Open-label Safety and Efficacy of SPN-812 (Viloxazine Extended-release Capsule) in Adults With ADHD and Mood Symptoms

The Adult ADHD Investigator Symptom Rating Scale (AISRS) is an ADHD-specific rating scale designed and validated to assess current ADHD symptomatology in adults. The AISRS consists of 18 items that directly correspond to the 18 symptoms of ADHD per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The scale is subdivided into two subscales: Inattention (IA; 9 items) and Hyperactivity/Impulsivity (HI; 9 items). The clinician/investigator rates the subject on each item using a 4-point scale, where 0=none, 1=mild, 2=moderate, and 3=severe. The sum of the ratings of all 18 items yields the raw Total score (range: 0-54; the higher the Total score, the more severe the ADHD symptoms). Post-baseline raw Total scores are converted to a change from baseline Total score. A lower change from baseline Total Score (<0) represents a better outcome.

The Adult ADHD Investigator Symptom Rating Scale (AISRS) is an ADHD-specific rating scale designed and validated to assess current ADHD symptomatology in adults. The AISRS consists of 18 items that directly correspond to the 18 symptoms of ADHD per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The scale is subdivided into two subscales: Inattention (IA; 9 items) and Hyperactivity/Impulsivity (HI; 9 items). The clinician/investigator rates the subject on each item using a 4-point scale, where 0=none, 1=mild, 2=moderate, and 3=severe. The sum of the ratings of the 9 IA items yields the raw IA subscale score (range: 0-27; the higher the IA Subscale score, the more severe the IA symptoms). Post-baseline raw Subscale score is converted to a change from baseline Subscale score. A lower change from baseline Subscale Score (<0) represents a better outcome.

The Adult ADHD Investigator Symptom Rating Scale (AISRS) is an ADHD-specific rating scale designed and validated to assess current ADHD symptomatology in adults. The AISRS consists of 18 items that directly correspond to the 18 symptoms of ADHD per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The scale is subdivided into two subscales: Inattention (IA; 9 items) and Hyperactivity/Impulsivity (HI; 9 items). The clinician/investigator rates the subject on each item using a 4-point scale, where 0=none, 1=mild, 2=moderate, and 3=severe. The sum of the ratings of the 9 HI items yields the raw HI subscale score (range: 0-27; the higher the HI Subscale score, the more severe the HI symptoms). Post-baseline raw Subscale score is converted to a change from baseline Subscale score. A lower change from baseline Subscale Score (<0) represents a better outcome.

The Adult ADHD Self-Report Scale (v1.1) Symptoms Checklist (ASRSv1.1-SC) is an ADHD-specific rating scale designed and validated to assess self-ratings of current ADHD symptomatology in adults. The ASRSv1.1-SC consists of 18 items that directly correspond to the 18 symptoms of ADHD per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The scale is subdivided into two subscales: Inattention (IA; 9 items) and Hyperactivity/Impulsivity (HI; 9 items). The subject rates the frequency of each item on a 5-point scale, where 0=never, 1=rarely, 2=sometimes, 3=often, and 4=very often. The sum of the ratings of all 18 items yields the raw Total score (range: 0-72; the higher the Total score, the more severe the ADHD symptoms). Post-baseline raw Total scores are converted to a change from baseline Total score. A lower change from baseline Total Score (<0) represents a better outcome.

The Adult ADHD Self-Report Scale (v1.1) Symptoms Checklist (ASRSv1.1-SC) is an ADHD-specific rating scale designed and validated to assess self-ratings of current ADHD symptomatology in adults. The ASRSv1.1-SC consists of 18 items that directly correspond to the 18 symptoms of ADHD per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The scale is subdivided into two subscales: Inattention (IA; 9 items) and Hyperactivity/Impulsivity (HI; 9 items). The subject rates the frequency of each item on a 5-point scale, where 0=never, 1=rarely, 2=sometimes, and 3=often, and 4=very often. The sum of the ratings of the 9 IA items yields the raw IA subscale score (range: 0-36; the higher the IA Subscale score, the more severe the IA symptoms). Post-baseline raw Subscale score is converted to a change from baseline Subscale score. A lower change from baseline Subscale Score (<0) represents a better outcome.

The Adult ADHD Self-Report Scale (v1.1) Symptoms Checklist (ASRSv1.1-SC) is an ADHD-specific rating scale designed and validated to assess self-ratings of current ADHD symptomatology in adults. The ASRSv1.1-SC consists of 18 items that directly correspond to the 18 symptoms of ADHD per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The scale is subdivided into two subscales: Inattention (IA; 9 items) and Hyperactivity/Impulsivity (HI; 9 items). The subject rates the frequency of each item on a 5-point scale, where 0=never, 1=rarely, 2=sometimes, and 3=often, and 4=very often. The sum of the ratings of the 9 HI items yields the raw HI subscale score (range: 0-36; the higher the HI Subscale score, the more severe the HI symptoms). Post-baseline raw Subscale score is converted to a change from baseline Subscale score. A lower change from baseline Subscale Score (<0) represents a better outcome.

