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

Primary Purpose

Attention Deficit Hyperactivity Disorder

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

OPDC-34712

Placebo

Stimulant Therapy

About this trial

This is an interventional treatment trial for Attention Deficit Hyperactivity Disorder focused on measuring Inattention, Hyperactivity, Impulsivity, Distractibility, Procrastination, Disorganized, ADHD

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male and female outpatients 18 to 55 years of age, inclusive, at the time of informed consent.
Subjects with a primary DSM-IV-TR diagnosis of ADHD (including inattentive, hyperactive, and combined subtypes) as confirmed by the CAADID. Subjects may have received prior treatment for adult ADHD, may be currently receiving treatment for adult ADHD at screening, or may be treatment-naive.
Subjects willing to discontinue all prohibited psychotropic medication starting from the time of signing the informed consent and during the study period.

Exclusion Criteria:

Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving study drug.
Subjects with an adequate response, as determined by the investigator, to any stimulant taken for the treatment of adult ADHD after 18 years of age.
Subjects with a clinically significant current Axis II (DSM-IV-TR) diagnosis of borderline,antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder.
Subjects who participated in a clinical trial within the last 180 days or who participated in more than two clinical trials within the past year.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Arm Label

Phase A (Single-blind Prospective Treatment Phase): Placebo + Stimulant

Phase B (Double-blind Randomization Phase): Brexpiprazole + Stimulant

Phase B (Double-blind Randomization Phase): Placebo + Stimulant

Phase A+ (Single-blind Phase A Responders and Non-responders): Placebo + Stimulant

Arm Description

Participants received single-blind matching-placebo tablets along with open-label stimulant determined by the investigator, once daily for 5 weeks. Once assigned to a stimulant by the investigator, participants remained on the same stimulant for the duration of the trial. Participants who met eligibility criteria i.e., who received prior treatment for adult ADHD and treatment-naïve participants were included in this arm group. Participants with incomplete response at the end of Phase A (Week 5) entered Phase B and rest of the participants continued to Phase A+.

Participants with incomplete response (with a > 0% and < 30% reduction in ADHD Symptoms Total Score {18 items} between the baseline of Phase A and the end of prospective treatment { Week 5} as measured by the CAARS-O:SV { Conners' Adult ADHD Rating Scale-Observer: Screening Version}, and a CAARS-O:SV ADHD Symptoms Total Score {18 items} of ≥ 24 at Week 5, and a clinical global impression - improvement scale (CGI-I) score of 3 or 4 at Week 5) at the end of Phase A (Week 5), received Brexpiprazole 2 milligram (mg) tablet along with stimulant determined by the investigator, once daily for 6 weeks (up to Week 11).

Participants with incomplete response (with a > 0% and < 30% reduction in ADHD Symptoms Total Score {18 items} between the Baseline of Phase A and the end of prospective treatment { Week 5} as measured by the CAARS-O:SV, and a CAARS-O:SV ADHD Symptoms Total Score {18 items} of ≥ 24 at Week 5, and a CGI-I score of 3 or 4 at Week 5) at the end of Phase A (Week 5), received matching-placebo tablets along with stimulant determined by the investigator, once daily for 6 weeks (up to Week 11).

Participants with response (with a ≥ 30% reduction in ADHD Symptoms Total Score {18 items} between Baseline of Phase A and the end of prospective treatment { Week 5} as measured by the CAARS-O:SV, or a CAARS-O:SV ADHD Symptoms Total Score {18 items} of < 24 at Week 5, or a CGI-I score of < 3 at Week 5) and non-response (with deterioration or no change in ADHD symptoms at Week 5) at the end of Phase A (Week 5), received single-blind matching-placebo tablets along with open-label stimulant determined by the investigator, once daily for an additional 6 weeks (up to Week 11).

Outcomes

Primary Outcome Measures

Mean Change From Baseline (End of Phase A) in the CAARS-O:SV ADHD Symptoms Total Score (18 Items) to End of Phase B

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.

Secondary Outcome Measures

Change From Baseline (End of Phase A) in Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) Total Score to End of Phase B

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.

Change From Baseline (End of Phase A) in Sleep Improvement Measured by Insomnia Severity Index (ISI) Total Score to End of Phase B

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.

Change From Baseline (End of Phase A) in Sleep Improvement Measured by ISI for Item 2 Score (Difficulty Staying Asleep) to End of Phase B

Change From Baseline (End of Phase A) in the Spatial Working Memory (SWM) Between Errors 4-8 Boxes Test Score as Measured by Cambridge Neuropsychological Test Automated Battery (CANTAB) to End of Phase B

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.

Change From Baseline (End of Phase A) in CAARS-O:SV ADHD Symptoms Total Score (18 Items) to Each Time Point in Phase B Other Than Week 11

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.

