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

The percent of subjects who took at least one dose of SPN-812 (Safety Population; N) and who reported at least one Adverse Event (n). The percent is calculated by dividing the number of subjects who reported at least one Adverse Event (n) by the number of subjects in the Safety Population (N) and multiplying the product by 100. The higher the percentage, the higher the incidence in the Safety Population

Time frame: Up to 156 weeks

Population: Safety Population, defined as subjects who signed Informed Consent and took at least one dose of SPN-812.

An additional secondary endpoint was the change from baseline in the Symptoms of Depression Questionnaire (SDQ) Anxiety, Agitation, Irritability, and Anger (SDQ-2) Score by visit. The SDQ is a 44-item self-rating scale assessing overall depression and 5 related symptoms/subscales, including 13 items related to anxiety, agitation, irritability, and anger (SDQ-2 subscale). Each item is rated on a 6-point scale based on a subject's perception in past month of what is normal (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The sum of these 13 items yields the raw SDQ-2 subscale score (range: 13-78); a higher SDQ-2 subscale score indicates worse anxiety, agitation, irritability, and anger. Post-baseline raw SDQ-2 subscale scores are converted to a change from baseline score. A lower change from baseline SDQ-2 subscale score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid SDQ assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Symptoms of Depression Questionnaire (SDQ) Appetite and Weight (SDQ-5) Subscale Score by visit. The SDQ is a 44-item self-rating scale assessing overall depression and 5 related symptoms/subscales, including 4 items related to changes in appetite and weight (SDQ-5). Each item is rated on a 6-point scale based on a subject's perception in past month of what is normal (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The sum of these 4 items yields the raw SDQ-5 subscale score (range: 4-24); a higher SDQ-5 subscale score indicates worse appetite and weight. Post-baseline raw SDQ-5 subscale scores are converted to a change from baseline score. A lower change from baseline SDQ-5 subscale score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid SDQ assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Behavioral Regulation Index (BRI) T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. 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). Post-baseline BRI T-scores are converted to a change from baseline T-score. A lower change from baseline BRI T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Symptoms of Depression Questionnaire (SDQ) Disruptions in Sleep Quality (SDQ-4) Subscale Score by visit. The SDQ is a 44-item self-rating scale assessing overall depression and 5 related symptoms/subscales, including 3 items related to disruptions in sleep quality (SDQ-4). Each item is rated on a 6-point scale based on a subject's perception in past month of what is normal (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The sum of these 3 items yields the raw SDQ-4 subscale score (range: 3-18); a higher SDQ-4 subscale score indicates worse disruptions in sleep quality. Post-baseline raw SDQ-4 subscale scores are converted to a change from baseline score. A lower change from baseline SDQ-4 subscale score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid SDQ assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) Hyperactivity/Impulsivity (H/I) subscale score. The 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 (9 items) and H/I (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 nine H/I items yields the raw H/I subscale score (range: 0-27; the higher the H/I subscale score, the more severe the H/I symptoms). Post-baseline raw H/I subscale scores are converted to a change from baseline score. A lower change from baseline H/I subscale score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid AISRS assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to the Safety Population.

An additional secondary endpoint was the change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) Inattention (IA) subscale score. The 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 (9 items) and Hyperactivity/Impulsivity (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 nine 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 IA subscale scores are converted to a change from baseline score. A lower change from baseline IA subscale score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid AISRS assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to the Safety Population.

