Study of the Safety and Efficacy of OPC-34712 as a Complementary Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder

The CAARS-O:SV is a 30 items scale with 3 subscales: Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Inattentive Symptoms (9 items), DSM- IV Hyperactive/Impulsive Symptoms (9 items), and DSM-IV ADHD Index (12 items). Total ADHD Symptoms Score (18 items) consisted of the combined score for the inattentive symptoms and hyperactive/impulsive symptoms subscales and is scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) for a total score ranging from of 0 to 54, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The Mixed model repeated measures (MMRM) model was used for analysis.

WRAADDS is used to measure the severity of symptoms in adults with ADHD. This structured interview consists of 28 items in 7 psychopathologic domains, which were rated by a clinical expert on a 0 to 2-point Likert scale. The psychopathologic 7 domains are inattention (6 items), impulsivity (3 items), and hyperactivity (3 items), disorganization (5 items), temper (3 items), affective lability (4 items), and emotional over-reactivity (4 items). The scale rated individual items from 0 to 2 (0=not present, 1=mild, 2=clearly present) and summarized each of the 7 categories on a 0-to-4 scale (0=none, 1=mild, 2=moderate, 3=quite a bit, 4=very much). The WRAADDS total score is defined as sum of all 28 item sub scores (range 0 - 56), higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The analysis of covariance (ANCOVA) method was used for analysis.

The ISI is self-report instrument that has been validated specifically for measuring the perceived severity of insomnia. The scale was composed of a total of 7 items based on self-report questionnaire based on several indicators assessing the perceived severity of difficulties initiating sleep, staying asleep, and early morning awakenings, satisfaction with current sleep pattern, interference with daily functioning, noticeability of impairment attributed to the sleep problem, and degree of distress or concern caused by the sleep problem. Each item was rated on a scale from 0 (none) to 4 (higher score indicating greater impairment/concern). A total score ranging from 0 to 28 was calculated from the sum of the individual item scores, higher scores indicate increased severity of insomnia. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The ISI is self-report instrument that has been validated specifically for measuring the perceived severity of insomnia. The scale was composed of a total of 7 items based on self-report questionnaire based on several indicators assessing the perceived severity of difficulties initiating sleep, staying asleep, and early morning awakenings, satisfaction with current sleep pattern, interference with daily functioning, noticeability of impairment attributed to the sleep problem, and degree of distress or concern caused by the sleep problem. Each item was rated on a scale from 0 (none) to 4 (higher score indicating greater impairment/concern). A total score ranging from 0 to 28 was calculated from the sum of the individual item scores, higher scores indicate increased severity of insomnia. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

ADHD was measured with the CANTAB. SWM test was one of the tasks of CANTAB, SWM measured the ability to retain spatial information and to manipulate remembered items in working memory. This test was sensitive measure of executive dysfunction. Participants search for colored tokens hidden inside boxes on screen by touching them. The critical instruction was that once token has been found inside box, no token was hidden inside that box again, so participants must not return to box where a token was found. The key measurement of the SWM task is the SWM Between Errors 4-8 Boxes, which measured the total number of times a participant revisits a box in which a token has previously been found is measured for the 4, 6, and 8-box stages. Total scores ranged from 0-153. A lower score indicated better performance. The ANCOVA model was used for analysis.

The CAARS-O:SV is a 30 items scale with 3 subscales DSM-IV Inattentive Symptoms (9 items), DSM-IV Hyperactive/Impulsive Symptoms (9 items), and DSM-IV ADHD Index (12 items). Total ADHD Symptoms Score (18 items) consisted of the combined score for the inattentive symptoms and hyperactive/impulsive symptoms subscales and is scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) for total score ranging from of 0 to 54, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The CAARS-O:SV is a 30 items scale with 3 subscales DSM-IV Inattentive Symptoms (9 items), DSM-IV Hyperactive/Impulsive Symptoms (9 items), and DSM-IV ADHD Index (12 items). The inattentive symptoms subscale (9 items) is scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) with total score ranging from 0 to 27, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The CAARS-O:SV is a 30 items scale with 3 subscales DSM-IV Inattentive Symptoms (9 items), DSM-IV Hyperactive/Impulsive Symptoms (9 items), and DSM-IV ADHD Index (12 items). The hyperactive/impulsive Symptoms Subscale is (9 items) scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) with total score ranging from 0 to 27, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The CAARS-S:SV is a 30 items scale with 3 subscales inattention (9 items), hyperactivity-impulsivity (9 items), and ADHD index (12 items). The ADHD index score (12 items) is scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) with total score ranging from 0 to 36, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The ISI is self-report instrument that has been validated specifically for measuring the perceived severity of insomnia. The scale was composed of a total of 7 items based on self-report questionnaire based on several indicators assessing the perceived severity of difficulties initiating sleep, staying asleep, and early morning awakenings, satisfaction with current sleep pattern, interference with daily functioning, noticeability of impairment attributed to the sleep problem, and degree of distress or concern caused by the sleep problem. Each item was rated on a scale from 0 (none) to 4 (higher score indicating greater impairment/concern). A total score ranging from 0 to 28 was calculated from the sum of the individual item scores, higher scores indicate increased severity of insomnia. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The ISI is self-report instrument that has been validated specifically for measuring the perceived severity of insomnia. The scale was composed of a total of 7 items based on self-report questionnaire based on several indicators assessing the perceived severity. difficulties initiating sleep, staying asleep, and early morning awakenings, satisfaction with current sleep pattern, interference with daily functioning, noticeability of impairment attributed to the sleep problem, and degree of distress or concern caused by the sleep problem. Each item was rated on a scale from 0 (none) to 4 (higher score indicating greater impairment/concern). A negative change from Baseline indicates improvement. The Cochran-Mantel-Haenszel model was used for analysis.

