Advertisement

Once-Daily SPN-812 200 and 400 mg in the treatment of ADHD in School-aged Children: A Phase III Randomized, Controlled Trial

Open AccessPublished:March 06, 2021DOI:https://doi.org/10.1016/j.clinthera.2021.01.027

      Highlights

      • SPN-812 (viloxazine extended-release) is a nonstimulant under development for ADHD.
      • Once-daily 200- and 400-mg SPN-812 improved ADHD-RS-5 and CGI-I scores vs. placebo.
      • SPN-812 was well tolerated with low rates of discontinuations due to adverse events.
      • Another Phase 3 trial demonstrated efficacy and safety of 100- and 200-mg SPN-812.

      Abstract

      Purpose

      SPN-812 (viloxazine extended-release) is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase III study evaluated the efficacy and tolerability of SPN-812 200 and 400 mg once daily in children 6–11 years of age with ADHD.

      Methods

      Patients were randomly assigned to receive SPN-812 200 mg, SPN-812 400 mg, or placebo, once daily for 8 weeks (including ≤3 weeks titration period). The primary efficacy endpoint was the change from baseline (CFB) in ADHD Rating Scale (RS)-5 Total score at end of study (EOS). Key secondary endpoints included Clinical Global Impression–Improvement (CGI-I) score at EOS, CFB in Conners 3–Parent Short Form (PS) composite T-score at EOS, and CFB in Weiss Functional Impairment Rating Scale–Parent (WFIRS-P) Total average score at EOS.

      Findings

      A total of 313 patients were enrolled, with 301 in the intent-to-treat population (194 boys, 107 girls; mean age [SD], 8.4 [1.7] years). At EOS, the CFBs in ADHD-RS-5 Total score and CGI-I score were significantly improved with both 200- and 400-mg/d SPN-812 versus placebo (ADHD-RS-5, P = 0.0038 and 0.0063, respectively; CGI-I, P = 0.0028 and 0.0099). At EOS, the CFB in Conners 3-PS composite T-score was significantly improved with 200- (P = 0.0064), but not 400-mg/d (P = 0.0917), SPN-812 compared to placebo. No significant difference between the groups was found in WFIRS-P Total average score. The rate of discontinuations due to adverse events in both SPN-812 treatment groups combined was <5%.

      Implications

      SPN-812 200 and 400 mg once daily was associated with improvements in ADHD symptoms in school-aged children and was generally well tolerated. ClinicalTrials.gov identifier: NCT03247543.

      Key words

      Introduction

      Attention-deficit/hyperactivity disorder (ADHD) is a chronic condition that often begins in childhood and is characterized by a developmentally inappropriate pattern of inattention, hyperactivity, and impulsivity.
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders.
      ,
      • Adesman A.R.
      The diagnosis and management of attention-deficit/hyperactivity disorder in pediatric patients.
      ADHD symptoms can persist through adulthood
      • Sibley M.H.
      • Swanson J.M.
      • Arnold L.E.
      • et al.
      Defining ADHD symptom persistence in adulthood: optimizing sensitivity and specificity.
      ,
      • Cortese S.
      Pharmacologic treatment of attention deficit-hyperactivity disorder.
      and, if left untreated, can negatively affect an individual's academic, familial, occupational, and social well-being.
      • Shaw M.
      • Hodgkins P.
      • Caci H.
      • et al.
      A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment.
      ,
      • Hamed A.M.
      • Kauer A.J.
      • Stevens H.E.
      Why the diagnosis of attention deficit hyperactivity disorder matters.
      Current pharmacologic treatments for ADHD include US Food and Drug Administration (FDA)-approved formulations of stimulant (methylphenidate and amphetamine) and nonstimulant (guanfacine, clonidine, and atomoxetine) medications.
      • Cortese S.
      Pharmacologic treatment of attention deficit-hyperactivity disorder.
      Stimulants are widely used and generally efficacious; in several studies, however, it has been demonstrated that in some patients with ADHD, an adequate treatment response or symptom remission was not achieved.
      • Biederman J.
      • Mick E.
      • Faraone S.V.
      Age-dependent decline of symptoms of attention deficit hyperactivity disorder: impact of remission definition and symptom type.
      • Chen M.H.
      • Tsai S.J.
      Treatment-resistant panic disorder: clinical significance, concept and management.
      • Mattingly G.W.
      • Weisler R.H.
      • Young J.
      • et al.
      Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.
      • Newcorn J.H.
      • Kratochvil C.J.
      • Allen A.J.
      • et al.
      Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response.
      • Cortese S.
      • Adamo N.
      • Del Giovane C.
      • et al.
      Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis.
      • De Crescenzo F.
      • Cortese S.
      • Adamo N.
      • Janiri L.
      Pharmacological and non-pharmacological treatment of adults with ADHD: a meta-review.
      In a retrospective medical records review, in 779 children with ADHD predominantly treated with stimulants (>80% of patients), only 30.8% showed “complete symptom control,” and only 31.8% of physicians reported being “very satisfied” with their patients' current treatment.
      • Hodgkins P.
      • Setyawan J.
      • Mitra D.
      • et al.
      Management of ADHD in children across Europe: patient demographics, physician characteristics and treatment patterns.
      In a cross-sectional study conducted across 8 European countries, 88% of caregivers reported that children continued experiencing core ADHD symptoms while on medication (66% of children were taking stimulant monotherapy); school issues were reported by 84% of caregivers, and peer difficulties, by 79%.
      • Sikirica V.
      • Flood E.
      • Dietrich C.N.
      • et al.
      Unmet needs associated with attention-deficit/hyperactivity disorder in eight European countries as reported by caregivers and adolescents: results from qualitative research.
      Some patients with ADHD are not ideal candidates for stimulant use due to potential risks and/or intolerability.
      • Briars L.
      • Todd T.
      A review of pharmacological management of attention-deficit/hyperactivity disorder.
      • Cox D.J.
      • Moore M.
      • Burket R.
      • Merkel R.L.
      • Mikami A.Y.
      • Kovatchev B.
      Rebound effects with long-acting amphetamine or methylphenidate stimulant medication preparations among adolescent male drivers with attention-deficit/hyperactivity disorder.
      • Steer C.R.
      Managing attention deficit/hyperactivity disorder: unmet needs and future directions.
      In a subset of patients, stimulant use has been linked to increased heart rate (HR) and blood pressure (BP) or risk for emergency department visits for cardiovascular issues.
      • St Amour M.D.
      • O'Leary D.D.
      • Cairney J.
      • Wade T.J.
      What is the effect of ADHD stimulant medication on heart rate and blood pressure in a community sample of children?.
      • Wolraich M.L.
      • Hagan Jr., J.F.
      • Allan C.
      • et al.
      Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents.
      • Winterstein A.G.
      • Gerhard T.
      • Shuster J.
      • Johnson M.
      • Zito J.M.
      • Saidi A.
      Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder.
      It is also well documented that stimulants come with risks for misuse and diversion.
      • Clemow D.B.
      Misuse of methylphenidate.
      • Wilens T.E.
      • Adler L.A.
      • Adams J.
      • et al.
      Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature.
      • Kollins S.H.
      Abuse liability of medications used to treat attention-deficit/hyperactivity disorder (ADHD).
      A systematic review of data from 21 studies indicated that the prevalence of stimulant misuse in school-aged children ranged from 5% to 9% in the previous year.
      • Wilens T.E.
      • Adler L.A.
      • Adams J.
      • et al.
      Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature.
      It has also been reported that 1 in 5 children and adolescents prescribed methylphenidate were approached to sell, give away, or trade their medication at least once in the previous 5 years.
      • Kollins S.H.
      Abuse liability of medications used to treat attention-deficit/hyperactivity disorder (ADHD).
      Being Schedule II controlled substances, psychostimulants fall under specific FDA requirements for prescriptions and refills, which presents certain barriers to obtaining these medications (eg, they cannot be refilled by phone).
      Code of federal regulations Title 21, Vol 9, Part 1305 orders for Schedule I and II controlled substance.
      Furthermore, the duration of action of stimulants often does not meet the all-day demands of patients with ADHD.
      • Childress A.
      • Tran C.
      Current investigational drugs for the treatment of attention-deficit/hyperactivity disorder.
      ,
      • Faraone S.V.
      • Schachar R.J.
      • Barkley R.A.
      • Nullmeier R.
      • Sallee F.R.
      Early morning functional impairments in stimulant-treated children with attention-deficit/hyperactivity disorder versus controls: impact on the family.
      In a survey of 300 providers of primary care for children with ADHD, 77% reported that patients treated with stimulants continued to experience moderate to severe functional impairments in the early morning.
      • Faraone S.V.
      • Schachar R.J.
      • Barkley R.A.
      • Nullmeier R.
      • Sallee F.R.
      Early morning functional impairments in stimulant-treated children with attention-deficit/hyperactivity disorder versus controls: impact on the family.
      Current FDA-approved nonstimulants can provide an alternative approach to treating ADHD.
      • Pliszka S.
      • Issues AWGoQ.
      Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder.
      Their use, however, comes with its own limitations.
      • Childress A.
      • Tran C.
      Current investigational drugs for the treatment of attention-deficit/hyperactivity disorder.
      ,
      • Faraone S.V.
      • Glatt S.J.
      A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes.
      Their effect size is generally lower than that of stimulants.
      • Cortese S.
      • Adamo N.
      • Del Giovane C.
      • et al.
      Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis.
      The following adverse effects are common for nonstimulants: somnolence, abdominal pain, vomiting, nausea, sedation, fatigue, and decreased appetite.
      Additionally, atomoxetine treatment has been associated with small but statistically significant increases in BP and HR,
      • Hennissen L.
      • Bakker M.J.
      • Banaschewski T.
      • et al.
      Cardiovascular effects of stimulant and non-stimulant medication for children and adolescents with ADHD: a systematic review and meta-analysis of trials of methylphenidate, amphetamines and atomoxetine.
      and in rare cases, drug-induced hepatic injury.
      • Lim J.R.
      • Faught P.R.
      • Chalasani N.P.
      • Molleston J.P.
      Severe liver injury after initiating therapy with atomoxetine in two children.
      Use of the nonstimulants guanfacine and clonidine has been associated with hypotension, bradycardia, and cardiac conduction abnormalities, and their abrupt discontinuation may cause rebound hypertension.
      • Wolraich M.L.
      • Hagan Jr., J.F.
      • Allan C.
      • et al.
      Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents.
      ,
      ,
      The onset of action of nonstimulant medications (eg, atomoxetine) is relatively slow, in some cases taking 12 weeks for a response to be fully established.
      • Asherson P.
      • Bushe C.
      • Saylor K.
      • Tanaka Y.
      • Deberdt W.
      • Upadhyaya H.
      Efficacy of atomoxetine in adults with attention deficit hyperactivity disorder: an integrated analysis of the complete database of multicenter placebo-controlled trials.
      • Montoya A.
      • Hervas A.
      • Cardo E.
      • et al.
      Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naive children and adolescents with attention deficit/hyperactivity disorder.
      • Kolar D.
      • Keller A.
      • Golfinopoulos M.
      • Cumyn L.
      • Syer C.
      • Hechtman L.
      Treatment of adults with attention-deficit/hyperactivity disorder.
      In addition, currently available nonstimulant ADHD medications are formulated as solid tablets or capsules, which poses a potential challenge for children who experience difficulty with swallowing or who prefer not to take pills (eg, children with autism, sensory processing disorder, or other developmental disabilities).
      • Cutler A.J.
      • Mattingly G.W.
      Beyond the pill: new medication delivery options for ADHD.
      There may be various reasons for low efficacy or tolerability of the currently available FDA-approved medications for ADHD, including complexity of the condition itself, high rates of comorbid psychiatric disorders, and difficulties with regimen or dose optimization.
      • Antshel K.M.
      • Hargrave T.M.
      • Simonescu M.
      • Kaul P.
      • Hendricks K.
      • Faraone S.V.
      Advances in understanding and treating ADHD.
      More treatment options are clearly needed for those patients in whom current prescription therapies offer inadequate benefit or are precluded due to tolerability issues or patient/caregiver preferences.
      SPN-812 (viloxazine extended-release) has demonstrated activity at serotonin receptors and norepinephrine transporter. In vivo studies showed that viloxazine increased serotonin, norepinephrine, and dopamine levels in the prefrontal cortex,
      • Yu C.
      • Garcia-Olivares J.
      • Candler S.
      • Schwabe S.
      • Maletic V.
      New insights into the mechanism of action of viloxazine: serotonin and norepinephrine modulating properties.
      a region strongly implicated in ADHD pathophysiology. Only a minimal increase in dopamine level was observed in the nucleus accumbens, a brain area that plays a key role in substance use disorders, suggesting low abuse potential with viloxazine. In vitro, antagonistic activity at 5-HT2B receptors and agonistic activity at 5-HT2C receptors were found with viloxazine.
      • Yu C.
      • Garcia-Olivares J.
      • Candler S.
      • Schwabe S.
      • Maletic V.
      New insights into the mechanism of action of viloxazine: serotonin and norepinephrine modulating properties.
      In a previous Phase II, randomized, placebo-controlled, 5-arm clinical trial (once-daily SPN-812 100, 200, 300, or 400 mg versus placebo) conducted in children aged 6–12 years, significant improvements in ADHD symptoms were observed with the 200-, 300-, and 400-mg doses compared to placebo.
      • Johnson J.K.
      • Liranso T.
      • Saylor K.
      • et al.
      A Phase II double-blind, placebo-controlled, efficacy and safety study of SPN-812 (extended-release viloxazine) in children with ADHD.
      Four pivotal Phase III clinical trials of SPN-812 for the treatment of ADHD have been completed, including two in children 6–11 years of age. In the first Phase III 6-week clinical trial in children, ADHD symptoms were reduced with once-daily SPN-812 100 and 200 mg versus placebo.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      Both doses were well tolerated, as demonstrated by a low rate of discontinuation due to adverse events (AEs).
      Here, we report the efficacy and tolerability of once-daily SPN-812 200 and 400 mg from the second Phase III 8-week placebo-controlled trial in children.

