOS was
significantly reduced (improved) in the 100-mg/day
(P ¼ 0.0019) and 200-mg/day (P ¼ 0.0002) SPN-812
treatment groups compared to placebo (Table III). The
SPN-812
100 mg/day (n ¼ 147) 200 mg/day (n ¼ 158)
−16.6 (1.16)* −17.7 (1.12)y
−8.6 (0.62)* −9.2 (0.60)y
−8.0 (0.60)* −8.7 (0.58)y
50 (34.2%)* 65 (41.2%)y
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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
EOS was significantly reduced (improved) in the 100-mg/
day and 200 mg/day SPN-812 treatment groups
compared to placebo, including the family (P ¼ 0.0276
and P ¼ 0.0003, respectively), school (P ¼ 0.0022 and
P ¼ 0.0009), social activities (P ¼ 0.0222 and
P ¼ 0.0052), and risky activities (P ¼ 0.0294 and
P ¼ 0.0036) domains. The CFB in the average score for
WFIRSeP self-concept and life skills domains at EOS
was not significantly reduced for either SPN-812
treatment group compared with placebo.
Conners 3−SRS and PSI-4-SF
The CFB in Conners 3−SRS Composite T-score or
the PSI-4-SF Total score at EOS was not significantly
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.

August 2020 1459

 Clinical Therapeutics
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
(P ¼ 0.1292 and P ¼ 0.3447; P ¼ 0.9974 and
P ¼ 0.4557, respectively).
Safety and Tolerability
Safety assessments were performed during weekly,
postbaseline outpatient study visits. The majority of AEs
reported were mild to moderate in severity (Table IV).
The most common TEAEs that were considered related
to treatment occurring in
5% of subjects in any SPN-
812 treatment group and greater in percentage than
placebo were somnolence (8.9%), decreased appetite
(6.0%), and headache (5.4%). Four subjects receiving
SPN-812 reported one or more AEs that were
considered severe. One subject (200-mg/day group)
experienced abdominal pain, nausea, vomiting, and
acute appendicitis considered unrelated to treatment,
which resolved without sequelae. One subject (100-mg/
day group) experienced severe somnolence, while
another subject (100-mg/day group) reported severe
initial insomnia, both of which were considered possibly
related to treatment but resolved without requiring
treatment interruption. The fourth subject (100-mg/day
group) reported severe pyromania considered unrelated
to treatment and discontinued the trial.
1460
Overall, discontinuations due to AEs were
infrequent, with 7 subjects receiving SPN-812 and 2
subjects in the placebo group discontinuing the trial
(placebo, n ¼ 2 [1.3%]; 100-mg/day SPN-812, n ¼ 5
[3.2%]; 200-mg/day SPN-812, n ¼ 2 [1.2%]). AEs
leading to discontinuation in the SPN-812 treatment
groups included tachycardia (0.3%), fatigue (0.3%),
ECG T-wave inversion (0.3%), dizziness (0.3%),
aggression (0.3%), conduct disorder (0.3%),
pyromania (0.3% [noted earlier]), sleep terror
(0.3%), and decreased appetite (0.3%), although
each occurred in no more than 1 subject (Table IV).
No clinically significant trends were found in clinical
laboratory test results. The majority of subjects had
normal hematology values at baseline, and these
remained normal at EOS. Decreases in neutrophil
levels were most common, observed in 19 (13.7%), 10
(7.4%), and 18 (13.0%) subjects in the placebo, 100-
mg/day SPN-812, and 200-mg/day SPN-812 groups,
respectively. In addition, a total of 42 subjects had a
post-baseline neutrophil count that was <1500 cells/
mL, including 33 African-American or Black subjects
(11 subjects in each of the 3 treatment arms). All 33 of
these subjects had neutrophil counts <1500 cells/mL at
baseline. No subjects had a neutrophil count that was
Volume 42 Number 8
 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 only 2 instances (100-mg/day SPN-812 and
200 mg/day SPN-812); the event was considered not
related to treatment in each case, and it was considered
moderate or mild in severity, respectively. Incidents of
hepatic enzyme abnormalities included above-normal
alanine aminotransferase (ALT; placebo, n ¼ 4
[2.9%]; 100-mg/day SPN-812, n ¼ 5 [3.7%]; 200-mg/
day SPN-812, n ¼ 7 [5.1%]), below-normal alkaline
phosphatase (ALP; placebo, n ¼ 4 [2.9%]; 100-mg/
day SPN-812, n ¼ 3 [2.2%]; 200-mg/day SPN-812,
n ¼ 4 [2.9%]); and above-normal aspartate
aminotransferase (AST; placebo, n ¼ 3 [2.2%]; 100-
mg/day SPN-812, n ¼ 3 [2.2%]; 200-mg/day SPN-
812, n ¼ 3 [2.2%]). There were only 2 subjects (one
each taking SPN-812 100 mg/day and SPN-
812 200 mg/day) in whom elevated hepatic enzyme
levels post-baseline (both ALT and AST) were reported
as an AE. In each case, the subject's ALT and AST
levels were within the normal range at screening; the
event was considered not related and unlikely related
to treatment, respectively, and it was considered mild
in severity in each case. Overall, clinical laboratory
abnormalities were reported as AEs in 0 subjects in the
placebo group, 2 subjects (1.3%) in the 100-mg/day
SPN-812 treatment group, and 2 subjects (1.2%) in
the 200-mg/day SPN-812 treatment group;
abnormalities included decreased neutrophil count,
decreased leukocytes and monocytes, and the incidents
of increased ALT and AST levels noted earlier (both of
which were considered mild in severity and unlikely
related to the study treatment).
Individual clinically relevant changes in vital signs
were infrequent, with the exception of respiratory rate
below normal (reported in >10% of subjects, with no
meaningful difference found vs placebo). Abnormal