The CAARS-S:SV is a self-reported 30 items scale with 3 subscales inattention (9 items), hyperactivity-impulsivity (9 items), and ADHD index (12 items). Total ADHD Symptoms Score (18 items) consisted of the combined score for the Inattentive Symptoms and Hyperactive/Impulsive Symptoms subscales and is scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) for total score ranging from of 0 to 54, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The CAARS-S:SV is a self-reported 30 items scale with 3 subscales inattention (9 items), hyperactivity-impulsivity (9 items), and ADHD index (12 items). The Inattentive Symptoms Subscale is (9 items) scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) with total score ranging from 0 to 27, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The CAARS-S:SV is a 30 items scale with 3 subscales inattention (9 items), hyperactivity-impulsivity (9 items), and ADHD index (12 items). The Hyperactive/Impulsive Symptoms Subscale is (9 items) scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) with total score ranging from 0 to 27, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The CAARS-S:SV is a 30 items scale with 3 subscales inattention (9 items), hyperactivity-impulsivity (9 items), and ADHD index (12 items). The ADHD Index Subscale is (12 items) scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) with total score ranging from 0 to 36, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The CGI-S is performed to rate the severity of a participant's condition on an 8-point scale ranging from 0 to 7 where 0=not assessed, 1=normal, not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7 = among the most extremely ill participants. A negative change from Baseline indicates improvement. The MMRM model was used for analysis.

The SWM test assesses the cognitive domain of executive function (high-level thinking and decision making). SWM task was SWM Strategy 6-8 Boxes, in which the total number of distinct boxes used by the participant to begin a new search for a token within the same problem was measured for the 6- and 8-box stages. The SWM strategy index of executive function represented the number of times a participant began a search with a different box. Participant was asked to find tokens in on-screen boxes and move them. Difficulty ranged from 4 to 8 box assessments. Strategy score was the number of unique boxes the participant searched in 6 and 8 box trials. 6 box trial scores ranged from 1 (1 box searched for all 6 tokens) to 6 (6 boxes searched for 6 tokens). 8 box trial score ranged from 1 (1 box searched) to 8 (8 boxes searched for 8 tokens). Total of the 2 trial scores ranged from 2 to 14. A lower score reflects better performance. The ANCOVA method was used for analysis.

Assessments were performed with CANTAB. SWM test assesses cognitive domain of executive function (high-level thinking and decision making). Participants search for colored tokens hidden inside boxes on screen by touching them. Critical instruction is that once a token has been found inside a box, there was never be a token hidden inside that box again, so participants must not return to a box where a token has been found. Within Errors 4-8 Boxes, which measured number of times a participant revisited a box that had already been found to be empty during the same search. Value was reported as total number of errors for 4-, 6-, and 8-box stages. Observed range for Phase B (Double-blind Randomization Phase): Brexpiprazole + Stimulant is -8.00 to 6.00 (change from baseline) and for Phase B (Double-blind Randomization Phase): Placebo + Stimulant is -10.0 to 23.00 (change from baseline). A lower score reflects better performance. LOCF method was used to impute missing data.

Assessments were performed with the CANTAB. The RVP task tested continuous performance and visual sustained attention. In the center of the computer screen, digits from 2 to 9 appear inside a white box in pseudorandom order at a rate of 100 digits per minute. Participants must touch the press pad when they detect a series of target digit sequences (eg, 2-4-6, 4-6-8, 3-5-7) which appeared at a rate of 9 sequences every 100 numbers. Data from the RVP task were summarized in 3 ways: RVP A prime, RVP median response latency, and RVP total false alarms. RVP A prime was the signal detection measure of sensitivity to the target, regardless of response tendency (range 0.00 to 1.00; bad to good). In essence, this metric was a measure of how good the participant was at detecting target sequences. Higher scores indicated better performance. The ANCOVA method was used for analysis.