      Patients and Methods

       Study Design

      This randomized, double-blind, placebo-controlled, 3-arm, parallel-group trial (Fig. 1) was conducted at 28 clinical centers in the United States (ClinicalTrials.gov identifier: NCT03247543). A total of 313 eligible patients were randomly assigned in a 1:1:1 ratio to receive SPN-812 200 mg, SPN-812 400 mg, or placebo, once daily for 8 weeks (including ≤3 weeks titration period).
      Figure 1
      Figure 1Study design. n values represent intent-to-treat population. ADHD-RS-5, ADHD Rating Scale–5; CFB, change from baseline; CGI-I, Clinical Global Impression–Improvement; CGI-S, Clinical Global Impression–Severity of Illness; Conners 3–PS, Conners 3–Parent Short Form; Conners 3–SRS, Conners 3–Self-Reported Short Form; EOS, end of study; PSI-4-SF, Parenting Stress Index, Fourth Edition–Short Form; WFIRS–P, Weiss Functional Impairment Rating Scale–Parent.
      Each study medication (SM) was administered as a single oral dose, with or without food (food did not alter pharmacokinetics of viloxazine when SPN-812 was administered with or without food), as either an intact capsule, or sprinkled on soft food (eg, applesauce) if the patient was unable to swallow capsules. Regardless of treatment assignment, all patients received 4 capsules daily. The SPN-812 and placebo capsules contained the same inactive ingredients in the same physical form. The taste, smell, and feel of the placebo capsules and their contents matched those of the SPN-812 capsules. Thus, the placebo product was formulated to make it highly unlikely for patients or investigators to predict treatment assignment. Patients assigned to the placebo group were given 4 placebo capsules daily for 8 weeks; patients assigned to the 200-mg/d SPN-812 group were given 3 placebo capsules and 1 100-mg SPN-812 capsule daily during week 1, then 2 placebo capsules and 2 100-mg SPN-812 capsules daily during weeks 2–8; patients assigned to the 400-mg/d SPN-812 group were given 3 placebo capsules and 1 100-mg SPN-812 capsule daily during week 1, 2 placebo capsules and 2 100-mg SPN-812 capsules daily during week 2, 1 placebo capsule and 3 100-mg SPN-812 capsules daily during week 3, then 4 100-mg SPN-812 capsules during weeks 4–8 (Fig. 1). The parent(s) or legal guardian(s) was asked to incorporate SM dosing into the family's morning routine and to make every attempt to keep the dosing time consistent throughout treatment; however, some day-to-day variability in the timing of daily dosing was acceptable, especially if an AE precluded or delayed SM administration.
      The study protocol and any amendments were approved by an independent institutional review board (Advarra, Columbia, Maryland) and conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guideline. The parent(s) or legal guardian(s) provided written informed consent for each patient's participation before any study-related procedures were conducted. Patients who completed the 8-week treatment phase and continued to meet all inclusion/exclusion criteria were eligible for participation in a long-term, open-label extension study (ClinicalTrials.gov identifier: NCT02736656).