The Clinical Global Impression of Severity (CGI-S) scale is a single item clinician-rated assessment of the severity of subject's condition (ADHD symptoms) in relation to the clinician's total experience with patients with ADHD. The CGI-S is evaluated on a 7-point scale with 1 = Asymptomatic, no symptoms; 2 = Borderline, 3 = Mild, 4 = Moderate, 5 = Marked, 6 = Severe, and 7 = Among the most extreme (the higher the score, the more severe the symptoms). Post-baseline (raw) CGI-S scores are converted to a change from baseline score. A lower change from baseline CGI-S score (<0) represents a better outcome.

The Clinical Global Impression of Change (CGI-C) scale is a single item clinician-rated assessment of how much the subject's condition (ADHD) has improved, worsened or has not changed relative to his/her baseline state prior to the beginning of treatment. The CGI-C is rated on a 7-point scale from 1 to 7, where 1 = "very much improved", 2 = "much improved", 3 = "minimally improved", 4 = "no change", 5 = "minimally worse", 6 = "much worse", and 7 = "very much worse". A CGI-C score <4 represents a better outcome.

The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item investigator-rated diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders and is designed to be sensitive to changes elicited by treatment. A Structured Interview Guide for the MADRS (SIGMA) was developed to improve inter- and intra-rater consistency and improve reliability. The clinician rates each of the 10 items (symptoms) on a 7-point scale [0-6 continuum, where 0=no abnormality to 6=severe]. The sum of the ratings of all 10 items yields the raw Total score (range: 0-60; the higher the Total score, the more severe the depression symptoms). The post-baseline raw Total score is converted to a change from baseline Total score. A lower change from baseline Total Score (<0) represents a better outcome.

The Patient Health Questionnaire 8-item (PHQ-8) is a multipurpose instrument for screening, diagnosing, monitoring and measuring the severity of depression per diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders. The PHQ-8 has been validated as a diagnostic and severity measure for depressive disorders in large clinical studies. The patient rates each item on 4-point scale (0-3), where 0 = not at all; 1 = several days; 2 = more than half the days; and 3 = nearly every day). The sum of the ratings of all 8 items yields the raw Total score (range: 0-24; the higher the Total score, the more severe the depression symptoms). The post-baseline raw Total score is converted to a change from baseline Total score. A lower change from baseline Total Score (<0) represents a better outcome.

The Hamilton Anxiety Scale (HAM-A) is a 14-item investigator-rated scale developed to assess/measure the severity of an individual's anxiety. The HAM-A has been used to assess severity of anxiety in children, adolescents, and adults in both clinical and research settings. A Structured Interview Guide for the HAM-A (SIGH-A) was developed to improve inter- and intra-rater consistency and improve reliability. The clinician rates each of the 14 items on a 5-point scale (0-4), where 0 = Not present, 1 = Mild, 2 = Moderate, 3 = Severe, and 4 = Very severe. The sum of the ratings of all 14 items yields the raw Total score (range: 0-56; the higher the Total score, the more severe the symptoms of anxiety). The post-baseline raw Total score is converted to a change from baseline Total score. A lower change from baseline Total Score (<0) represents a better outcome.

The Generalized Anxiety Disorder 7-Item (GAD-7) is a self-reported 7-item questionnaire for screening and measuring the severity of generalized anxiety disorder. The subject rates each item on 4-point scale (0-3), where 0 = "Not at all", 1 = "Several days", 2 = "Over half the days", and 3 = "Nearly every day". The sum of the 7 items yields a raw GAD-7 Total score (range between 0 to 21); the higher the Total score, the more severe the symptoms of anxiety. Post-baseline raw Total scores are converted to a change from baseline Total score. A lower change from baseline Total score (<0) represents a better outcome.

The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) is a 75-item self-rating scale that assesses overall functioning (GEC) and 9 non-overlapping scales among 2 summary index scales (Metacognition Index [MI] and Behavioral Regulation Index [BRI]) that assess aspects of executive function and problems with self-regulation from the perspective of the individual. Subjects rate each item on a 3-point scale (1=Never, 2=Sometimes, or 3=Often) based on their experience in past month. The sum of 70 items yields the GEC raw score (range: 70-210), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). The post-baseline GEC T-score is converted to a change from baseline T-score. A lower change from baseline GEC T-score (<0) represents a better outcome.