Assessments were performed with CANTAB. RVP task tested continuous performance and visual sustained attention. In the center of computer screen, digits from 2 to 9 appear inside white box in pseudorandom order at a rate of 100 digits per minute. Participants must touch press pad when they detect a series of target digit sequences (eg, 2-4-6, 4-6-8, 3-5-7) which appeared at a rate of 9 sequences every 100 numbers. Data from RVP task were summarized in 3 ways: RVP A prime, RVP median response latency, and RVP total false alarms. Median response latency was measured during the assessed part of test (7-minute continuous part of test after initial 2 minutes training phase). Observed range for Phase B (Double-blind Randomization Phase): Brexpiprazole + Stimulant is -338 to 282.0 (change from baseline) and for Phase B (Double-blind Randomization Phase): Placebo + Stimulant is -134 to 235.0 (change from baseline). Lower scores indicate better performance. ANCOVA method was used for analysis.

RVP task tested continuous performance and visual sustained attention. In center of computer screen, digits from 2- 9 appear inside a white box in pseudorandom order at a rate of 100 digits per minute. Participants must touch press pad when they detect a series of target digit sequences (e.g., 2-4-6, 4-6-8, 3-5-7) which appeared at a rate of 9 sequences every 100 numbers. Data from RVP task were summarized in 3 ways: RVP A prime, RVP median response latency, and RVP total false alarms. False alarms were determined from number of times that participants responded outside response window of a target sequence during assessed part of test. Observed range for Phase B (Double-blind Randomization Phase): Brexpiprazole + Stimulant is -26.0 to 13.00 (change from baseline) and for Phase B (Double-blind Randomization Phase): Placebo + Stimulant is -25.0 to 144.0 (change from baseline). Lower scores indicate better performance. ANCOVA model was used for analysis.

In SST, an arrow pointing either left or right is displayed on computer screen. Participant responded to arrow by pressing corresponding button (i.e., left or right) on press pad. If an audio tone is presented when arrow is displayed, participant inhibited response. Proportion of successful stops, and median reaction time on Go trials was measured. SST SSRT was an estimate of length of time between go stimulus and stop stimulus at which participant was able to successfully inhibit response on 50% of trials and calculated from SST reaction time on Go trials measure and SST stop signal delay (SSD) 50% measure as [reaction time on Go trials] - [SSD (50%)], where SSD (50%) measure was calculated as arithmetic mean of measured SSD, or failed stop reaction time, from completed assessment stop trials. Observed change from baseline range for Phase B: Brexpiprazole + Stimulant: -204 to 237.0 and for Phase B: Placebo + Stimulant: -176 to 113.0. Lower scores indicate better performance.

SST measures participants ability to inhibit a response. An arrow pointing either left or right is displayed on computer screen. Participant responded to arrow by pressing corresponding button (i.e., left or right) on press pad. If an audio tone is presented when arrow is displayed, participant inhibited his/her response. Proportion of successful stops, and median reaction time on Go trials was measured. The proportion of successful stops is calculated as the number of times that the participant stopped successfully, divided by the total number of stop signals. Observed range for Phase B (Double-blind Randomization Phase): Brexpiprazole + Stimulant: -0.40 to 0.40 (change from baseline) and for Phase B (Double-blind Randomization Phase): Placebo + Stimulant: -0.38 to 0.38 (change from baseline). Higher scores indicate a positive outcome for proportion of successful stops.

SST measures participants ability to inhibit a response. An arrow pointing either left or right is displayed on computer screen. Participant responded to arrow by pressing corresponding button (i.e., left or right) on press pad. If an audio tone is presented when arrow is displayed, participant inhibited his/her response. Proportion of successful stops, and median reaction time on Go trials was measured. The median reaction time on Go trials is the median of the reaction time assessed on Go trials to which the participant responded correctly. Observed range for Phase B (Double-blind Randomization Phase): Brexpiprazole + Stimulant: -277 to 266.0 (change from baseline) and for Phase B (Double-blind Randomization Phase): Placebo + Stimulant: -462 to 358.0 (change from baseline). Lower scores indicate better performance.

WRAADDS is used to measure the severity of symptoms in adults with ADHD. This structured interview consists of 28 items in 7 psychopathologic domains, which were rated by a clinical expert on a 0 to 2-point Likert scale. The psychopathologic 7 domains are inattention (6 items), impulsivity (3 items), and hyperactivity (3 items), disorganization (5 items), temper (3 items), affective lability (4 items), and emotional over-reactivity (4 items). The scale rated individual items from 0 to 2 (0=not present, 1=mild, 2=clearly present). The score for attention + organization subscale score ranges from 0-22, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The ANCOVA method was used for analysis.