       Patients

      Male and female children with ADHD who were aged 6–11 years and having a body weight of ≥20 kg were eligible for inclusion in the study. The key inclusion criteria were a primary diagnosis of ADHD as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5),1 confirmed using the Mini International Neuropsychiatric Interview for Children and Adolescents,
      • Sheehan D.V.
      • Sheehan K.H.
      • Shytle R.D.
      • et al.
      Reliability and validity of the Mini international neuropsychiatric Interview for children and adolescents (MINI-KID).
      and an ADHD-RS-5 score of ≥28 and a Clinical Global Impression–Severity of Illness (CGI-S) score of ≥4 at screening.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      Patients were eligible for participation if they were considered medically healthy by the study investigator via assessment of physical examination, medical history, clinical laboratory tests, vital sign measurement, and ECG. Eligible females of childbearing potential were either sexually inactive (abstinent) or agreed to use an acceptable method of birth control beginning 30 days prior to the administration of the first dose and throughout the study.
      Exclusion criteria were a current diagnosis of a major psychiatric or neurologic disorder (including seizures or a history of seizure disorder within the immediate family, or a history of seizure-like events); a significant systemic disease; evidence of suicidality (defined as active suicidal plan/intent, active suicidal thoughts, or more than 1 lifetime suicide attempt) within 6 months of screening; a body mass index in the >95th percentile for age and sex; history of an allergic reaction to viloxazine or related drugs; and/or food allergy, intolerance, or restricted or special diet that, in the opinion of the site investigator, might have precluded the patient's participation in the study.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      Patients with major depressive disorder who were free of episodes, both current and for the 6 months prior to screening, were eligible for participation. Patients were excluded from the study if they received any investigational drug within the longer of 30 days or 5 half-lives prior to day 1 of administration of SM or had a positive drug test result at screening.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      The safety population included randomized patients who received at least 1 dose of SM. The intent-to-treat (ITT) population for efficacy included patients who were randomized, took at least 1 dose of SM, and had data available from a baseline and at least 1 post-randomization ADHD-RS-5 assessment.

       Assessments

      Efficacy assessment using investigator-rated ADHD-RS-5 was conducted at each study visit (visits 2–10) (Fig. 1). The CGI-S investigator ratings were obtained at visits 1 and 2, and CGI-I ratings were obtained and tolerability assessments were performed during weekly, post-baseline outpatient study visits (visits 3–10). Parent/guardian- or self-administered ratings were obtained at baseline (visit 2) and at end of study (EOS; visit 10). Parent/guardian- or self-administered assessments included the Conners 3-PS, WFIRS-P, Parenting Stress Index, Fourth Edition–Short Form (PSI-4-SF), and Conners 3–Self-Reported Short Form (Conners 3-SRS).
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.

       Statistical Analysis

      It was calculated that in the ITT population, 72 patients per treatment group would yield 90% power at a significance level of 0.05 (2-sided) using a 2-sample t test with equal allocation to the treatment groups. This calculation assumed an effect size of 0.547, obtained for ADHD-RS-5 Total score in the comparison of SPN-812 200 mg/d and placebo in a previous Phase IIb study.
      • Johnson J.K.
      • Liranso T.
      • Saylor K.
      • et al.
      A Phase II double-blind, placebo-controlled, efficacy and safety study of SPN-812 (extended-release viloxazine) in children with ADHD.
      A total of 300 patients (100 patients per group) were planned to be randomized to account for an anticipated 27.9% of randomized patients not completing the study.
      The methodology for the primary and secondary endpoint analyses was previously described.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      The primary efficacy endpoint was the change from baseline (CFB) in the ADHD-RS-5 Total score at EOS (visit 10). Key secondary endpoints included CGI-I score at EOS, CFB in Conners 3-PS composite T-score at EOS, and CFB in WFIRS-P Total average score at EOS.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      Additional secondary endpoints included CFBs in ADHD-RS-5 Inattention and Hyperactivity/Impulsivity subscale scores, PSI-4-SF Total score, and Conners 3-SRS composite T-score at EOS; the percentages of ADHD-RS-5 responders (reduction in Total score of ≥50%) and CGI-I responders (score of 1 or 2 [very much improved or much improved]) at EOS. Exploratory endpoints included individual content scale/domain scores on the Conners 3-PS/SRS, WFIRS-P, and PSI-4-SF.
      The ADHD-RS-5 is a commonly used, validated measure of drug efficacy in ADHD treatment. It includes 18 items that directly correspond to the 18 DSM-5 symptoms, which are divided into Inattention and Hyperactivity/Impulsivity subscales.
      • DuPaul G.J.
      • Power T.J.
      • Anastopoulos A.D.
      • et al.
      ADHD Rating Scale-5 for Children and Adolescents: Checklists, Norms, and Clinical Interpretation.
      The CGI-S scale is a clinician assessment of the severity of ADHD symptoms in relation to the clinician's total experience with patients with ADHD, and the CGI-I is an assessment of improvement or worsening of a patient's symptoms relative to baseline, as evaluated on a 7-point Likert scale (1 = very much improved to 7 = very much worse).
      • Guy W.
      Clinical Global Impression (CGI). Early Clinical Drug Evaluation Unit (ECDEU) Assessment Manual for Psychopharmacology.
      The Conners 3-PS (45 items) and Conners 3-SRS (41 items) assess ADHD-related behaviors across 6 content scales: Inattention, Hyperactivity, Learning Problems, Executive Functioning, Defiance/Aggression, and Peer Relations, with 43 and 39 items, respectively, scored on a 4-point Likert scale (higher scores indicate more severe symptoms).
      • Sparrow E.P.
      Essentials of Conners Behavior Assessments.
      Conners 3-PS scores were evaluated in all children, and Conners 3-SRS scores, only in children aged 8–11 years. The WFIRS-P evaluates ADHD-related functional impairment using 50 items grouped into 6 domains—Family, School, Life Skills, Individual's Self-Concept, Social Activities, and Risky Activities—that are scored using a 4-point Likert scale (higher scores indicate more severe impairment).
      • Gajria K.
      • Kosinski M.
      • Sikirica V.
      • et al.
      Psychometric validation of the Weiss functional impairment rating scale–parent report Form in children and adolescents with attention-deficit/hyperactivity disorder.
      ,
      • Thompson T.
      • Lloyd A.
      • Joseph A.
      • Weiss M.
      The Weiss Functional Impairment Rating Scale–Parent Form for assessing ADHD: evaluating diagnostic accuracy and determining optimal thresholds using ROC analysis.
      The statistical analysis was previously reported.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      Briefly, the primary efficacy endpoint was analyzed using a mixed model for repeated measures.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      The family-wise error rate was controlled at <5% using sequential testing.
      • Westfall P.H.
      • Tobias R.D.
      • Wolfinger R.D.
      Multiple Comparisons and Multiple Tests Using SAS.
      All secondary measures were analyzed using ANCOVA.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      The least squares (LS) mean values, differences in LS means between SPN-812 and placebo, and P values were determined for all measures. Statistical analyses were performed using SAS system software version 9.2 or higher (SAS Institute, Cary, North Carolina).
      Tolerability was assessed by monitoring the incidence of AEs,
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      clinical laboratory tests, physical examinations, vital sign measurements, ECGs, and the assessment of suicidal ideation and suicidal behavior as measured using the Columbia-Suicide Severity Rating Scale.
      • Posner K.
      • Brown G.K.
      • Stanley B.
      • et al.
      The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults.
      Seriousness and severity of AEs, as well as their relationship to SM, were evaluated by the trial investigator, and were considered mild if the symptom(s) was easily tolerated, moderate if discomfort interfered with daily activity and may have required intervention, and severe if the symptom/event significantly affected the patient's clinical status or daily activity and required intervention.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.

      Results

       Baseline Demographic and Clinical Characteristics

      A total of 393 patients were screened; 20.4% discontinued from the trial prior to randomization (Fig. 2). A total of 313 patients (6–11 years of age) were enrolled in the trial (placebo, n = 104; 200-mg/d SPN-812, n = 107; 400-mg/d SPN-812, n = 102), with the safety population consisting of 310 patients (placebo, n = 103; 200-mg/d SPN-812, n = 107; 400-mg/d SPN-812, n = 100), and the ITT population consisting of 301 patients (placebo, n = 97; 200-mg/d SPN-812, n = 107; 400-mg/d SPN-812, n = 97). The majority of patients were male (64.5%), and either white (52.8%) or black (41.5%). There were no major differences in baseline demographic or clinical characteristics between the placebo group and either SPN-812 group (Table I).
      Figure 2
      Figure 2Disposition of patients. aNumber of patients in the safety population (assigned treatment) was used as the denominator in this section.
      Table IBaseline demographic and clinical characteristics (intent-to-treat population).
      CharacteristicSPN-812

      200 mg/d

      (n = 107)
      SPN-812

      400 mg/d

      (n = 97)
      Placebo

      (n = 97)
      All Patients

      (n = 301)
      Age
       Mean (SD), y8.5 (1.7)8.4 (1.7)8.5 (1.7)8.4 (1.7)
       Median (range), y8.0 (6–11)8.0 (6–11)8.0 (6–11)8.0 (6–11)
       Age group, no. (%)
      6–9 y71 (66.4)68 (70.1)64 (66.0)203 (67.4)
      10–11 y36 (33.6)29 (29.9)33 (34.0)98 (32.6)
      Sex, no. (%)
       Male74 (69.2)59 (60.8)61 (62.9)194 (64.5)
       Female33 (30.8)38 (39.2)36 (37.1)107 (35.5)
      Ethnicity/race, no. (%)
       Non-Hispanic/Latino80 (74.8)63 (64.9)67 (69.1)210 (69.8)
       Hispanic or Latino27 (25.2)34 (35.1)30 (30.9)91 (30.2)
      Race, no. (%)
       White54 (50.5)52 (53.6)53 (54.6)159 (52.8)
       Black49 (45.8)39 (40.2)37 (38.1)125 (41.5)
       Multiple4 (3.7)5 (5.2)4 (4.1)13 (4.3)
       Native American/Alaskan01 (1.0)2 (2.1)3 (1.0)
       Asian001 (1.0)1 (0.3)
      Weight, mean (SD), kg32.6 (9.4)32.2 (8.4)30.6 (7.2)31.8 (8.4)
      Body mass index, mean (SD), kg/m217.7 (2.5)17.4 (2.4)17.0 (2.4)17.4 (2.4)
      ADHD-RS-5 score, mean (SD)
       Total43.8 (6.54)45 (6.55)43.5 (6.79)44.1 (6.63)
       Inattention subscale22.6 (3.42)23 (3.21)22.5 (3.20)22.7 (3.28)
       Hyperactivity/Impulsivity subscale21.2 (4.54)22 (4.11)21.0 (4.78)21.4 (4.49)
      CGI-S, mean (SD)4.8 (0.7)4.8 (0.7)4.8 (0.7)ND
      ADHD-RS-5 = ADHD Rating Scale-5; CGI-S = Clinical Global Impression–Severity of Illness; ND = not determined.