Change From Baseline (End of Phase A) in CAARS-O:SV Inattentive Symptoms Subscale Score (9 Items) to Each Time Point in Phase B

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.

Change From Baseline (End of Phase A) in CAARS-O:SV Hyperactive/Impulsive Symptoms Subscale Score (9 Items) to Each Time Point in Phase B

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.

Change From Baseline (End of Phase A) in CAARS-O:SV ADHD Index Score (12 Items) to Each Time Point in Phase B

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.

Change From Baseline (End of Phase A) to Weeks 7 and 9 in ISI Total Score

Percentage of Participants With Categorical Change in Sleep Improvement Measured by Individual Scores for Items 1, 2, and 3 of the ISI at End of Phase B

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.

Change From Baseline (End of Phase A) in Conners' Adult ADHD Rating Scale-Self-Report: Screening Version (CAARS-S:SV) ADHD Symptoms Total Score (18 Items) to Each Timepoint in Phase B

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.

Change From Baseline (End of Phase A) in CAARS-S:SV Inattentive Symptoms Subscale Score (9 Items) to Each Timepoint in Phase B

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.

Change From Baseline (End of Phase A) in CAARS-S:SV Hyperactive/Impulsive Symptoms Subscale Score (9 Items) to Each Timepoint in Phase B

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.

Change From Baseline (End of Phase A) in CAARS-S:SV ADHD Index Score (12 Items) to Each Timepoint in Phase B

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.

Change From Baseline (End of Phase A) in Clinical Global Impression - Severity of Illness Scale (CGI-S) Score to Each Timepoint in Phase B

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.

Change From Baseline (End of Phase A) in the SWM Strategy 6-8 Boxes Test Score as Measured by CANTAB to End of Phase B

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.

Change From Baseline (End of Phase A) in the SWM Within Errors 4-8 Boxes Test Score as Measured by CANTAB to End of Phase B

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.

Change From Baseline (End of Phase A) in the Rapid Visual Information Processing (RVP) A Prime Test Score as Measured by CANTAB to End of Phase B

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.

Change From Baseline (End of Phase A) in the RVP Median Response Latency Score as Measured by CANTAB to End of Phase B

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.

Change From Baseline (End of Phase A) in RVP Total False Alarms Score as Measured by CANTAB to End of Phase B

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.

Change From Baseline (End of Phase A) in the Stop Signal Task (SST) Stop Signal Reaction Time (SSRT) Score as Measured by CANTAB to End of Phase B

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.

Change From Baseline (End of Phase A) in the SST Proportion of Successful Stops Score as Measured by CANTAB to End of Phase B

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.

Change From Baseline (End of Phase A) in SST Median Reaction Time Score on Go Trials as Measured by CANTAB to End of Phase B

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.

Change From Baseline (End of Phase A) in WRAADDS Attention + Organization Subscale Score to End of Phase B

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.

Change From End of Phase A (Week 5 Visit) to End of Phase B (Week 11 Visit) in WRAADDS Hyperactivity + Impulsivity Subscale Score to End of Phase B

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.

Change From Baseline (End of Phase A) in WRAADDS Temper + Mood Lability + Emotional Over-reactivity Subscale Score to End of Phase B

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.

Mean CGI-I Score at Each Timepoint in Phase B

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.

Percentage of Participants With CAARS-O:SV ADHD Symptoms Response Rate in Phase B

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.

Percentage of Participants With CAARS-O:SV ADHD Symptoms Remission Rate in Phase B

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.

Percentage of Participants With CAARS-S:SV ADHD Symptoms Response Rate in Phase B

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.

Percentage of Participants With CAARS-S:SV ADHD Symptoms Remission Rate in Phase B

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.

Percentage of Participants With CGI-I Response Rate in Phase B

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.

Full Information

NCT ID

NCT01074294

First Posted

February 22, 2010

Last Updated

January 6, 2023

Sponsor

Otsuka Pharmaceutical Development & Commercialization, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01074294

Brief Title

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

Acronym

STEP-A

Official Title

A Phase 2, Multicenter, Randomized, Double-blind, Placebo Controlled Study of the Safety and Efficacy of OPC-34712 as Adjunctive Therapy in the Treatment of Adult Attention Deficit/ Hyperactivity Disorder

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Completed

Study Start Date

March 16, 2010 (Actual)

Primary Completion Date

June 20, 2011 (Actual)

Study Completion Date

June 20, 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Otsuka Pharmaceutical Development & Commercialization, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study tests the effects of an investigational antipsychotic drug (called OPC-34712) in adults with attention deficit hyperactivity disorder (ADHD) when taken with an approved stimulant medication to explore a possible impact on sleep, quality of life and cognitive function.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Attention Deficit Hyperactivity Disorder

Keywords

Inattention, Hyperactivity, Impulsivity, Distractibility, Procrastination, Disorganized, ADHD

