Critical appraisal for a Randomized trial

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

1Supernus 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

Accepted for publication May 29, 2020 https://doi.org/10.1016/j.clinthera.2020.05.021 0149-2918/$ - see front matter

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license

ABSTRACT

Purpose: The limitations of current US Food and Drug Administration (FDA)eapproved medications for the treatment of attention-deficit/hyperactivity disorder (ADHD) set the need for the development of novel, effective, and tolerable medications to treat this disorder. The purpose of this study was to evaluate whether treatment with SPN-812 (viloxazine extended-release) significantly reduces symptoms of ADHD in children.

Methods: This study was a randomized, double- blind, placebo-controlled 6-week trial to assess the efficacy and safety of once-daily 100- and 200-mg SPN-812 in the treatment of ADHD in male and female children 6e11 years of age. Inclusion criteria required subjects to have a confirmed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, ADHD diagnosis, an ADHD-Rating Scale-5 (ADHD- RS-5) score �28, a Clinical Global Impression- Severity score �4, and for subjects to be free of ADHD medication �1 week before randomization. The primary efficacy endpoint was the change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 Total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) scores at EOS and CFB at EOS in the Conners 3eParent Short Form (Conners 3ePS) Composite T-

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score and the Weiss Functional Impairment Rating ScaleeParent (WFIRSeP) Total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical examinations, ECGs, and the Columbia-Suicide Severity Rating Scale. The primary efficacy endpoint was analyzed by using a mixed model for repeated measures; all secondary measures were analyzed by using an ANCOVA model.

Results: A total of 477 subjects were randomized to treatment (intent-to-treat population, n ¼ 460). The majority of subjects were male (63%) and either White (51.3%) or African American (43.7%). The demographic and baseline characteristics between the groups were similar. Statistically significant improvements in ADHD-RS-5 Total score were observed in both the 100- and 200-mg/day SPN-812 treatment groups compared to placebo at week 1 of treatment (P ¼ 0.0004 and P ¼ 0.0244, respectively), which was maintained through EOS (P ¼ 0.0004 and P < 0.0001). Significant improvements were also observed at EOS in the CGI-I scale (P ¼ 0.0020 and P < 0.0001), Conners 3ePS Composite T-score

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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(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. Thediscontinuation rate due toAEswas<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

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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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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. aNumber of subjects in the safety population i

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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:

s used as denominator for this section.

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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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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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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

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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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RESULTS 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

Table I. Demographic and baseline characteristics in the

Characteristic Placebo

N (ITT) 155 Age, mean (SD), y 8.5 (1.7) Sex, n (%)

Male 97 (62.6) Female 58 (37.4)

Ethnicity, n (%) Hispanic or Latino 32 (20.6) Not Hispanic or Latino 123 (79.4)

Race, n (%) American-Indian or Alaska Native 1 (0.6) Asian 1 (0.6) Black or African American 69 (44.5) Multiple 7 (4.5) White 77 (49.7)

Weight, mean (SD), kg 31.1 (8.0) Body mass index, mean (SD), kg/m2 16.9 (2.2) ADHD-RS-5, mean (SD)

Total score 43.6 (7.1) Inattention 22.5 (3.8) Hyperactivity/Impulsivity 21.1 (4.9)

CGI-S score, mean (SD) 4.8 (0.7)

ADHD-RS-5 ¼ ADHD Rating Scale-5; CGI-S ¼ Clinical Global Im standard deviation.

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treatment group were similar. Previous ADHD 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

intent-to-treat (ITT) population.

SPN-812 Overall

100 mg/day 200 mg/day

147 158 460 8.5 (1.7) 8.5 (1.7) 8.5 (1.7)

94 (63.9) 99 (62.7) 290 (63.0) 53 (36.1) 59 (37.3) 170 (37.0)

38 (25.9) 51 (32.3) 121 (26.3) 108 (73.5) 107 (67.7) 338 (73.5)

1 (0.7) 0 2 (0.4) 0 0 1 (0.2) 63 (42.9) 69 (43.7) 201 (43.7) 7 (4.8) 6 (3.8) 20 (4.3)

76 (51.7) 83 (52.5) 236 (51.3) 31.7 (8.9) 31.8 (8.4) 31.5 (8.4) 17.3 (2.2) 17.2 (2.4) 17.1 (2.3)

45.0 (6.5) 44.0 (6.8) 44.2 (6.8) 22.8 (3.2) 22.9 (3.5) 22.7 (3.5) 22.2 (4.7) 21.1 (5.2) 21.5 (4.9) 4.8 (0.8) 4.8 (0.7) ND

pressioneSeverity of Illness; ND ¼ not determined; SD ¼

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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 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.

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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 TheCFB inWFIRSePTotal average score at EOSwas

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

the intent-to-treat population at end of study by

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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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.

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CFB in the average score for 4 of 6WFIRSeP domains at EOSwas 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

Figure 3. Analysis of ADHD-Rating Scale-5 50% respond tion. *P < 0.05. yP < 0.0001.

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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

er rate at end of study in the intent-to-treat popula-

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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.

Clinical Therapeutics

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.

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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

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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.

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<500 cells/mL.Decreased neutrophil countwas 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

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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

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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)

Clinical Therapeutics

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

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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

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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 inADHD 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

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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, themajorityof participantswhoreceived100- 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

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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

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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.

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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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