       ADHD-RS-5

      The CFBs in ADHD-RS-5 Total score at EOS were significantly reduced (improved) in both the 200-mg/d SPN-812 (P = 0.0038) and 400-mg/d SPN-812 (P = 0.0063) treatment groups versus placebo. The CFB in ADHD-RS-5 Total score separated from placebo in the first week of 200-mg/d SPN-812 treatment, with statistically significant difference being fully established in both SPN-812 groups by week 5 (this included up to 3 weeks of titration) and maintained through EOS (Fig. 3). The CFBs in the ADHD-RS-5 Total score at EOS (LS mean [SE]) were −11.7 (1.48) in the placebo group, −17.6 (1.43) in the 200-mg/d SPN-812 group, and −17.5 (1.52) in the 400-mg/d SPN-812 group. The placebo-adjusted CFBs at EOS were −6.0 (2.05) (200 mg/d) and −5.8 (2.11) (400 mg/d) (Table II).
      Figure 3
      Figure 3Changes from baseline in ADHD Rating Scale–5 (ADHD-RS-5) Total score. ∗P < 0.05. CFB, change from baseline; LS, least squares.
      Table IIChanges from baseline (CFB) in ADHD-RS-5 scores, and ADHD-RS-5 response rates (percentages of patients who had a reduction in Total score of ≥50%) at end of study.
      ADHD-RS-5 MeasureSPN-812

      200 mg/d

      (n = 107)
      SPN-812

      400 mg/d

      (n = 97)
      Placebo

      (n = 97)
      CFB, LS mean (SE)
       Total score−17.6 (1.4)
      P < 0.05 vs placebo.
      −17.5 (1.5)
      P < 0.05 vs placebo.
      −11.7 (1.5)
       Inattention subscale
      Least squares (LS) means and P values from ANCOVA model with baseline, age group, and treatment as fixed independent variables.
      −8.9 (0.7)
      P < 0.05 vs placebo.
      −8.6 (0.8)
      P < 0.05 vs placebo.
      −6.2 (0.8)
       Hyperactivity/Impulsivity subscale
      Least squares (LS) means and P values from ANCOVA model with baseline, age group, and treatment as fixed independent variables.
      −8.4 (0.8)
      P < 0.05 vs placebo.
      −8.3 (0.8)
      P < 0.05 vs placebo.
      −5.1 (0.8)
      Response rate, no. (%)
      P values derived from the Fisher exact test in cases of expected value counts of <5; otherwise, Pearson χ2 test was used.
      38 (36.0)40 (41.2)
      P < 0.05 vs placebo.
      25 (25.8)
      ADHD-RS-5 = ADHD Rating Scale-5.
      P < 0.05 vs placebo.
      Least squares (LS) means and P values from ANCOVA model with baseline, age group, and treatment as fixed independent variables.
      P values derived from the Fisher exact test in cases of expected value counts of <5; otherwise, Pearson χ2 test was used.
      The CFBs in ADHD-RS-5 Inattention subscale score at EOS were significantly improved in the 200-mg/d (P = 0.0020) and 400-mg/d (P = 0.0039) SPN-812 treatment groups versus placebo (Table II). Statistically significant differences were also observed in the CFBs in ADHD-RS-5 Hyperactivity/Impulsivity subscale score at EOS in both the 200- and 400-mg/d SPN-812 treatment groups versus placebo (P = 0.0087 and 0.0248, respectively). There were higher percentages of ADHD-RS-5 responders (a ≥50% reduction in Total score at EOS) in the SPN-812 treatment groups, with a statistically significant difference with the 400-mg/d (P = 0.0265), but not the 200-mg/d (P = 0.1303), dose versus placebo (Table II).

       CGI-I

      Statistically significant improvements compared to placebo were observed in CGI-I score at EOS: 3.1 (0.12) (LS mean [SE]), 2.6 (0.12), and 2.6 (0.12) in the placebo, 200-mg/d (P = 0.0028), and 400-mg/d (P = 0.0099) groups, respectively. Additionally, the percentages of patients who achieved a CGI-I score of 1 (very much improved) or 2 (much improved) were significantly higher at multiple study visits in both SPN-812 treatment groups versus placebo (Fig. 4).
      Figure 4
      Figure 4Percentages of patients with clinical improvement per categorical Clinical Global Impression–Improvement (CGI-I). aImprovement was defined as a score of 1 (very much improved) or 2 (much improved). ∗P < 0.05.

       Conners 3

      The CFB in the Conners 3−PS composite T-score at EOS was significantly improved in the 200-mg/d SPN-812 treatment group compared to the placebo group (P = 0.0064) (Table III). There were statistically significant reductions in the CFBs in the Conners 3-PS T-score at EOS for Inattention and Executive Functioning content scale T-scores in the 200-mg/d group versus placebo (P = 0.0196 and 0.0399, respectively) and for the Hyperactivity content scale T-score in both the 200- and 400-mg/d groups versus placebo (P < 0.0001 and P = 0.0030).
      Table IIIConners 3-PS and WFIRS-P results by treatment group and domain.
      ScaleSPN-812

      200 mg/d

      (n = 107)
      SPN-812

      400 mg/d

      (n = 97)
      Placebo

      (n = 97)
      Conners 3-PS T-score
       Composite T-score
      Baseline, mean (SD)76.6 (7.72)77.3 (8.93)76.0 (8.22)
      CFB at end of study
      LS mean (SE)−9.1 (0.96)−7.8 (1.06)−5.3 (1.00)
      Difference of LS mean (SE) vs placebo−3.8 (1.39)−2.5 (1.46)
      95% CI of difference−6.5 to −1.1−5.3 to 0.4
      P (vs placebo)0.00640.0917
       CFB in content scale T-scores at end of study, LS mean (SE)
      Inattention−9.2 (1.22)
      P < 0.05 versus placebo.
      −8.4 (1.33)−5.1 (1.27)
      Hyperactivity−12.2 (1.30)
      P < 0.05 versus placebo.
      −10.0 (1.40)
      P < 0.05 versus placebo.
      −4.2 (1.35)
      Learning Problems−7.0 (1.11)−6.4 (1.22)−5.8 (1.16)
      Executive Functioning−10.3 (1.23)
      P < 0.05 versus placebo.
      −7.9 (1.33)−6.6 (1.29)
      Defiance/Aggression−7.3 (1.40)−6.2 (1.53)−4.9 (1.45)
      Peer Relations−9.0 (1.51)−8.2 (1.65)−5.3 (1.59)
      WFIRS-P average score
       Total average score
      Baseline, mean (SD)1.08 (0.493)1.17 (0.482)1.11 (0.457)
      CFB at end of study
      LS mean (SE)−0.35 (0.041)−0.33 (0.044)−0.24 (0.042)
      Difference of LS mean (SE) vs placebo−0.11 (0.059)−0.08 (0.061)
      95% CI of difference−0.22 to 0.01−0.20 to 0.04
      P (vs placebo)0.06510.1680
       CFB in domain average scores at end of study, LS mean (SE)
      Family−0.40 (0.056)−0.29 (0.061)−0.28 (0.059)
      Self-Concept−0.30 (0.047)−0.25 (0.051)−0.27 (0.050)
      School−0.47 (0.064)
      P < 0.05 versus placebo.
      −0.48 (0.068)
      P < 0.05 versus placebo.
      −0.29 (0.067)
      Life Skills−0.34 (0.050)−0.31 (0.054)−0.22 (0.052)
      Social Activities−0.39 (0.051)−0.41 (0.055)−0.26 (0.053)
      Risky Activities−0.19 (0.037)−0.16 (0.039)−0.19 (0.038)
      Conners 3-PS = Conners 3–Parent Short Form; WFIRS-P = Weiss Functional Impairment Rating Scale–Parent.
      Least squares (LS) means, 95% CIs, and P values from ANCOVA model, with baseline and treatment as fixed independent variables.
      P < 0.05 versus placebo.
      While the CFBs in the Conners 3-SRS composite T-score at EOS exhibited greater reductions in the SPN-812 treatment groups compared to placebo, the differences were not statistically significant. There was a statistically significant reduction in the CFB at EOS in the Conners 3-SRS Defiance/Aggression content scale T-score in the 400-mg/d (P = 0.0281), but not the 200-mg/d (P = 0.3556), SPN-812 group versus placebo.