The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales, the Metacognition Index (MI) and the Behavioral Regulation Index (BRI). The BRI captures the ability to maintain appropriate regulatory control of one's own behavior and emotional responses. Subjects rate each item on a 3-point scale (1=Never, 2=Sometimes, or 3=Often) based on their experience in past month. The sum of 30 items yields the BRI raw score (range: 30-90), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). The post-baseline BRI T-score is converted to a change from baseline T-score. A lower change from baseline BRI T-score (<0) represents a better outcome.

The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales, the Metacognition Index (MI) and the Behavioral Regulation Index (BRI). MI reflects individual's ability to problem solve (includes initiate activity, generate ideas, sustain working memory, plan/organize approaches, monitor success/failure, and organize materials/environment). Subjects rate each item on a 3-point scale (1=Never, 2=Sometimes, or 3=Often) based on their experience in past month. The sum of 40 items yields the MI raw score (range: 40-120), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). The post-baseline MI T-score is converted to a change from baseline T-score. A lower change from baseline MI T-score (<0) represents a better outcome.

The Work Productivity and Activity Impairment:Specific Health Problem (WPAI:SHP) Questionnaire is a self-assessment questionnaire that measures the impact of health problems on work productivity and regular activities based on specific health problem (e.g., ADHD). The WPAI:SHP consists of 6 questions that ask about the number of hours missed from work or regular activities due to the specific health problem. The WPAI:SHP yields 4 scores: absenteeism (percentage of time absent from work), presenteeism (percentage of time impaired/unproductive at work), total work productivity impairment (absenteeism plus presenteeism), and total activity impairment (percentage of time affected outside the workplace); range 0-100%; the higher percentage, the greater the impairment). Post-baseline percentages are converted to a change from baseline percentage. A lower change from baseline Absenteeism percentage (<0) represents a better outcome.

The Work Productivity and Activity Impairment:Specific Health Problem (WPAI:SHP) Questionnaire is a self-assessment questionnaire that measures the impact of health problems on work productivity and regular activities based on specific health problem (e.g., ADHD). The WPAI:SHP consists of 6 questions that ask about the number of hours missed from work or regular activities due to the specific health problem. The WPAI:SHP yields 4 scores: absenteeism (percentage of time absent from work), presenteeism (percentage of time impaired/unproductive at work), total work productivity impairment (absenteeism plus presenteeism), and total activity impairment (percentage of time affected outside the workplace); range 0-100%; the higher percentage, the greater the impairment). Post-baseline percentages are converted to a change from baseline percentage. A lower change from baseline Presenteeism percentage (<0) represents a better outcome.

The Work Productivity and Activity Impairment:Specific Health Problem (WPAI:SHP) Questionnaire is a self-assessment questionnaire that measures the impact of health problems on work productivity and regular activities based on specific health problem (e.g., ADHD). The WPAI:SHP consists of 6 questions that ask about the number of hours missed from work or regular activities due to the specific health problem. The WPAI:SHP yields 4 scores: absenteeism (percentage of time absent from work), presenteeism (percentage of time impaired/unproductive at work), total work productivity impairment (absenteeism plus presenteeism), and total activity impairment (percentage of time affected outside the workplace); range 0-100%; the higher percentage, the greater the impairment). Post-baseline percentages are converted to a change from baseline percentage. A lower change from baseline Regular Activity percentage (<0) represents a better outcome.

The Work Productivity and Activity Impairment:Specific Health Problem (WPAI:SHP) Questionnaire is a self-assessment questionnaire that measures the impact of health problems on work productivity and regular activities based on specific health problem (e.g., ADHD). The WPAI:SHP consists of 6 questions that ask about the number of hours missed from work or regular activities due to the specific health problem. The WPAI:SHP yields 4 scores: absenteeism (percentage of time absent from work), presenteeism (percentage of time impaired/unproductive at work), total work productivity impairment (absenteeism plus presenteeism), and total activity impairment (percentage of time affected outside the workplace); range 0-100%; the higher percentage, the greater the impairment). Post-baseline percentages are converted to a change from baseline percentage. A lower change from baseline Work Productivity percentage (<0) represents a better outcome.

The Pittsburgh Sleep Quality Index (PSQI) is a validated and effective instrument used to measure the quality and patterns of sleep in adults. The PSQI is a self-rated, 19-item questionnaire out of which generate 7 component scores (or domains): subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction. Each component is scored on a 4-point scale based on an individual algorithm; range: 0 to 3, whereby 0=better and 3=worse). The sum of all 7 component scores yields the Global score (range:0 to 21); a global score >5 is associated with poor sleep quality. A post-baseline raw Global score is converted to a change from baseline Global score. A lower change from baseline Global score (<0) represents a better outcome.