Please read the clinical trial attached and complete the critical appra

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 con

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