       WFIRS-P

      The CFB in WFIRS-P Total average score at EOS was not significantly reduced in either treatment group compared to placebo (P = 0.0651 and 0.1680, respectively); however, the CFBs at EOS in the average score for the WFIRS-P School domain indicated significant improvements in both the 200- and 400-mg/d SPN-812 groups versus placebo (P = 0.0436 and 0.0459, respectively) (Table III).

       PSI-4-SF

      Greater numeric reductions were observed in the CFBs in the PSI-4-SF Total score (LS mean [SD]) at EOS in the 200- and 400-mg/d SPN-812 groups (−9.2 [1.88] and −11.6 [2.01], respectively) versus placebo (−5.8 [1.95]), yet the difference was statistically significant only in the 400-mg/d group (P = 0.0409). The CFB in the PSI-4-SF Parental Distress domain score at EOS was significantly reduced in the 400-mg/d (P = 0.0255), but not the 200-mg/d (P = 0.1316), SPN-812 group versus placebo.

       Tolerability

      Overall, SPN-812 was well tolerated, as demonstrated by low discontinuation rates and mild or moderate severity of the majority of reported AEs.
      The most common AEs that were considered related to treatment and occurring in ≥5% of patients in any SPN-812 treatment group, and at a greater prevalence than with placebo, were somnolence (14%), decreased appetite (7.7%), fatigue (7.2%), headache (6.8%), and upper abdominal pain (4.8%) (Table IV). Severe AEs were reported in 4 patients in the placebo group, 4 in the 200-mg/d SPN-812 group, and 3 in the 400-mg/d SPN-812 group. In the 200-mg/d group, 1 patient experienced severe headache (the AE was reassessed as moderate after 1 day), and 1 patient experienced panic attack and separation anxiety disorder; all 3 AEs were considered possibly related to treatment and resolved without changes to SM. One patient in the 200-mg/d group experienced severe fatigue considered possibly related to SM, and 1 patient experienced severe mood swings considered definitely related to SM; both patients discontinued the treatment. In the 400-mg/d group, 1 patient experienced severe viral gastritis on 2 separate occasions (both considered unrelated to SM); during the second episode, ondansetron was prescribed, and the SM was interrupted for 1 day and the AE resolved within 1–4 days. One patient in the 400-mg/d group expressed severe suicidal behavior (considered unlikely related to treatment), which resolved without changes to SM, and 1 patient had severe mood alteration considered definitely related to SM, which led to study discontinuation. In the placebo group, 1 patient experienced severe somnolence and severe headache, 2 patients experienced severe enuresis, and 1 patient had gastroenteritis; all AEs resolved without changes to treatment.
      Table IVSummary of adverse events (AEs). Data are given as number (%) of patients.
      Tolerability MeasureSPN-812

      200 mg/d

      (n = 107)
      SPN 812

      400 mg/d

      (n = 100)
      Placebo

      (n = 103)
      All SPN-812-treated Patients

      (n = 207)
      At least 1 AE56 (52.3)58 (58.0)47 (45.6)114 (55.1)
      Treatment related (≥5% of patients)
       Somnolence15 (14.0)14 (14.0)1 (1.0)29 (14.0)
       Decreased appetite8 (7.5)8 (8.0)016 (7.7)
       Fatigue8 (7.5)7 (7.0)5 (4.9)15 (7.2)
       Headache9 (8.4)5 (5.0)1 (1.0)14 (6.8)
       Upper abdominal pain4 (3.7)6 (6.0)2 (1.9)10 (4.8)
      Led to discontinuation6 (5.6)4 (4.0)3 (2.9)10 (4.8)
       Irritability2 (1.9)002 (1.0)
       Nausea2 (1.9)002 (1.0)
       Somnolence2 (1.9)002 (1.0)
       Fatigue1 (1.0)001 (0.5)
       Affect lability1 (0.9)01 (1.0)1 (0.5)
       Abdominal discomfort1 (0.9)001 (0.5)
       Decreased appetite1 (0.9)001 (0.5)
       Erection increased1 (0.9)001 (0.5)
       Headache1 (0.9)001 (0.5)
       Hot flush1 (0.9)001 (0.5)
       Hyperacusis1 (0.9)001 (0.5)
       Impulsive behavior1 (0.9)001 (0.5)
       Insomnia1 (0.9)001 (0.5)
       Mood swings1 (0.9)001 (0.5)
       Tachycardia1 (0.9)001 (0.5)
       Flat affect01 (1.0)01 (0.5)
       Gastroenteritis01 (1.0)01 (0.5)
       Mood alteration01 (1.0)01 (0.5)
       Sedation01 (0.9)01 (0.5)
       Aggression001 (1.0)0
       Tic001 (1.0)0
      Overall, discontinuation due to AEs was infrequent, occurring in 6 patients receiving 200-mg/d SPN-812, 4 patients receiving 400-mg/d SPN-812, and 3 patients receiving placebo (Table IV). Most AEs leading to SM discontinuation occurred during the titration period (10 patients), compared to 1 AE that led to discontinuation during the maintenance period. Most AEs that led to discontinuation in the SPN-812 groups occurred in no more than 1 patient, except for somnolence, nausea, and irritability, which each occurred in 2 patients (Table IV).
      Few changes observed during vital sign examinations were reported as AEs: increased BP in 1 patient in the 400-mg/d group, increased body temperature in 1 patient in each SPN-812 group, increased HR in 1 patient in the 400-mg/d group, and palpitations in 1 patient in the placebo group, all of which were mild or moderate. Changes in vital sign measurements were generally small and infrequent, with the exception of respiratory rate abnormalities observed in >10% of patients in all 3 arms across several time points. The mean (SD) CFBs at EOS in diastolic and systolic BP (mm Hg) and HR (beats/min) were −0.5 (8.55), +0.3 (10.29), and +1.0 (11.00) in the placebo group, respectively; +2.3 (8.89), −0.6 (9.76), and +5.7 (11.82) in the 200-mg/d group; and +1.2 (9.57), +2.8 (8.94), and +5.3 (13.26) in the 400-mg/d group. Cardiovascular-related AEs and ECG abnormalities were infrequent, with 1 case of moderate tachycardia (132 beats/min, 200 mg/d) that led to trial discontinuation and 1 case of mild sinus tachycardia (102 beats/min, 400 mg/d) that was determined to be unrelated to treatment and resolved without adjustment to SM.
      No patient deaths occurred during the trial. Serious AEs were reported in 3 patients: suicidal ideation in the 200-mg/d group, and suicidal behavior and syncope in the 400-mg/d group (all considered not likely related to treatment).
      The most frequently observed laboratory abnormalities that occurred in ≥10.0% of patients per group were depressed chloride and neutrophil concentrations, with no significant differences between the groups. Clinical laboratory abnormalities were reported as AEs in 1 patient in the placebo group (elevated leukocytes [13.91 × 109 cells/L] and elevated neutrophils [11.0 × 109 cells/L] considered mild and unrelated to treatment), 1 patient in the 200-mg/d group (depressed neutrophil count [1.6 × 109 cells/L] considered mild and possibly related to SM), and 2 patients in the 400-mg/d group (elevated alanine aminotranferase [86 U/L] in 1 patient, considered mild and possibly related to treatment, and elevated blood creatinine [122 μmol/L] in 1 patient, considered moderate and possibly related to treatment).