An additional secondary endpoint was the change from baseline in the Symptoms of Depression Questionnaire (SDQ) Lassitude, Mood, and Cognitive Functioning (SDQ-1) Subscale Score by visit. The SDQ is a 44-item self-rating scale assessing overall depression and 5 related symptoms/subscales, including 18 items related to lassitude, mood, and cognitive functioning (SDQ-1 subscale). Each item is rated on a 6-point scale based on a subject's perception in past month of what is normal (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The sum of these 18 items yields the raw SDQ-1 subscale score (range: 17-102); a higher SDQ-1 subscale score indicates worse lassitude, mood, and cognitive functioning. Post-baseline raw SDQ-1 subscale scores are converted to a change from baseline score. A lower change from baseline SDQ-1 subscale score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid SDQ assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Metacognition Index (MI) T-score. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. 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). Post-baseline MI T-scores are converted to a change from baseline T-score. A lower change from baseline MI T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Organization of Materials scale T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. The Organization of Materials scale is one of five Metacognition Index-related scales; it captures one's ability to keep areas orderly and maintain materials. Subjects rate each item on a 3-point scale (1=Never, 2=Sometimes, 3=Often) based on their experience in past month. The sum of 8 items yields the Organization of Materials raw score (range: 8-24), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). Post-baseline T-scores are converted to a change from baseline (CFB) T-score. A lower CFB Organization of Materials T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Global Executive Composite (GEC) T-score by visit. The 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). Post-baseline GEC T-scores are converted to a change from baseline T-score. A lower change from baseline GEC T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Adult ADHD Quality of Life Scale (AAQoL) Total score by visit. The AAQoL is a 29-item self-rating scale assessing how ADHD has impacted his/her quality of life. It includes 4 related aspects (subscales) of quality of life, including Life Productivity (11 items), Psychological Health (6 items), Relationships (5 items), and Life Outlook (7 items). Each item is rated on a 5-point scale based on a subject's perception in past 2 weeks, where 1 = Not at all/Never, 2 = A little, 3 = Somewhat, 4 = A lot, and 5 = Extremely/Very often. Item scores are transformed to a 0 to 100-point scale (1=0; 2=5; 3=50; 4=75; 5=100). The sum of the transformed 29 items is divided by 29 to yield the raw Total score (range: 0-100); a higher raw Total score represents better quality of life. Post-baseline raw Total scores are converted to a change from baseline (CFB) Total score. A higher CFB Total score (\>0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid AAQoL assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Symptoms of Depression Questionnaire (SDQ) Total Score by visit. The SDQ is a 44-item self-rating scale assessing overall depression and 5 related symptoms/subscales, including items related to lassitude, mood, and cognitive functioning (18 items; SDQ-1); anxiety, agitation, irritability, and anger (13 items; SDQ-2); suicidal ideation (6 items; SDQ-3); disruptions in sleep quality (3 items; SDQ-4); and changes in appetite and weight (4 items; SDQ-5). Each item is rated on a 6-point scale based on a subject's perception in past month of what is normal (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The sum of 44 items yields the raw Total score (range: 44-264); a higher Total score indicates worse depression. Post-baseline raw Total scores are converted to a change from baseline score. A lower change from baseline Total score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid SDQ assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Symptoms of Depression Questionnaire (SDQ) Suicidal Ideation (SDQ-3) Subscale by visit. The SDQ is a 44-item self-rating scale assessing overall depression and 5 related symptoms/subscales, including 6 items related to suicidal ideation (SDQ-3). Each item is rated on a 6-point scale based on a subject's perception in past month of what is normal (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The sum of these 6 items yields the raw SDQ-3 subscale score (range: 6-36); a higher SDQ-3 subscale score indicates worse suicidal ideation. Post-baseline raw SDQ-3 subscale scores are converted to a change from baseline score. A lower change from baseline SDQ-3 subscale score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid SDQ assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Generalized Anxiety Disorder 7-Item (GAD-7) Total Score by visit. The 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 GAD-7 Total score, the more severe the symptoms of anxiety. Post-baseline raw GAD-7 Total scores are converted to a change from baseline score. A lower change from baseline GAD-7 Total score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid GAD-7 assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the 30% Adult ADHD Investigator Symptom Rating Scale (AISRS) Responder Rate by visit. The AISRS is an ADHD-specific rating scale designed/validated to assess the 18 symptoms (items) of ADHD per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Each item is rated on a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). The sum of the 18 ratings yields the Total score (range: 0-54; higher score represents severer symptoms). Percent reduction is calculated for each post-baseline AISRS score: \[(Post-baseline - Baseline)/Baseline\] x 100; range: 0 to 100%; a responder is a subject with a 50% or greater reduction in change from baseline Total score. Responder rate (percent of responders) is calculated: \[number of 'responders' (m) / number of subjects analyzed (n)\] X 100; range: 0 to 100%. A Responder Rate greater than 30%, represents more responders versus nonresponders.

Time frame: Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, the percent is based on number of responders (m) and number of subjects analyzed (n; subjects with a valid AISRS assessment at baseline \[pre-dosing\] and at respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the 50% Adult ADHD Investigator Symptom Rating Scale (AISRS) Responder Rate by visit. The AISRS is an ADHD-specific rating scale designed/validated to assess the 18 symptoms (items) of ADHD per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Each item is rated on a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). The sum of the 18 ratings yields the Total score (range: 0-54; higher score represents severer symptoms). Percent reduction is calculated for each post-baseline AISRS score: \[(Post-baseline - Baseline)/Baseline\] x 100; range: 0 to 100%; a responder is a subject with a 50% or greater reduction in change from baseline Total score. Responder rate (percent of responders) is calculated: \[number of 'responders' (m) / number of subjects analyzed (n)\] X 100; range: 0 to 100%. A Responder Rate greater than 50%, represents more responders versus nonresponders.