August 2020 1461

 Clinical Therapeutics

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

1462 Volume 42 Number 8


reduction in ADHD symptoms within 1 week of
treatment initiation.
Significant improvements were also found within
both ADHD-RS-5 Inattention and Hyperactivity/
Impulsivity subscale scores for 100-mg/day and 200-
mg/day SPN-812 treatment at EOS, which was further
supported by the significant improvement in the
responder rate per the ADHD-RS-5 (percentage of
subjects who had a
50% reduction in the CFB
ADHD-RS-5 Total score) at EOS. This finding suggests
that a significant proportion of subjects in this trial had
a clinically meaningful, global improvement in ADHD
symptoms. Analyses of the relationship between
ADHD-RS-5 Total score and the CGI-I score suggest
that a substantial improvement on the ADHD-RS-5
Total score (50%e60% reduction) is in concordance
with CGI-I score of 2 (much improved).34 The
significantly greater responder rate per the CGI-I score
(ie, percentage of subjects who had a CGI-I score of 1
[much improved] or 2 [very much improved]) that was
also observed in both SPN-812 treatment groups
compared to placebo is consistent with the strong
concordance between 50% responder rate per the
ADHD-RS-5 Total score and the overall clinical
impression of subject health.34 These statistically
significant findings are therefore clinically meaningful.
In addition to the significant improvements in ADHD
symptoms that were observed on the investigator-rated
ADHD-RS-5 and CGI-I assessments with SPN-812
treatment, there were significant improvements in
ADHD symptoms and ADHD-related deficits in
functionality and behavior observed on the parental
self-rated Conners 3−PS and WFIRS−P with SPN-812
treatment. For instance, on the Conners 3−PS, parents
whose child was treated with SPN-812 reported
significantly greater improvements in the areas of
inattention, hyperactivity, learning problems,
executive functioning, and peer relations compared to
the parents whose child received placebo. On the
WFIRS−P, parents whose child was treated with SPN-
812 reported significantly greater improvement in the
domains of family, school, social activities, and risky
activities. These parent-reported data support the
investigator-rated observations, as well as indicate that
treatment with SPN-812 can improve the deficits in
daily functioning inherent in ADHD.
Although significant improvements were not
observed on parent self-rated PSI-4-SF for parental
stress level and subject self-rated Conners 3−SRS for
August 2020
A. Nasser et al.
ADHD symptoms and functionality, there are several
factors that may have influenced the threshold for
detecting improvements via these particular scales.
First, this trial was statistically powered for the
primary endpoint and not for secondary endpoints.
As such, the sample size may have been insufficient
to detect effects in some of the secondary measures,
including the PSI-4-SF and the Conners 3−SRS.
Second, subjects in this trial who were 6e7 years of
age did not complete the Conners 3−SRS as this
measure is only validated in children 8e17 years of
age.29 Given that the ITT population ranged from
ages 6e11 years, responses were limited to those
subjects aged
8 years and thus had a reduced
sample size, which may have confounded the power
to detect a significant change. Furthermore, older
subjects may be more cognizant of the extent of their
symptoms and experience with ADHD during self-
evaluation. Lastly, although the 6-week duration of
the current trial is typical for pivotal investigations in
ADHD,35 the impact of a therapeutic agent on
overall quality of life may be more discernible after a
longer duration, or following clinical follow-up that
tracks the life trajectory of trial subjects.
Overall, the majority of participants who received 100-
mg/day and 200 mg/day SPN-812 completed the trial
(n ¼ 126 [80.3%] and n ¼ 141 [87.6%], respectively).
Both doses of SPN-812 were generally well tolerated,
with most AEs being mild or moderate in severity.
Severe AEs rarely occurred (4 total with SPN-812
treatment). No cases of suicidal ideation, as measured
by the C-SSRS, were noted in the subjects receiving 100-
mg/day or 200 mg/day SPN-812. Most abnormalities in
clinical laboratory results were not clinically significant
and were transient. The incidence of clinical laboratory
abnormalities for hepatic enzymes was low and similar
across all treatment groups. The cutoff for low
neutrophil count was set to <1500 cells/mL. Decreased
neutrophil count was reported as an AE in only 2
instances (one each taking 100-mg/day SPN-812 and
200-mg/day SPN-812); the event was considered not
related to treatment in each case, and it was considered
moderate or mild in severity, respectively. Decreases in
neutrophil levels were observed in 19 (13.7%), 10
(7.4%), and 18 (13.0%) subjects in the placebo, 100-
mg/day, and 200-mg/day groups, respectively. The