      Discussion

      In this Phase III trial in school-aged children, ADHD symptoms were improved with SPN-812, meeting the primary efficacy endpoint (CFB in the ADHD-RS-5 Total score), at both doses (200 and 400 mg/d). Significant improvements in ADHD symptoms were also detected as measured by the ADHD-RS-5 Inattention and Hyperactivity/Impulsivity subscale scores with both SPN-812 doses at EOS. Furthermore, the improvement in ADHD-RS-5 Total score versus placebo was apparent at week 1 in the 200-mg/d group, and at week 5 in the 400-mg/d group (despite up to 3 weeks of titration). These results are consistent with those from another Phase III trial in school-aged children, evaluating 100-mg/d and 200-mg/d SPN-812,
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      in which a separation from placebo in CFB ADHD-RS-5 Total score was first observed at week 1 with both doses and sustained through EOS. The efficacy of SPN-812 in the present study was further supported by a significantly higher rate of ADHD-RS-5 responders (patients with reduction in Total score of ≥50%) at EOS versus placebo in the 400-mg/d SPN-812 group. Higher percentages of ADHD-RS-5 responders as well as the improvements in CFBs in the ADHD-RS-5 subscales scores with 100- and 200-mg/d SPN-812 versus placebo were also previously reported in this age group.
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      Significantly greater improvements versus placebo were also found in the CGI-I score in both SPN-812 treatment groups at EOS. Although this study was not powered to detect a difference in the rates of CGI-I response (patients who had score of 1 or 2 at EOS), the differences in the percentages of patients who had an improved CGI-I score between the 200-mg/d SPN-812 and placebo groups were statistically significant at weeks 1, 4, 5, 6, and 7, and between the 400-mg/d SPN-812 and placebo groups at weeks 3 and 6. Similar results were obtained in the Phase III study that investigated 100-mg/d and 200-mg/d SPN-812 in children,
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      in which improvement in CGI-I scores and rates of CGI-I responders (a CGI-I score of 1 or 2), versus placebo were observed with both doses at EOS. Historically, clinical trials have defined the efficacy threshold for ADHD-RS symptom improvement as 25%–30%; evidence exists, however, that such improvement often leaves patients with ADHD with significant symptoms and functional impairment.
      • Mattingly G.W.
      • Anderson R.H.
      Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems.
      ,
      • Steele M.
      • Jensen P.S.
      • Quinn D.M.
      Remission versus response as the goal of therapy in ADHD: a new standard for the field?.
      Therefore, a clinical response that takes into account both a ≥50% reduction in ADHD-RS score and a second measure of clinical improvement (eg, CGI-I score of 1 or 2) has been suggested as a more meaningful clinical measure of treatment effectiveness.
      • Mattingly G.W.
      • Weisler R.H.
      • Young J.
      • et al.
      Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.
      ,
      • Goodman D.
      • Faraone S.V.
      • Adler L.A.
      • et al.
      Interpreting ADHD rating scale scores: linking ADHD rating scale scores and CGI levels in two randomized controlled trials of lisdexamfetamine dimesylate in ADHD.
      ,
      • Nasser A.
      • Kosheleff A.R.
      • Hull J.T.
      • et al.
      Translating ADHD-RS-5 and WFIRS-P effectiveness scores into CGI clinical significance levels in four randomized clinical trials of SPN-812 (viloxazine extended-release) in children and adolescents with ADHD.
      Collectively, these findings suggest that SPN-812 treatment would lead to a clinically meaningful improvement in ADHD symptoms in a significant percentage of children shortly after the initiation of treatment.
      In addition to the reduced scores observed on the investigator-rated scales (ADHD-RS and CGI-I), parent-rated scales also demonstrated improvements in ADHD symptoms, behavior, and overall functionality with SPN-812 treatment at EOS. These improvements included significantly greater CFBs versus placebo in the Conners 3-PS composite T-score (200-mg/d SPN-812), the Inattention and Executive Functioning Conners 3-PS content scale T-scores (200-mg/d SPN-812), the Hyperactivity Conners 3-PS content scale T-score (both doses of SPN-812), and the WFIRS-P School domain average score (both doses of SPN-812). These observations are supported by the improvements in function and ADHD-related behavior found in the previous Phase III trial in children who received 100- and 200-mg/d SPN-812. The greater consistency of the findings on these scales observed in the previous trial may be attributable to the higher number of patients. The present trial was statistically powered for detecting differences in the primary, but not the secondary, objectives; hence, the sample size may have been insufficient for detecting some of the effects on the Conners 3-PS and WFIRS-P scale scores. Variable effects on the Conners 3-PS and WFIRS-P scale scores were previously observed with other medications used for treating ADHD.
      • Mischoulon D.
      • Shelton R.C.
      • Baer L.
      • et al.
      Ziprasidone augmentation of escitalopram for major depressive disorder: cardiac, endocrine, metabolic, and motoric effects in a randomized, double-blind, placebo-controlled study.
      ,
      • Wilens T.E.
      • Robertson B.
      • Sikirica V.
      • et al.
      A randomized, placebo-controlled trial of guanfacine extended release in adolescents with attention-deficit/hyperactivity disorder.
      Similarly, the lack of significant improvement versus placebo in the Conners 3-SRS composite T-score observed in both Phase III trials conducted in children aged 6–11 years may be explained by the smaller sample size. The self-reported scales such as the Conners 3-SRS are not validated for use in children <8 years of age; therefore, they were excluded from these assessments. It is also possible that improvements versus placebo may require a longer trial duration. Finally, some of the effects observed in secondary efficacy endpoints in a shorter trial may be more apparent with higher treatment doses. For instance, a statistically significant difference in the CFBs in PSI-4-SF score between SPN-812 and placebo was seen with 400-mg/d SPN-812, but not with 200 mg/d, in the present trial or with 100- or 200-mg/d in the previous trial.
      SPN-812 was generally well tolerated, with a low discontinuation rate due to AEs (<5%). Consistent with these findings, reported differences in clinical laboratory results, ECG findings, and vital sign measurements were minimal and transient in nature, with no clinically meaningful differences observed between the treatment groups.
      To summarize, the results reported in this trial are consistent with the data obtained in the previous Phase III trial in the same age group
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      as well as another Phase III trial in adolescents
      • Nasser A.
      • Liranso T.
      • Adewole T.
      • et al.
      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.
      , suggesting that all 3 doses of SPN-812 (100, 200, and 400 mg/d) are efficacious in reducing the symptoms of ADHD and are well tolerated. In a post hoc analysis of data from SPN-812 trials in the pediatric population, the number needed to treat (a measure of effect size) in children with ADHD (6–11 years of age) was 6–7. These results are consistent with those from trials of other nonstimulant drugs used in the treatment of ADHD
      • Hirota T.
      • Schwartz S.
      • Correll C.U.
      Alpha-2 agonists for attention-deficit/hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy.
      • Schwartz S.
      • Correll C.U.
      Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression.
      .
      New effective and well-tolerated therapies, especially nonstimulants, for ADHD are necessary, as evidenced by the significant proportion of individuals who do not respond to currently available FDA-approved stimulant and/or nonstimulant medications, who have restrictive tolerability issues, or for whom an optimal dose regimen cannot be achieved.
      • Biederman J.
      • Mick E.
      • Faraone S.V.
      Age-dependent decline of symptoms of attention deficit hyperactivity disorder: impact of remission definition and symptom type.
      • Chen M.H.
      • Tsai S.J.
      Treatment-resistant panic disorder: clinical significance, concept and management.
      • Mattingly G.W.
      • Weisler R.H.
      • Young J.
      • et al.
      Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.
      • Newcorn J.H.
      • Kratochvil C.J.
      • Allen A.J.
      • et al.
      Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response.
      ,
      • Hodgkins P.
      • Setyawan J.
      • Mitra D.
      • et al.
      Management of ADHD in children across Europe: patient demographics, physician characteristics and treatment patterns.
      • Sikirica V.
      • Flood E.
      • Dietrich C.N.
      • et al.
      Unmet needs associated with attention-deficit/hyperactivity disorder in eight European countries as reported by caregivers and adolescents: results from qualitative research.
      • Briars L.
      • Todd T.
      A review of pharmacological management of attention-deficit/hyperactivity disorder.
      • Cox D.J.
      • Moore M.
      • Burket R.
      • Merkel R.L.
      • Mikami A.Y.
      • Kovatchev B.
      Rebound effects with long-acting amphetamine or methylphenidate stimulant medication preparations among adolescent male drivers with attention-deficit/hyperactivity disorder.
      • Steer C.R.
      Managing attention deficit/hyperactivity disorder: unmet needs and future directions.
      • St Amour M.D.
      • O'Leary D.D.
      • Cairney J.
      • Wade T.J.
      What is the effect of ADHD stimulant medication on heart rate and blood pressure in a community sample of children?.
      ,
      • Winterstein A.G.
      • Gerhard T.
      • Shuster J.
      • Johnson M.
      • Zito J.M.
      • Saidi A.
      Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder.
      ,
      • Faraone S.V.
      • Schachar R.J.
      • Barkley R.A.
      • Nullmeier R.
      • Sallee F.R.
      Early morning functional impairments in stimulant-treated children with attention-deficit/hyperactivity disorder versus controls: impact on the family.
      ,
      • Faraone S.V.
      • Glatt S.J.
      A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes.
      ,
      • Hennissen L.
      • Bakker M.J.
      • Banaschewski T.
      • et al.
      Cardiovascular effects of stimulant and non-stimulant medication for children and adolescents with ADHD: a systematic review and meta-analysis of trials of methylphenidate, amphetamines and atomoxetine.
      ,
      • Lim J.R.
      • Faught P.R.
      • Chalasani N.P.
      • Molleston J.P.
      Severe liver injury after initiating therapy with atomoxetine in two children.
      One challenge associated with the treatment of ADHD in children is a high rate of comorbid disorders leading to modest improvements in function observed in clinical practice, and even in noncomorbid ADHD, optimal functioning occurs in only ~1 in 4 children with ADHD.
      • Antshel K.M.
      • Hargrave T.M.
      • Simonescu M.
      • Kaul P.
      • Hendricks K.
      • Faraone S.V.
      Advances in understanding and treating ADHD.
      Additionally, medications may improve some but not all aspects of cognitive function, with many patients experiencing residual disabilities in several areas, including executive function, emotional self-regulation, and academic performance.
      • Sikirica V.
      • Flood E.
      • Dietrich C.N.
      • et al.
      Unmet needs associated with attention-deficit/hyperactivity disorder in eight European countries as reported by caregivers and adolescents: results from qualitative research.
      ,
      • Antshel K.M.
      • Hargrave T.M.
      • Simonescu M.
      • Kaul P.
      • Hendricks K.
      • Faraone S.V.
      Advances in understanding and treating ADHD.
      ,
      • Baweja R.
      • Mattison R.E.
      • Waxmonsky J.G.
      Impact of attention-deficit hyperactivity disorder on school performance: what are the effects of medication?.
      Furthermore, current formulations of nonstimulant ADHD medications as solid tablets or capsules that cannot be sprinkled over food may preclude their use in children who experience difficulty swallowing or who prefer not to take pills (eg, individuals with autism, sensory processing disorder, or other developmental disabilities).
      • Cutler A.J.
      • Mattingly G.W.
      Beyond the pill: new medication delivery options for ADHD.
      Considering the complexity of ADHD and the potential tolerability-related limitations of currently available FDA-approved medications noted earlier, new effective treatment options with diminished risk could improve the management of this common neurodevelopmental disorder.

