Trial Outcomes & Findings for Evaluation of SPN-812 (Viloxazine Extended-release Capsule) in Adults With ADHD (NCT NCT04016779)

NCT ID: NCT04016779

Last Updated: 2022-07-12

Results Overview

The Primary Endpoint was the change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) Total score at Week 6. 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. A Total score is calculated by summating the ratings of all 18 items (range: 0-54; the higher the score, the more severe the ADHD symptoms). A lower change from baseline AISRS Total score (\<0) represents a better outcome.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 374 participants
• Primary outcome timeframe: Baseline and Week 6
• Results posted on: 2022-07-12

Participant Flow

Participant milestones

Measure	Placebo Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Overall Study STARTED	184	190
Overall Study Treated	183	189
Overall Study COMPLETED	140	127
Overall Study NOT COMPLETED	44	63

Reasons for withdrawal

Measure	Placebo Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Overall Study Adverse Event	9	17
Overall Study Lack of Efficacy	4	1
Overall Study Lost to Follow-up	5	14
Overall Study Physician Decision	1	3
Overall Study Withdrawal by Subject	6	8
Overall Study Non-compliance with Study Drug	2	3
Overall Study Other, Multiple categories	17	17

Baseline Characteristics

Evaluation of SPN-812 (Viloxazine Extended-release Capsule) in Adults With ADHD

Baseline characteristics by cohort

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo	Total n=354 Participants Total of all reporting groups
Age, Continuous	35.4 years STANDARD_DEVIATION 10.04 • n=5 Participants	34.1 years STANDARD_DEVIATION 10.16 • n=7 Participants	34.8 years STANDARD_DEVIATION 10.11 • n=5 Participants
Age, Customized 18 to <25 years of age	29 Participants n=5 Participants	40 Participants n=7 Participants	69 Participants n=5 Participants
Age, Customized 25 to <33 years of age	48 Participants n=5 Participants	42 Participants n=7 Participants	90 Participants n=5 Participants
Age, Customized 33 to <41 years of age	52 Participants n=5 Participants	46 Participants n=7 Participants	98 Participants n=5 Participants
Age, Customized 41 to 65 years of age	50 Participants n=5 Participants	47 Participants n=7 Participants	97 Participants n=5 Participants
Sex: Female, Male Female	83 Participants n=5 Participants	77 Participants n=7 Participants	160 Participants n=5 Participants
Sex: Female, Male Male	96 Participants n=5 Participants	98 Participants n=7 Participants	194 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	32 Participants n=5 Participants	47 Participants n=7 Participants	79 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	147 Participants n=5 Participants	128 Participants n=7 Participants	275 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	28 Participants n=5 Participants	21 Participants n=7 Participants	49 Participants n=5 Participants
Race (NIH/OMB) White	136 Participants n=5 Participants	142 Participants n=7 Participants	278 Participants n=5 Participants
Race (NIH/OMB) More than one race	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Region of Enrollment United States	179 participants n=5 Participants	175 participants n=7 Participants	354 participants n=5 Participants
Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score	37.6 units on a scale STANDARD_DEVIATION 6.62 • n=5 Participants	38.5 units on a scale STANDARD_DEVIATION 6.56 • n=7 Participants	38.1 units on a scale STANDARD_DEVIATION 6.60 • n=5 Participants
Adult ADHD Investigator Symptom Rating Scale (AISRS) Inattention Subscale Score	21.1 units on a scale STANDARD_DEVIATION 3.46 • n=5 Participants	21.5 units on a scale STANDARD_DEVIATION 3.53 • n=7 Participants	21.3 units on a scale STANDARD_DEVIATION 3.49 • n=5 Participants
Adult ADHD Investigator Symptom Rating Scale (AISRS) Hyperactivity/Impulsivity Subscale Score	16.5 units on a scale STANDARD_DEVIATION 5.04 • n=5 Participants	17.0 units on a scale STANDARD_DEVIATION 5.02 • n=7 Participants	16.8 units on a scale STANDARD_DEVIATION 5.03 • n=5 Participants
Clinical Global Impression of Severity of Illness (CGI-S) Score	4.6 units on a scale STANDARD_DEVIATION 0.60 • n=5 Participants	4.6 units on a scale STANDARD_DEVIATION 0.65 • n=7 Participants	4.6 units on a scale STANDARD_DEVIATION 0.62 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

The Primary Endpoint was the change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) Total score at Week 6. 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. A Total score is calculated by summating the ratings of all 18 items (range: 0-54; the higher the score, the more severe the ADHD symptoms). A lower change from baseline AISRS Total score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Efficacy of SPN-812 on Symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) as Assessed by the Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score	-11.7 units on a scale Standard Error 0.90	-15.5 units on a scale Standard Error 0.91

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

The Key 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. Successful therapy is indicated by a lower overall score in subsequent testing. A lower change from baseline CGI-S score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the Clinical Global Impression - Severity of Illness (CGI-S) Scale	-1.0 units on a scale Standard Deviation 0.10	-1.4 units on a scale Standard Deviation 0.10

SECONDARY outcome

Timeframe: Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

An additional secondary endpoint was the percentage of subjects with a Clinical Global Impression - Severity of Illness (CGI-S) score of 1 or 2 ("responders") 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. Responder rate values range from 0 to 100%. A higher percentage represents a greater number of subjects who are "responders".