majority of these subjects were African American or
Black, who usually have lower neutrophil counts at
baseline. The overall observations of low neutrophil
1463
 Clinical Therapeutics
counts could likely be explained by benign ethnic
neutropenia.36 Abnormalities in vital signs and ECG
results were mild and transient in nature. Few AEs
relating to cardiovascular events or changes in blood
pressure were reported.
The positive results of this Phase III trial suggest that
SPN-812 may have potential advantages for children
(6e11 years of age) with ADHD compared with other
ADHD medications. For instance, it is well documented
that stimulant therapy provides variable effectiveness
throughout the day,37 and a subset of patients are not
appropriate candidates for stimulant use due to
contraindications and/or tolerability issues.38e40
Alternatively, currently approved nonstimulants can
have variable latencies for patient response, suboptimal
response, and AE profiles that may also preclude their
use in certain populations.20e23,41 Long acting forms of
nonstimulant medication, such as SPN-812 (viloxazine
extended-release), may provide more consistent,
effective, and safe treatment for these patients. This
Phase III trial results suggest that the efficacy of SPN-
812 for ADHD symptoms can begin as early as week 1
of treatment, along with a safe and well-tolerated
clinical profile.
CONCLUSIONS
This Phase III trial met the efficacy objective and
showed statistically significant differences between
SPN-812 (100-mg/day and 200-mg/day) and placebo
in the primary endpoint (CFB in ADHD-RS-5 at
EOS). Statistical improvements in ADHD-RS-5 Total
score compared to placebo were seen after 1 week of
SPN-812 treatment and were maintained throughout
the 6-week trial, indicating an early and sustained
effect. Significantly more improvement per the CGI-I
score at EOS was observed with SPN-812 treatment
versus placebo. Furthermore, SPN-812 exhibited
efficacy across both the Inattention and
Hyperactivity/Impulsivity subscales of the ADHD-RS-
5. Investigator-rated assessments were also supported
by parent self-rated assessments (Conners 3−PS and
WFIRS−P), which indicated improvement not only in
their child's ADHD symptoms but also in ADHD-
associated impairments (learning problems, executive
functioning, defiance/aggression, and peer relations)
and functioning in different settings (family, school,
social activities, and risky activities). Thus, the
benefits of treatment with SPN-812 appear to be
clinically meaningful, and not just statistically
1464
significant, across a variety of behavioral and social
domains. These data also indicate functional
improvement in addition to symptomatic
improvement. Overall, once-daily SPN-812 (100 mg
and 200 mg) was well tolerated, as demonstrated by
the low rate of discontinuation due to TEAEs
observed for either SPN-812 dose. Collectively, the
results of this Phase III clinical trial indicate that
SPN-812 is an effective and overall well-tolerated
pharmacotherapy that could be a future treatment
option for children (6e11 years of age) with ADHD.
DISCLOSURES
Drs. Nasser, Liranso, Adewole, Hull, Chowdhry, Busse,
and Schwabe and Mr. Fry are employees of Supernus
Pharmaceuticals, Inc. Dr. Findling receives or has
received research support, acted as a consultant, and/
or has received honoraria from Acadia, Aevi, Akili,
Alcobra, Allergan, Alkermes, Amerex, American
Academy of Child & Adolescent Psychiatry, American
Psychiatric Press, Arbor, Axsome, Daiichi-Sankyo,
Genentech, KemPharm, Luminopia, Lundbeck,
MedAvante-ProPhase, Merck, the National Institutes
of Health, Neurim, Noven, Nuvelution, Otsuka,
PCORI, Pfizer, Physicians Postgraduate Press, Purinix,
Q BioMed, Receptor Life Sciences, Roche, Sage,
Signant Health, Sunovion, Supernus Pharmaceuticals,
Inc., Syneurx, Takeda, Teva, TouchPoint, Tris
Pharma, and Validus. Dr. Cutler is a consultant for
Adlon Therapeutics, Aevi Genomics, Akili Interactive,
Arbor Pharmaceuticals, Ironshore, KemPharm,
Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka,
Purdue, Shire, Sunovion, Supernus Pharmaceuticals,
Inc., Takeda, and Tris Pharma; has received speaker/
promotional honoraria from Adlon Therapeutics,
Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics,
Otsuka, Shire, Sunovion, Takeda, and Tris Pharma;
and has received research grants from Aevi Genomics,
Akili Interactive, Arbor Pharmaceuticals, Ironshore,
KemPharm, Lundbeck, Neos Therapeutics, Otsuka,
Purdue, Shire, Sunovion, Supernus Pharmaceuticals,
Inc., Takeda, and Tris Pharma. The authors have
indicated that they have no other conflicts of interest
regarding the content of this article.
Supernus Pharmaceuticals Inc. employees
participated in study design; in the collection, analysis
and interpretation of data; in the writing of the report;
and in the decision to submit the article for publication.
Volume 42 Number 8