      Conclusions

      SPN-812 (viloxazine extended-release), a novel medication being evaluated for the treatment of ADHD, comes with potential advantages as demonstrated in 2 Phase III clinical trials in school-aged children. The consistent improvements in ADHD symptoms, as measured using 2 clinical assessment scales (ADHD-RS-5 and CGI-I), with SPN-812 compared to placebo start early after the initiation of treatment. This finding is supported by higher rates of response and parent-rated improvements in ADHD symptoms and function. These data, taken together with a low overall incidence of AEs and no clinically relevant trends observed on clinical laboratory tests, vital sign measurements, or ECG, indicate that SPN-812 may be an effective and overall well-tolerated treatment option for ADHD in children aged 6–11 years. The minimal effects on BP and HR, in particular, are a potential differentiator from currently available ADHD medications.

      Author Contributions

      A. Nasser contributed study conceptualization; oversight of all aspects of the study methods, analysis, and data interpretation; and writing, review, and updating of the manuscript drafts. T. Liranso contributed statistical methodology, statistical analysis, data-interpretation support, critical review, and help with updating of the manuscript drafts. T. Adewole contributed development, planning, and data analysis for the tolerability section, and critical review of the manuscript. N. Fry contributed project management, implementation of the study protocols, execution of the study, and critical review of the manuscript. J.T. Hull contributed execution of the study protocols; protocol amendments; analysis of the data; interpretation of the results; and writing, review, and updating the manuscript drafts. F. Chowdhry contributed development of the study protocols, analysis of the data, interpretation of the results, and critical review of the manuscript drafts. G.D. Busse contributed data interpretation support; writing, review, and updating of the manuscript drafts; and publication management. Z. Melyan contributed data interpretation support; writing, review, and updating of the manuscript drafts and figures; and publication management. A.J. Cutler was a site investigator and contributed study conceptualization, help with developing the study protocols, data interpretation, and critical review of the manuscript. R.L. Findling contributed help with developing the study protocols, data analysis and interpretation, and critical review of the manuscript. S. Schwabe contributed study conceptualization, oversight of patient tolerability, study conduct and data interpretation, and critical review and updating of the manuscript drafts.

      Disclosures

      This research and its publication were supported by Supernus Pharmaceuticals, Inc. A. Nasser, T. Liranso, T. Adewole, N. Fry, J.T. Hull, F. Chowdhry, G.D. Busse, Z. Melyan, and S. Schwabe are employees of Supernus Pharmaceuticals. A.J. Cutler has received consultant's fees from Adlon Therapeutics , Aevi Genomics , AiCure , Akili Interactive , Arbor Pharmaceuticals , Attentive , Ironshore , KemPharm , Lundbeck , MedAvante-ProPhase , Neos Therapeutics , NLS Pharma, Otsuka , Purdue , Shire , Sunovion , Supernus , Takeda , and Tris Pharma ; speaker's/promotional honoraria from Arbor Pharmaceuticals , Ironshore , Lundbeck , Neos Therapeutics , Otsuka , Shire , Sunovion , Supernus , Takeda , and Tris Pharma ; and research grants from Aevi Genomics , Akili Interactive , Arbor Pharmaceuticals , Ironshore , KemPharm , Lundbeck , Neos Therapeutics , Otsuka , Purdue , Shire , Sunovion , Supernus , Takeda , and Tris Pharma , and he is an employee and board member of the Neuroscience Education Institute. R.L. Findling has received research support, consultant's fees, and/or honoraria from Acadia , Adamas , Aevi , Akili , Alcobra , Alkermes , Allergan , Amerex , American Academy of Child & Adolescent Psychiatry , American Psychiatric Press , Arbor , Axsome , Daiichi-Sankyo , Genentech , KemPharm , Luminopia , Lundbeck , MedAvante-ProPhase , Merck , NIH , Neurim , Noven , Nuvelution , Otsuka , PCORI , PaxMedica , Pfizer , Physicians Postgraduate Press , Q BioMed , Receptor Life Sciences , Roche , Sage , Signant Health , Sunovion , Supernus Pharmaceuticals Inc., Syneos , Syneurx , Takeda , Teva , TouchPoint , Tris , and Validus . The authors have indicated that they have no other conflicts of interest with regard to the content of this article.