Time frame: Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, the percent is based on number of responders (m) and number of subjects analyzed (n; subjects with a valid AISRS assessment at baseline \[pre-dosing\] and at respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Emotional Control scale T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. The Emotional Control scale is one of four Behavioral Regulation Index-related scales; it captures an individual's ability to modulate their emotional responses appropriately. 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 10 items yields the Emotional Control raw score (range: 10-30), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). Post-baseline T-scores are converted to a change from baseline (CFB) T-score. A lower CFB Emotional Control T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Inhibit scale T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. The Inhibit scale is one of four Behavioral Regulation Index-related scales; it captures the ability to control impulses and appropriately stop verbal, attentional, and physical behavior at the proper time. Subject's 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 8 items yields the Inhibit raw score (range: 8-24), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). Post-baseline T-scores are converted to a change from baseline (CFB) T-score. A lower CFB Inhibit T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Initiate scale T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. The Initiate scale is one of five Metacognition Index-related scales; it captures an individual's ability to begin a task or activity without external prompting and to independently generate ideas. 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 8 items yields the Initiate scale raw score (range: 8-24), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). Post-baseline T-scores are converted to a change from baseline (CFB) T-score. A lower CFB Initiate T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Plan/Organize scale T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. The Plan/Organize scale is one of five Metacognition Index-related scales; captures an individual's ability to anticipate events, set goals, pre-plan, organize, and carry out tasks systematically. Subjects rate each item on a 3-point scale (1=Never, 2=Sometimes, 3=Often) based on their experience in past month. The sum of 10 items yields the Plan/Organize raw score (range: 10-30), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥65 is considered abnormally elevated). Post-baseline T-scores are converted to a change from baseline (CFB) T-score. A lower CFB Plan/Organize T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Self-Monitor scale T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. The Self-Monitor scale is one of four Behavioral Regulation Index-related scales; it reflects an individual's ability to recognize the effect of their own behavior on others. The subject rates each item on a 3-point scale (1=Never, 2=Sometimes, or 3=Often) based on their experience in past month. The sum of 6 items yields the Self-Monitor raw score (range: 6-18), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). Post-baseline T-scores are converted to a change from baseline (CFB) T-score. A lower CFB Self-Monitor T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Shift scale T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. The Shift scale is one of four Behavioral Regulation Index-related scales; it captures one's ability to move freely from one situation/activity/aspect of a problem to another and think flexibly to aid problem-solving. 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 6 items yields the Shift raw score (range: 6-18), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). Post-baseline T-scores are converted to a change from baseline (CFB) T-score. A lower CFB Shift T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Task Monitor scale T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. The Task Monitor scale is one of five Metacognition Index-related scales; it captures an individual's ability to assess performance for mistakes during or after finishing a task. The subject rates each item on a 3-point scale (1=Never, 2=Sometimes, or 3=Often) based on their experience in past month. The sum of 6 items yields the Task Monitor raw score (range: 6-18), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥ 65 is considered abnormally elevated). Post-baseline T-scores are converted to a change from baseline (CFB) T-score. A lower CFB Task Monitor T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Working Memory scale T-score by visit. The BRIEF-A is a 75-item self-rating scale that assesses overall functioning and 9 non-overlapping scales among 2 summary index scales. The Working Memory scale is one of five Metacognition Index-related scales; it captures one's ability to hold information in mind in order to complete a task and stay with, or stick to, an activity. Subjects rate each item on a 3-point scale (1=Never, 2=Sometimes, 3=Often) based on their experience in past month. The sum of 8 items yields the Working Memory raw score (range: 8-24), which is converted to a T-score (normative population mean=50 and standard deviation=10; T-score ≥65 is considered abnormally elevated). Post-baseline T-scores are converted to a change from baseline (CFB) T-score. A lower CFB Working Memory T-score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid BRIEF-A assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Adult ADHD Quality of Life Scale (AAQoL) Life Outlook subscale score by visit. The AAQoL is a 29-item self-rating scale assessing how ADHD has impacted his/her quality of life, which includes 7 items related to Life Outlook. Each item is rated on a 5-point scale based on a subject's perception in past 2 weeks, where 1 = Not at all/Never, 2 = A little, 3 = Somewhat, 4 = A lot, and 5 = Extremely/Very often. Item scores are transformed to a 0 to 100-point scale (1=0; 2=5; 3=50; 4=75; 5=100). The sum of the transformed 7 items is divided by 7 to yield the raw Life Outlook subscale score (range: 0-100); the higher the subscale score, the better Life Outlook. Post-baseline raw Life Outlook subscale scores are converted to a change from baseline score. A higher change from baseline Life Outlook subscale score (\>0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid AAQoL assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Adult ADHD Quality of Life Scale (AAQoL) Life Productivity subscale score by visit. The AAQoL is a 29-item self-rating scale assessing how ADHD has impacted his/her quality of life, which includes 11 items related to Life Productivity. Each item is rated on a 5-point scale based on a subject's perception in past 2 weeks, where 1 = Not at all/Never, 2 = A little, 3 = Somewhat, 4 = A lot, and 5 = Extremely/Very often. Item scores are transformed to a 0 to 100-point scale (1=0; 2=5; 3=50; 4=75; 5=100). The sum of the transformed 11 items is divided by 11 to yield the raw Life Productivity subscale score (range: 0-100); the higher the Life Productivity subscale score, the better Life Productivity. Post-baseline raw Life Productivity subscale scores are converted to a change from baseline score. A higher change from baseline Life Productivity subscale score (\>0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid AAQoL assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Adult ADHD Quality of Life Scale (AAQoL) Psychological Health subscale score by visit. The AAQoL is a 29-item self-rating scale assessing how ADHD has impacted his/her quality of life, which includes 6 items related to Psychological Health. Each item is rated on a 5-point scale based on a subject's perception in past 2 weeks, where 1 = Not at all/Never, 2 = A little, 3 = Somewhat, 4 = A lot, and 5 = Extremely/Very often. Item scores are transformed to a 0 to 100-point scale (1=0; 2=5; 3=50; 4=75; 5=100). The sum of the transformed 6 items is divided by 6 to yield the raw Psychological Health subscale score (range: 0-100); the higher the subscale score, the better Psychological Health. Post-baseline raw Psychological Health subscale scores are converted to a change from baseline score. A higher change from baseline Psychological Health subscale score (\>0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid AAQoL assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Adult ADHD Quality of Life Scale (AAQoL) Relationships subscale score by visit. The AAQoL is a 29-item self-rating scale assessing how ADHD has impacted his/her quality of life, which includes 5 items related to Relationships. Each item is rated on a 5-point scale based on a subject's perception in past 2 weeks, where 1 = Not at all/Never, 2 = A little, 3 = Somewhat, 4 = A lot, and 5 = Extremely/Very often. Item scores are transformed to a 0 to 100-point scale (1=0; 2=5; 3=50; 4=75; 5=100). The sum of the transformed 5 items is divided by 5 to yield the raw Relationships subscale score (range: 0-100); the higher the subscale score, the better the Relationships. Post-baseline raw Relationships subscale scores are converted to a change from baseline score. A higher change from baseline Relationships subscale score (\>0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid AAQoL assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional endpoint was Clinical Global Impression - Improvement (CGI-I) Responder Rate by visit. The CGI-I Responder Rate was defined as the percent of subjects with a CGI-I score of 1 or 2 (responders). The CGI-I 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-I 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. The responder rate (percent) is calculated by dividing the number of 'responders' (m) by the number of subjects analyzed at the respective Visit/Week (n) and multiplying the product by 100. Responder Rate values range from 0 to 100%. A percent \>50% represents a greater number of responders versus non-responders.