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the Clinical Response Rate as Assessed by the Clinical Global Impression - Severity of Illness (CGI-S) Scale	25.2 percentage of subjects	30.8 percentage of subjects

SECONDARY outcome

Timeframe: Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

An additional secondary endpoint was the Clinical Global Impression - Improvement (CGI-I) score at Week 6. 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.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the Clinical Global Impression - Improvement (CGI-I) Scale	2.9 units on a scale Standard Error 0.09	2.6 units on a scale Standard Error 0.09

SECONDARY outcome

Timeframe: Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

An additional secondary endpoint was the percentage of subjects with a CGI-I score of 1 or 2 ("responders") at Week 6. 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". Responder rate values can range from 0 to 100%. A higher percentage represents a greater number of subjects who are "responders".

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on Clinical Response Rate as Assessed by the Clinical Global Impression - Improvement (CGI-I) Scale	37.8 Percentage of subjects	48.5 Percentage of subjects

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

An additional secondary endpoint was the change from baseline in the Generalized Anxiety Disorder 7-Item (GAD-7) Total score at Week 6. 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 total score is calculated by summated the ratings of all 7 items. The total score can range between 0 to 21; the higher the score, the more severe the symptoms of anxiety. A lower change from baseline GAD-7 total score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on Symptoms of Anxiety as Assessed by the Generalized Anxiety Disorder 7-Item (GAD-7) Scale	-1.6 units on a scale Standard Error 0.30	-1.6 units on a scale Standard Error 0.31

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

An additional secondary endpoint was the change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) "Inattention" subscale score at Week 6. 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 Inattention subscale score is calculated by summating the ratings of all 9 Inattention items (range: 0-27; the higher the score, the more severe the symptoms). A lower change from baseline Inattention subscale score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on Inattention Symptoms as Assessed by the Inattention Subscale of the Adult ADHD Investigator Symptom Rating Scale (AISRS)	-6.1 units on a scale Standard Error 0.53	-8.5 units on a scale Standard Error 0.55

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

An additional secondary endpoint was the change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) "Hyperactivity/Impulsivity" subscale score at Week 6. 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 Hyperactivity/Impulsivity subscale score is calculated by summating the ratings of all 9 Hyperactivity/Impulsivity items (range: 0-27; the higher the score, the more severe the symptoms). A lower change from baseline Hyperactivity/Impulsivity subscale score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on Hyperactivity/Impulsivity Symptoms as Assessed by the Hyperactivity/Impulsivity Subscale of the Adult ADHD Investigator Symptom Rating Scale (AISRS)	-5.8 units on a scale Standard Error 0.46	-7.2 units on a scale Standard Error 0.48

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

An additional secondary endpoint was the percentage of subjects with a 30% or greater reduction in their change from baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) Total score at Week 6. 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 clinician/investigator rates the subject on each item using a 4-point scale, where 0=none, 1=mild, 2=moderate, and 3=severe. A Total score is calculated by summating the ratings of all 18 items (range: 0-54; the higher the score, the more severe the symptoms). The Total score is converted to a percent change from baseline. 30% responder rate values can range between 0 and 100%. A higher percentage represents a greater number of subjects who are "responders".

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on 30% Clinical Response Rate as Assessed by the Adult ADHD Investigator Symptom Rating Scale (AISRS)	47.6 percentage of subjects	60.0 percentage of subjects

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

An additional secondary endpoint was the percentage of subjects with a 50% or greater reduction in their change from baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) Total score at Week 6. 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 clinician/investigator rates the subject on each item using a 4-point scale, where 0=none, 1=mild, 2=moderate, and 3=severe. A Total score is calculated by summating the ratings of all 18 items (range: 0-54; the higher the score, the more severe the symptoms). The Total score is converted to a percent change from baseline. 50% responder rate values can range between 0 and 100%. A higher percentage represents a greater number of subjects who are "responders".