      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        5th ed. American Psychiatric Publishing, Washington, DC2013
        • Adesman A.R.
        The diagnosis and management of attention-deficit/hyperactivity disorder in pediatric patients.
        Prim Care Companion J Clin Psychiatr. 2001; 3: 66-77
        • Sibley M.H.
        • Swanson J.M.
        • Arnold L.E.
        • et al.
        Defining ADHD symptom persistence in adulthood: optimizing sensitivity and specificity.
        J Child Psychol Psychiatr. 2017; 58: 655-662
        • Cortese S.
        Pharmacologic treatment of attention deficit-hyperactivity disorder.
        N Engl J Med. 2020; 383: 1050-1056
        • Shaw M.
        • Hodgkins P.
        • Caci H.
        • et al.
        A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment.
        BMC Med. 2012; 10: 99
        • Hamed A.M.
        • Kauer A.J.
        • Stevens H.E.
        Why the diagnosis of attention deficit hyperactivity disorder matters.
        Front Psychiatr. 2015; 6: 168
        • Biederman J.
        • Mick E.
        • Faraone S.V.
        Age-dependent decline of symptoms of attention deficit hyperactivity disorder: impact of remission definition and symptom type.
        Am J Psychiatr. 2000; 157: 816-818
        • Chen M.H.
        • Tsai S.J.
        Treatment-resistant panic disorder: clinical significance, concept and management.
        Prog Neuropsychopharmacol Biol Psychiatr. 2016; 70: 219-226
        • Mattingly G.W.
        • Weisler R.H.
        • Young J.
        • et al.
        Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.
        BMC Psychiatry. 2013; 13: 39
        • Newcorn J.H.
        • Kratochvil C.J.
        • Allen A.J.
        • et al.
        Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response.
        Am J Psychiatr. 2008; 165: 721-730
        • Cortese S.
        • Adamo N.
        • Del Giovane C.
        • et al.
        Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis.
        Lancet Psychiatry. 2018; 5: 727-738
        • De Crescenzo F.
        • Cortese S.
        • Adamo N.
        • Janiri L.
        Pharmacological and non-pharmacological treatment of adults with ADHD: a meta-review.
        Evid Based Ment Health. 2017; 20: 4-11
        • Hodgkins P.
        • Setyawan J.
        • Mitra D.
        • et al.
        Management of ADHD in children across Europe: patient demographics, physician characteristics and treatment patterns.
        Eur J Pediatr. 2013; 172: 895-906
        • Sikirica V.
        • Flood E.
        • Dietrich C.N.
        • et al.
        Unmet needs associated with attention-deficit/hyperactivity disorder in eight European countries as reported by caregivers and adolescents: results from qualitative research.
        Patient. 2015; 8: 269-281
        • Briars L.
        • Todd T.
        A review of pharmacological management of attention-deficit/hyperactivity disorder.
        J Pediatr Pharmacol Ther. 2016; 21: 192-206
        • Cox D.J.
        • Moore M.
        • Burket R.
        • Merkel R.L.
        • Mikami A.Y.
        • Kovatchev B.
        Rebound effects with long-acting amphetamine or methylphenidate stimulant medication preparations among adolescent male drivers with attention-deficit/hyperactivity disorder.
        J Child Adolesc Psychopharmacol. 2008; 18: 1-10
        • Steer C.R.
        Managing attention deficit/hyperactivity disorder: unmet needs and future directions.
        Arch Dis Child. 2005; 90: i19-i25
        • St Amour M.D.
        • O'Leary D.D.
        • Cairney J.
        • Wade T.J.
        What is the effect of ADHD stimulant medication on heart rate and blood pressure in a community sample of children?.
        Can J Publ Health. 2018; 109: 395-400
        • Wolraich M.L.
        • Hagan Jr., J.F.
        • Allan C.
        • et al.
        Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents.
        Pediatrics. 2019; 144: 1-25
        • Winterstein A.G.
        • Gerhard T.
        • Shuster J.
        • Johnson M.
        • Zito J.M.
        • Saidi A.
        Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder.
        Pediatrics. 2007; 120: e1494-e1501
        • Clemow D.B.
        Misuse of methylphenidate.
        Curr Top Behav Neurosci. 2017; 34: 99-124
        • Wilens T.E.
        • Adler L.A.
        • Adams J.
        • et al.
        Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature.
        J Am Acad Child Adolesc Psychiatr. 2008; 47: 21-31
        • Kollins S.H.
        Abuse liability of medications used to treat attention-deficit/hyperactivity disorder (ADHD).
        Am J Addict. 2007; 16 (quiz 3-4): 35-42
      1. Code of federal regulations Title 21, Vol 9, Part 1305 orders for Schedule I and II controlled substance.
        (Available at:)
        • Childress A.
        • Tran C.
        Current investigational drugs for the treatment of attention-deficit/hyperactivity disorder.
        Expert Opin Investig Drugs. 2016; 25: 463-474
        • Faraone S.V.
        • Schachar R.J.
        • Barkley R.A.
        • Nullmeier R.
        • Sallee F.R.
        Early morning functional impairments in stimulant-treated children with attention-deficit/hyperactivity disorder versus controls: impact on the family.
        J Child Adolesc Psychopharmacol. 2017; 27: 715-722
        • Pliszka S.
        • Issues AWGoQ.
        Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder.
        J Am Acad Child Adolesc Psychiatr. 2007; 46: 894-921
        • Faraone S.V.
        • Glatt S.J.
        A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes.
        J Clin Psychiatr. 2010; 71: 754-763
      2. Intuniv (Guanfacine) [prescribing Information]. Shire US Inc, Lexington, MA2019
      3. Kapvay (Clonidine HCl) [prescribing Information St. Michael. Concordia Pharmaceuticals Inc, Barbados2016
      4. Strattera (Atomoxetine HCl) Prescribing Information Indianapolis. Lilly USA LLC, 2017
        • Hennissen L.
        • Bakker M.J.
        • Banaschewski T.
        • et al.
        Cardiovascular effects of stimulant and non-stimulant medication for children and adolescents with ADHD: a systematic review and meta-analysis of trials of methylphenidate, amphetamines and atomoxetine.
        CNS Drugs. 2017; 31: 199-215
        • Lim J.R.
        • Faught P.R.
        • Chalasani N.P.
        • Molleston J.P.
        Severe liver injury after initiating therapy with atomoxetine in two children.
        J Pediatr. 2006; 148: 831-834
        • Asherson P.
        • Bushe C.
        • Saylor K.
        • Tanaka Y.
        • Deberdt W.
        • Upadhyaya H.
        Efficacy of atomoxetine in adults with attention deficit hyperactivity disorder: an integrated analysis of the complete database of multicenter placebo-controlled trials.
        J Psychopharmacol. 2014; 28: 837-846
        • Montoya A.
        • Hervas A.
        • Cardo E.
        • et al.
        Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naive children and adolescents with attention deficit/hyperactivity disorder.
        Curr Med Res Opin. 2009; 25: 2745-2754
        • Kolar D.
        • Keller A.
        • Golfinopoulos M.
        • Cumyn L.
        • Syer C.
        • Hechtman L.
        Treatment of adults with attention-deficit/hyperactivity disorder.
        Neuropsychiatr Dis Treat. 2008; 4: 389-403
        • Cutler A.J.
        • Mattingly G.W.
        Beyond the pill: new medication delivery options for ADHD.
        CNS Spectr. 2017; 22: 463-474
        • Antshel K.M.
        • Hargrave T.M.
        • Simonescu M.
        • Kaul P.
        • Hendricks K.
        • Faraone S.V.
        Advances in understanding and treating ADHD.
        BMC Med. 2011; 9: 72
        • Yu C.
        • Garcia-Olivares J.
        • Candler S.
        • Schwabe S.
        • Maletic V.
        New insights into the mechanism of action of viloxazine: serotonin and norepinephrine modulating properties.
        J Exp Pharmacol. 2020; 12: 285-300
        • Johnson J.K.
        • Liranso T.
        • Saylor K.
        • et al.
        A Phase II double-blind, placebo-controlled, efficacy and safety study of SPN-812 (extended-release viloxazine) in children with ADHD.
        J Atten Disord. 2020; 24: 348-358
        • Nasser A.
        • Liranso T.
        • Adewole T.
        • et al.
        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.
        Clin Ther. 2020; 42: 1452-1466
        • Sheehan D.V.
        • Sheehan K.H.
        • Shytle R.D.
        • et al.
        Reliability and validity of the Mini international neuropsychiatric Interview for children and adolescents (MINI-KID).
        J Clin Psychiatr. 2010; 71: 313-326
        • DuPaul G.J.
        • Power T.J.
        • Anastopoulos A.D.
        • et al.
        ADHD Rating Scale-5 for Children and Adolescents: Checklists, Norms, and Clinical Interpretation.
        The Guilford Press, New York, NY2016
        • Guy W.
        Clinical Global Impression (CGI). Early Clinical Drug Evaluation Unit (ECDEU) Assessment Manual for Psychopharmacology.
        US Dept of Health, Education, and Welfare; Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration; National Institute of Mental Health; Psychopharmacology Research Branch; Division of Extramural Research Programs, Rockville, MD1976 (218–222)
        • Sparrow E.P.
        Essentials of Conners Behavior Assessments.
        John Wiley & Sons Inc, Hoboken, NJ2010
        • Gajria K.
        • Kosinski M.
        • Sikirica V.
        • et al.
        Psychometric validation of the Weiss functional impairment rating scale–parent report Form in children and adolescents with attention-deficit/hyperactivity disorder.
        Health Qual Life Outcomes. 2015; 13: 184
        • Thompson T.
        • Lloyd A.
        • Joseph A.
        • Weiss M.
        The Weiss Functional Impairment Rating Scale–Parent Form for assessing ADHD: evaluating diagnostic accuracy and determining optimal thresholds using ROC analysis.
        Qual Life Res. 2017; 26: 1879-1885
        • Westfall P.H.
        • Tobias R.D.
        • Wolfinger R.D.
        Multiple Comparisons and Multiple Tests Using SAS.
        SAS Institute, Cary, NC2011
        • Posner K.
        • Brown G.K.
        • Stanley B.
        • et al.
        The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults.
        Am J Psychiatr. 2011; 168: 1266-1277
        • Mattingly G.W.
        • Anderson R.H.
        Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems.
        CNS Spectr. 2016; 21: 45-59
        • Steele M.
        • Jensen P.S.
        • Quinn D.M.
        Remission versus response as the goal of therapy in ADHD: a new standard for the field?.
        Clin Ther. 2006; 28: 1892-1908
        • Goodman D.
        • Faraone S.V.
        • Adler L.A.
        • et al.
        Interpreting ADHD rating scale scores: linking ADHD rating scale scores and CGI levels in two randomized controlled trials of lisdexamfetamine dimesylate in ADHD.
        Prim Psychiatr. 2010; 17: 44-52
        • Nasser A.
        • Kosheleff A.R.
        • Hull J.T.
        • et al.
        Translating ADHD-RS-5 and WFIRS-P effectiveness scores into CGI clinical significance levels in four randomized clinical trials of SPN-812 (viloxazine extended-release) in children and adolescents with ADHD.
        J Child Adolesc Psychopharmacol. 2020; (in press)
        • Mischoulon D.
        • Shelton R.C.
        • Baer L.
        • et al.
        Ziprasidone augmentation of escitalopram for major depressive disorder: cardiac, endocrine, metabolic, and motoric effects in a randomized, double-blind, placebo-controlled study.
        J Clin Psychiatr. 2017; 78: 449-455
        • Wilens T.E.
        • Robertson B.
        • Sikirica V.
        • et al.
        A randomized, placebo-controlled trial of guanfacine extended release in adolescents with attention-deficit/hyperactivity disorder.
        J Am Acad Child Adolesc Psychiatr. 2015; 54: 916-925 e2
        • Hirota T.
        • Schwartz S.
        • Correll C.U.
        Alpha-2 agonists for attention-deficit/hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy.
        J Am Acad Child Adolesc Psychiatry. 2014; 53: 153-157https://doi.org/10.1016/j.jaac.2013.11.009
        • Schwartz S.
        • Correll C.U.
        Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression.
        J Am Acad Child Adolesc Psychiatry. 2014; 53: 174-187https://doi.org/10.1016/j.jaac.2013.11.005
        • Baweja R.
        • Mattison R.E.
        • Waxmonsky J.G.
        Impact of attention-deficit hyperactivity disorder on school performance: what are the effects of medication?.
        Paediatr Drugs. 2015; 17: 459-477