Time frame: Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, the percent is based on number of responders (m; CGI-I score of 1 or 2) and number of subjects analyzed (n; subjects with a valid CGI-I assessment at respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the Clinical Global Impression - Severity of Illness (CGI-S) Responder Rate by visit. The CGI-S Responder Rate was defined as the percent of subjects with a CGI-S score of 1 or 2 (responders). The CGI-S 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 = Normal, not at all ill, asymptomatic, 2 = Borderline Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = Severely Ill, and 7 = Among the most extremely ill patients. The responder rate (percent) is calculated by dividing the number of 'responders' (m) by the number of subjects analyzed at the respective Visit/Week (n) and multiplying the product by 100. Responder Rate values range from 0 to 100%. A percent \>50% represents a greater number of responders versus non-responders.

Time frame: Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, percent is based on number of responders (m; CGI-S score of 1 or 2) and number of subjects analyzed (n; subjects with valid CGI-S assessment at baseline \[pre-dosing\] and at respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the change from baseline in the Clinical Global Impression - Severity of Illness (CGI-S) score at Week 6. The CGI-S 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 = Normal, not at all ill, asymptomatic, 2 = Borderline Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = Severely Ill, and 7 = Among the most extremely ill patients (the higher the score, the more severe the overall ADHD 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.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid CGI-S assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

An additional secondary endpoint was the Clinical Global Impression - Improvement (CGI-I) score by visit. The CGI-I 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-I 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-I score \<4 represents a better outcome.

Time frame: Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the total number of subjects analyzed (n; subjects with a valid CGI-I assessment at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.

A secondary endpoint was the change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) Total score by visit. The 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 (9 items) and Hyperactivity/Impulsivity (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 AISRS Total Score (\<0) represents a better outcome.

Time frame: Baseline and Week 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, and 124

Population: Safety Population (N), defined as subjects who signed Informed Consent and took at least 1 dose of SPN-812. At each Visit/Week, data is summarized with descriptive statistics for the number of subjects analyzed (n; subjects with a valid AISRS assessment at baseline \[pre-dosing\] and at the respective post-baseline \[after first dose\] Visit/Week). Due to attrition and/or missing data, the number of subjects analyzed at each Visit/Week may be less than and unequal to Safety Population.