WRAADDS is used to measure the severity of symptoms in adults with ADHD. This structured interview consists of 28 items in 7 psychopathologic domains, which were rated by a clinical expert on a 0 to 2-point Likert scale. The psychopathologic 7 domains are inattention (6 items), impulsivity (3 items), and hyperactivity (3 items), disorganization (5 items), temper (3 items), affective lability (4 items), and emotional over-reactivity (4 items). The scale rated individual items from 0 to 2 (0=not present, 1=mild, 2=clearly present). The score for hyperactivity + impulsivity subscale score ranges from 0-12, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The ANCOVA model was used for analysis.

WRAADDS is used to measure the severity of symptoms in adults with ADHD. This structured interview consists of 28 items in 7 psychopathologic domains, which were rated by a clinical expert on a 0 to 2-point Likert scale. The psychopathologic 7 domains are inattention (6 items), impulsivity (3 items), and hyperactivity (3 items), disorganization (5 items), temper (3 items), affective lability (4 items), and emotional over-reactivity (4 items). The scale rated individual items from 0 to 2 (0=not present, 1=mild, 2=clearly present). The score for temper + mood Lability + emotional over-reactivity subscale score ranges from 0-22, higher scores indicate worsening of symptoms. A negative change from Baseline indicates improvement. The ANCOVA model was used for analysis.

The CGI-I permits a global evaluation of the participant's improvement over time. The CGI-I is a 8-point scale ranging from 0 to 7 where 0=not assessed, 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 CGI-I is completed by the clinician and assesses the participant's improvement relative to the symptoms at Baseline. The Cochran-Mantel-Haenszel model was used for analysis.

Response was defined as ≥ 30% reduction in CAARS-O:SV ADHD Symptoms Total Score (18 items) from end of Phase A (Week 5 visit). An 18-item ADHD Symptoms Total Score consisted of the combined score for the Inattentive Symptoms and Hyperactive/Impulsive Symptoms subscales. The CAARS-O:SV was designed to measure a cross-section of ADHD-related symptoms and behaviors in adults using observer and self-report scales. Total ADHD Symptoms Score (18 items) consisted of the combined score for the inattentive symptoms and hyperactive/impulsive symptoms subscales and is scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) for a total score ranging from of 0 to 54, higher scores indicate worsening of symptoms.

Remission was defined as CAARS-O:SV ADHD Symptoms Total Score (18 items) of ≤ 18 and a ≥ 30% reduction in CAARS-O:SV ADHD Symptoms Total Score (18 items) from end of Phase A (Week 5 visit). An 18-item ADHD Symptoms Total Score consisted of the combined score for the Inattentive Symptoms and Hyperactive/Impulsive Symptoms subscales. The CAARS-O:SV was designed to measure a cross-section of ADHD-related symptoms and behaviors in adults using observer and self-report scales. Total ADHD Symptoms Score (18 items) consisted of the combined score for the inattentive symptoms and hyperactive/impulsive symptoms subscales and is scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) for a total score ranging from of 0 to 54, higher scores indicate worsening of symptoms. The Cochran-Mantel-Haenszel model was used for analysis.

Response was defined as ≥ 30% reduction in CAARS-S:SV ADHD Symptoms Total Score (18 items) from end of Phase A (Week 5 visit). The CAARS-S:SV is a 30 items scale with 3 subscales inattention (9 items), hyperactivity-impulsivity (9 items), and ADHD index (12 items). Total ADHD Symptoms Score (18 items) consisted of the combined score for the Inattentive Symptoms and Hyperactive/Impulsive Symptoms subscales is scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) for total score ranging from of 0 to 54, higher scores indicate worsening of symptoms. The Cochran-Mantel-Haenszel model was used for analysis.

Remission was defined as CAARS-S:SV ADHD Symptoms Total Score (18 items) of ≤ 18 and a ≥ 30% reduction in CAARS-S:SV ADHD Symptoms Total Score (18 items) from end of Phase A (Week 5 visit). The CAARS-S:SV is a 30 items scale with 3 subscales inattention (9 items), hyperactivity-impulsivity (9 items), and ADHD index (12 items). Total ADHD Symptoms Score (18 items) consisted of the combined score for the Inattentive Symptoms and Hyperactive/Impulsive Symptoms subscales is scored on a 4-point scale from 0 (not at all; never) to 3 (very much, very frequently) for total score ranging from of 0 to 54, higher scores indicate worsening of symptoms. The Cochran-Mantel-Haenszel model was used for analysis.

Response was defined as a CGI-I score of 1 or 2 (very much improved or much improved). The CGI-I permits a global evaluation of the participant's improvement over time. The CGI-I is a 8-point scale ranging from 0 to 7 where 0=not assessed, 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 Cochran-Mantel-Haenszel model was used for analysis.