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

740 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phase A (Single-blind Prospective Treatment Phase): Placebo + Stimulant

Arm Type

Experimental

Arm Description

Arm Title

Phase B (Double-blind Randomization Phase): Brexpiprazole + Stimulant

Arm Type

Experimental

Arm Description

Arm Title

Phase B (Double-blind Randomization Phase): Placebo + Stimulant

Arm Type

Placebo Comparator

Arm Description

Arm Title

Phase A+ (Single-blind Phase A Responders and Non-responders): Placebo + Stimulant

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

OPDC-34712

Other Intervention Name(s)

Brexpiprazole

Intervention Description

OPDC-34712 tablets, daily, Orally.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Matching-placebo tablets, daily, Orally.

Intervention Type

Drug

Intervention Name(s)

Stimulant Therapy

Intervention Description

Mixed amphetamine salts or Dexmethylphenidate hydrochloride (HCL) or Methylphenidate HCl or Lisdexamfetamine dimesylate as per standard of care.

Primary Outcome Measure Information:

Title

Mean Change From Baseline (End of Phase A) in the CAARS-O:SV ADHD Symptoms Total Score (18 Items) to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Secondary Outcome Measure Information:

Title

Change From Baseline (End of Phase A) in Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) Total Score to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in Sleep Improvement Measured by Insomnia Severity Index (ISI) Total Score to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in Sleep Improvement Measured by ISI for Item 2 Score (Difficulty Staying Asleep) to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in CAARS-O:SV ADHD Symptoms Total Score (18 Items) to Each Time Point in Phase B Other Than Week 11

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Weeks 6, 7, 8, 9 and 10

Title

Change From Baseline (End of Phase A) in CAARS-O:SV Inattentive Symptoms Subscale Score (9 Items) to Each Time Point in Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)]; Weeks 6, 7, 8, 9, 10 and 11

Title

Change From Baseline (End of Phase A) in CAARS-O:SV Hyperactive/Impulsive Symptoms Subscale Score (9 Items) to Each Time Point in Phase B

Description

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.

Time Frame

Baseline [end of Phase A (Week 5)]; Weeks 6, 7, 8, 9, 10 and 11

Title

Change From Baseline (End of Phase A) in CAARS-O:SV ADHD Index Score (12 Items) to Each Time Point in Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)]; Weeks 6, 7, 8, 9, 10 and 11

Title

Change From Baseline (End of Phase A) to Weeks 7 and 9 in ISI Total Score

Description

Time Frame

Baseline [end of Phase A (Week 5)]; Weeks 7 and 9

Title

Percentage of Participants With Categorical Change in Sleep Improvement Measured by Individual Scores for Items 1, 2, and 3 of the ISI at End of Phase B

Description

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.

Time Frame

Baseline [(end of Phase A (Week 5)] to Weeks 7, 9 and 11

Title

Change From Baseline (End of Phase A) in Conners' Adult ADHD Rating Scale-Self-Report: Screening Version (CAARS-S:SV) ADHD Symptoms Total Score (18 Items) to Each Timepoint in Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)]; Weeks 6, 7, 8, 9, 10 and 11

Title

Change From Baseline (End of Phase A) in CAARS-S:SV Inattentive Symptoms Subscale Score (9 Items) to Each Timepoint in Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)]; Weeks 6, 7, 8, 9, 10 and 11

Title

Change From Baseline (End of Phase A) in CAARS-S:SV Hyperactive/Impulsive Symptoms Subscale Score (9 Items) to Each Timepoint in Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)]; Weeks 6, 7, 8, 9, 10 and 11

Title

Change From Baseline (End of Phase A) in CAARS-S:SV ADHD Index Score (12 Items) to Each Timepoint in Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)]; Weeks 6, 7, 8, 9, 10 and 11

Title

Change From Baseline (End of Phase A) in Clinical Global Impression - Severity of Illness Scale (CGI-S) Score to Each Timepoint in Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)]; Weeks 6, 7, 8, 9, 10 and 11

Title

Change From Baseline (End of Phase A) in the SWM Strategy 6-8 Boxes Test Score as Measured by CANTAB to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in the SWM Within Errors 4-8 Boxes Test Score as Measured by CANTAB to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in the Rapid Visual Information Processing (RVP) A Prime Test Score as Measured by CANTAB to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in the RVP Median Response Latency Score as Measured by CANTAB to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in RVP Total False Alarms Score as Measured by CANTAB to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in the Stop Signal Task (SST) Stop Signal Reaction Time (SSRT) Score as Measured by CANTAB to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in the SST Proportion of Successful Stops Score as Measured by CANTAB to End of Phase B

Description

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in SST Median Reaction Time Score on Go Trials as Measured by CANTAB to End of Phase B

Description

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.

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in WRAADDS Attention + Organization Subscale Score to End of Phase B

Description

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.