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on 50% Clinical Response Rate as Assessed by the Adult ADHD Investigator Symptom Rating Scale (AISRS).	32.9 percentage of subjects	39.2 percentage of subjects

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

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 at Week 6. 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline GEC T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the Global Executive Composite (GEC) of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-6.8 T-score Standard Error 0.85	-9.3 T-score Standard Error 0.87

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

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 at Week 6. 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline BRI T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the Behavioral Regulation Index (BRI) of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-6.4 T-score Standard Error 0.73	-7.2 T-score Standard Error 0.74

SECONDARY outcome

Timeframe: Baseline and week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

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 at Week 6. 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline MI T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the Metacognitive Index (MI) of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-6.5 T-score Standard Error 0.90	-9.8 T-score Standard Error 0.92

SECONDARY outcome

Timeframe: Baseline and Week 6

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 at Week 6. 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, appropriately stop verbal, attentional, 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline "Inhibit" T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the "Inhibit" Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-6.4 T-score Standard Error 0.81	-7.8 T-score Standard Error 0.82

SECONDARY outcome

Timeframe: Baseline and Week 6

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 at Week 6. 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 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline "Shift" T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the "Shift" Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-4.8 T-score Standard Error 0.77	-7.2 T-score Standard Error 0.79

SECONDARY outcome

Timeframe: Baseline and Week 6

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 at Week 6. 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline "Emotional Control" T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the "Emotional Control" Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-4.0 T-score Standard Error 0.69	-3.1 T-score Standard Error 0.70

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

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 at Week 6. 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline "Self-Monitor" T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the "Self-Monitor" Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-6.7 T-score Standard Error 0.77	-7.3 T-score Standard Error 0.78

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

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 at Week 6. 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline "Initiate" T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the "Initiate" Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-5.4 T-score Standard Error 0.84	-7.1 T-score Standard Error 0.85

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

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 at Week 6. 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; it 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline "Plan/Organize" T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the "Plan/Organize" Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-6.3 T-score Standard Error 0.91	-9.7 T-score Standard Error 0.93

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

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 at Week 6. 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline "Task Monitor" T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the "Task Monitor" Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-4.4 T-score Standard Error 0.94	-7.9 T-score Standard Error 0.95

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

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 at Week 6. 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline "Organization of Materials" T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the "Organization of Materials" Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-4.4 T-score Standard Error 0.79	-7.1 T-score Standard Error 0.80

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Full Analysis Set (FAS) Population: The FAS population includes subjects who were randomized, took at least one dose of study medication, have a baseline Adult ADHD Investigator Symptom Rating Scale (AISRS) assessment and have at least one post-baseline AISRS assessment.

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 at Week 6. 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 within the last 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). T-score is converted to a change from baseline T-score. A lower change from baseline "Working Memory" T-score (<0) represents a better outcome.

Outcome measures

Measure	Placebo n=179 Participants Placebo oral capsule Treatment A: Placebo was administered once daily	SPN-812 n=175 Participants SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Effect of SPN-812 on the "Working Memory" Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)	-6.9 T-score Standard Error 0.94	-10.1 T-score Standard Error 0.96

Adverse Events

Placebo

Serious events: 2 serious events

Other events: 43 other events

Deaths: 0 deaths

SPN-812

Serious events: 0 serious events

Other events: 147 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=183 participants at risk Placebo oral capsule Treatment A: Placebo: Placebo was administered once daily	SPN-812 n=189 participants at risk SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Cardiac disorders Cardiac failure congestive/ Congestive Heart Failure	0.55% 1/183 • Number of events 1 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).	0.00% 0/189 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).
Gastrointestinal disorders Pancreatitis/	0.55% 1/183 • Number of events 1 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).	0.00% 0/189 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).

Other adverse events

Measure	Placebo n=183 participants at risk Placebo oral capsule Treatment A: Placebo: Placebo was administered once daily	SPN-812 n=189 participants at risk SPN-812 oral capsule Treatment B: SPN-812 was administered once daily and compared to Placebo
Gastrointestinal disorders Constipation	1.1% 2/183 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).	5.8% 11/189 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).
Gastrointestinal disorders Dry mouth	2.2% 4/183 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).	9.5% 18/189 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).
Gastrointestinal disorders Nausea	2.7% 5/183 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).	12.2% 23/189 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).
General disorders Fatigue	3.3% 6/183 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).	12.2% 23/189 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).
Metabolism and nutrition disorders Decreased appetite	2.7% 5/183 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).	10.1% 19/189 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).
Nervous system disorders Headache	6.6% 12/183 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).	12.2% 23/189 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).
Psychiatric disorders Insomnia	4.9% 9/183 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).	15.9% 30/189 • 6 weeks Number of subjects is based on the Safety Population (defined as subjects who were randomized and took at least one dose of study medication).

Additional Information

Joseph Hull, Ph.D., Director Clinical research

Supernus

Phone: 240-403-5324

Email: jhull@supernus.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place