ACKNOWLEDGMENTS
This work was funded by Supernus Pharmaceuticals,
Inc. Writing and editorial support was provided by
Imprint Science.
Dr. Nasser contributed to study conceptualization;
oversight of all aspects of the study methods,
analysis, and data interpretation; and writing,
reviewing, and updating the manuscript drafts. Dr.
Liranso contributed to statistical methodology,
statistical analyses, data interpretation support,
critical review of the manuscript, and help with
updating the manuscript drafts. Dr. Adewole
contributed to drug safety, development of the safety
sections and plans, oversight of the study protocols,
safety data analyses support, and critical review of
the manuscript. Mr. Fry contributed to project
management, implementation of the study protocols,
execution of the study, and critical review of the
manuscript. Dr. Hull contributed to execution of
study protocols; protocols amendments; analyzing the
data; interpreting the results; and writing, reviewing,
and updating the manuscript drafts. Dr. Chowdhry
contributed to development of study protocols,
analyzing the data, interpreting the results, and
critical review of the manuscript drafts. Dr. Busse
contributed to data interpretation support; writing,
reviewing, and updating the manuscript drafts; and
publication management. Dr. Cutler was a site
investigator; he contributed to study
conceptualization; and assisted with developing study
protocols, data interpretation, and critical review of
the manuscript. Dr. Jones was a site investigator; she
reviewed all aspects of the study report, including
data interpretation; and critically reviewed the
manuscript. Dr. Findling contributed to developing
study protocols, analysis, and data interpretation,
and critically reviewed the manuscript. Dr. Schwabe
contributed to study conceptualization, oversight of
patient safety, study conduct and data interpretation,
and critical review and updating the manuscript drafts.
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Address correspondence to: Azmi Nasser, PhD, Supernus Pharmaceuticals,
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