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From End of Phase A (Week 5 Visit) to End of Phase B (Week 11 Visit) in WRAADDS Hyperactivity + Impulsivity Subscale Score to End of Phase B

Description

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.

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Change From Baseline (End of Phase A) in WRAADDS Temper + Mood Lability + Emotional Over-reactivity Subscale Score to End of Phase B

Description

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.

Time Frame

Baseline [end of Phase A (Week 5)] to Week 11

Title

Mean CGI-I Score at Each Timepoint in Phase B

Description

Time Frame

Weeks 6, 7, 8, 9, 10 and 11

Title

Percentage of Participants With CAARS-O:SV ADHD Symptoms Response Rate in Phase B

Description

Time Frame

Weeks 6, 7, 8, 9, 10 and 11

Title

Percentage of Participants With CAARS-O:SV ADHD Symptoms Remission Rate in Phase B

Description

Time Frame

Weeks 6, 7, 8, 9, 10 and 11

Title

Percentage of Participants With CAARS-S:SV ADHD Symptoms Response Rate in Phase B

Description

Time Frame

Weeks 6, 7, 8, 9, 10 and 11

Title

Percentage of Participants With CAARS-S:SV ADHD Symptoms Remission Rate in Phase B

Description

Time Frame

Weeks 6, 7, 8, 9, 10 and 11

Title

Percentage of Participants With CGI-I Response Rate in Phase B

Description

Time Frame

Weeks 6, 7, 8, 9, 10 and 11

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male and female outpatients 18 to 55 years of age, inclusive, at the time of informed consent. Participants with a primary diagnostic and statistical manual of mental disorders, fourth edition, text revision (DSM-IV-TR) diagnosis of ADHD (including inattentive, hyperactive, and combined subtypes) as confirmed by the Conners' Adult ADHD diagnostic interview (CAADID). Participants may have received prior treatment for adult ADHD, may be currently receiving treatment for adult ADHD at screening, or may be treatment-naive. Participants willing to discontinue all prohibited psychotropic medication starting from the time of signing the informed consent and during the study period. Exclusion Criteria: Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving study drug. Participants with an adequate response, as determined by the investigator, to any stimulant taken for the treatment of adult ADHD after 18 years of age. Participants with a clinically significant current Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder. Participants who participated in a clinical trial within the last 180 days or who participated in more than two clinical trials within the past year.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Study Director

Organizational Affiliation

Otsuka Pharmaceutical Development & Commercialization, Inc.

Official's Role

Study Director

Facility Information:

City

Little Rock

State/Province

Arkansas

Country

United States

City

Beverly Hills

State/Province

California

Country

United States

City

Irvine

State/Province

California

ZIP/Postal Code

92612

Country

United States

City

Pasadena

State/Province

California

Country

United States

City

San Francisco

State/Province

California

Country

United States

City

Bradenton

State/Province

Florida

Country

United States

City

Jacksonville

State/Province

Florida

Country

United States

City

Maitland

State/Province

Florida

Country

United States

City

North Miami

State/Province

Florida

Country

United States

City

Orlando

State/Province

Florida

Country

United States

City

South Miami

State/Province

Florida

ZIP/Postal Code

33173

Country

United States

City

Atlanta

State/Province

Georgia

Country

United States

City

Smyrna

State/Province

Georgia

Country

United States

City

Indianapolis

State/Province

Indiana

Country

United States

City

Overland Park

State/Province

Kansas

Country

United States

City

Rochester Hills

State/Province

Michigan

Country

United States

City

Saint Charles

State/Province

Missouri

Country

United States

City

Cherry Hill

State/Province

New Jersey

Country

United States

City

Willingboro

State/Province

New Jersey

Country

United States

City

New York

State/Province

New York

Country

United States

City

Chapel Hill

State/Province

North Carolina

Country

United States

City

Durham

State/Province

North Carolina

Country

United States

City

Cincinnati

State/Province

Ohio

Country

United States

City

Dayton

State/Province

Ohio

Country

United States

City

Oklahoma City

State/Province

Oklahoma

Country

United States

City

Portland

State/Province

Oregon

Country

United States

City

Philadelphia

State/Province

Pennsylvania

Country

United States

City

Memphis

State/Province

Tennessee

Country

United States

City

Austin

State/Province

Texas

Country

United States

City

Houston

State/Province

Texas

Country

United States

City

Salt Lake City

State/Province

Utah

Country

United States

City

Woodstock

State/Province

Vermont

Country

United States

City

Herndon

State/Province

Virginia

Country

United States

City

Bellevue

State/Province

Washington

Country

United States

City

Seattle

State/Province

Washington

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.

IPD Sharing Time Frame

Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.

IPD Sharing Access Criteria

Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

IPD Sharing URL

https://clinical-trials.otsuka.com

Learn more about this trial

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

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