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Monotherapy Brexpiprazole (OPC-34712) Trial in the Treatment of Adults With Schizophrenia With Impulsivity

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ClinicalTrials.gov Identifier: NCT02194933
Recruitment Status : Completed
First Posted : July 21, 2014
Results First Posted : September 11, 2018
Last Update Posted : September 11, 2018
Sponsor:
Collaborator:
Otsuka Pharmaceutical Co., Ltd.
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Brief Summary:
The purpose of this study is to evaluate the effect of brexpiprazole, via functional magnetic resonance imaging (fMRI), on the right ventrolateral prefrontal cortex (VLPFC) activated by impulsive behavior.

Condition or disease Intervention/treatment Phase
Schizophrenia With Impulsivity Drug: Brexpiprazole Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Protocol 331-13-009: An Exploratory, Multicenter, Randomized, Double-Blind, fMRI Study of Fixed-dose Brexpiprazole (OPC-34712) (2 and 4 mg/Day Tablets) in Adults With Schizophrenia With Impulsivity
Study Start Date : February 2015
Actual Primary Completion Date : April 2016
Actual Study Completion Date : April 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: Brexpiprazole 2 mg
Brexpiprazole 2 mg/day, once daily dose, tablet, orally
Drug: Brexpiprazole
Brexpiprazole 2 mg/day, once daily dose, tablet, orally, for 6 weeks - Brexpiprazole 4 mg/day, once daily dose, tablet, orally, for 6 weeks
Other Name: OPC-34712

Experimental: Brexpiprazole 4 mg
Brexpiprazole 4 mg/day, once daily dose, tablet, orally
Drug: Brexpiprazole
Brexpiprazole 2 mg/day, once daily dose, tablet, orally, for 6 weeks - Brexpiprazole 4 mg/day, once daily dose, tablet, orally, for 6 weeks
Other Name: OPC-34712




Primary Outcome Measures :
  1. Change From Baseline Brain Activation in the Ventrolateral Prefrontal Cortex (VLPFC) Based on Change From Baseline to Week 6 in fMRI Blood Oxygen-level Dependent (BOLD) Activation Score in the Right VLPFC During Performance of the Go/No-go Task [ Time Frame: At baseline (Day 0), and week 6 (Day 42) of the treatment phase ]
    To evaluate the effect of brexpiprazole on brain regions activated by impulsive behavior (specifically, activation of the right VLPFC). Assessed by fMRI measurements taken when participants perform tasks designed to assess impulsivity. The tasks to be performed in the scanner included the Go/No-go. Participants were asked to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) & to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The Go trials were presented at a higher frequency (eg, 75% of the time) than the No-go trials to build up a pre-potent response/response bias. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity.

  2. Change From Baseline Brain Activation in the VLPFC Based on Change From Baseline to Week 6 in fMRI BOLD Activation Score in the Right VLPFC During Performance of the SSRT Task [ Time Frame: At baseline (Day 0), and week 6 (Day 42) of the treatment phase ]
    To evaluate the effect of brexpiprazole on brain regions activated by impulsive behavior (specifically, activation of the right VLPFC). Assessed by fMRI measurements taken when participants performed impulsivity assessment tasks. A white circle was shown for 500ms, followed by a left (<)/right (>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity.


Secondary Outcome Measures :
  1. Change From Baseline to Week 3 in fMRI BOLD Activation Score in the Right VLPFC, Scanned by fMRI During Performance of Tasks Associated With Impulsivity (SSRT Task, Go/No-go Task) [ Time Frame: At baseline (Day 0), and week 3 (Day 21) of the treatment phase ]

    Go/No-go: Participants were to press button fast to Stimulus A (neutral face) (Go trials) & to NOT press button to Stimulus B (happy face) (No-go trials). Task comprised 4 runs of 3 minutes & 8 seconds each. Each run included 36 target (Go) & 13 non target (No-go) stimuli. The stimuli were presented for 500ms with 2 to 14.5 inter-stimulus interval fixation cross in between. Target stimuli were pseudo-randomized across runs so that each participant was presented with 2 Happy Go & 2 Neutral Go conditions.

    SSRT: White circle was shown for 500ms, followed by left (<)/right (>) arrow. When an arrow was presented, participants were to respond fast with their index/middle finger. A titration procedure with 4 staircases that started with stop signal delay (SSD) values of 100, 150, 200 & 250ms determined participant's SSRT.

    Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity.


  2. Change From Baseline to Week 6 in Barratt Impulsiveness Scale (BIS-11) [ Time Frame: At baseline (Day 0), and Week 6 (Day 42) of the treatment. ]
    A subject-rated scale was used to assess impulsive personality traits. The BIS-11 consisted of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/ always) and the scores were used to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance and cognitive instability impulsiveness) and 3 second-order factors ( motor impulsiveness, nonplanning impulsiveness and attentional impulsiveness). The total score ranged from 30 to 120 and took 10 to 15 minutes to complete the BIS-11.

  3. Change From Baseline to Week 3 in BIS-11 [ Time Frame: At baseline (Day 0), and Week 3 (Day 21) of the treatment. ]
    A subject-rated scale was used to assess impulsive personality traits. The BIS-11 consisted of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/ always) and the scores were used to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance and cognitive instability impulsiveness) and 3 second-order factors ( motor impulsiveness, nonplanning impulsiveness and attentional impulsiveness). The total score ranged from 30 to 120 and took 10 to 15 minutes to complete the BIS-11.

  4. Change From Baseline to Week 6 in Go/No-go Task Behavior [ Time Frame: At baseline (Day 0), week 6 (Day 42) of the treatment phase ]
    Brexpiprazole reduced impulsivity was measured by a change in false alarm rate on the Go/No-go task (a lower false alarm rate was suggestive of better inhibition).

  5. Change From Baseline to Week 3 in Go/No-go Task Behavior [ Time Frame: At baseline (Day 0), and week 3 (Day 21) of the treatment phase ]
    Brexpiprazole reduced impulsivity was measured by a change in false alarm rate on the Go/No-go task (a lower false alarm rate was suggestive of better inhibition).

  6. Change From Baseline to Week 6 in Monetary Choice Questionnaire (MCQ) Score [ Time Frame: During trial visits from Day 0 to Week 6 (Day 42). ]

    To measure "delay discounting" as an index of impulsive behavior. It measured the extent to which the value of a reward decreased as the delay to obtaining that reward increased. The propensity of participants to delay reward was assessed with an MCQ. Discounting rate is estimated using, k= (A/V)1/D, where k is the discounting rate parameter, V is the immediate reward, A is the higher delayed reward and D is the amount of days to the delayed reward. The MCQ consisted of 27 choices between immediate and delayed rewards. The participants chose repeatedly between 2 hypothetical sums of money: a smaller amount now or a larger amount in the future (ex: ''Would you prefer $27 today or $50 in 21 days?"). The answers provided an estimate of the subject's discounting rate, higher discounting rates indicated impulsivity.

    It took 5 to10 minutes to complete the MCQ


  7. Change From Baseline to Week 3 in MCQ Score [ Time Frame: During trial visits from Day 0 to Week 3 (Day 21). ]
    To measure "delay discounting" as an index of impulsive behavior. It measured the extent to which the value of a reward decreased as the delay to obtaining that reward increased. The propensity of participants to delay reward was assessed with an MCQ. Discounting rate is estimated using, k= (A/V)1/D, where k is the discounting rate parameter, V is the immediate reward, A is the higher delayed reward and D is the amount of days to the delayed reward. The MCQ consisted of 27 choices between immediate and delayed rewards. The participants chose repeatedly between 2 hypothetical sums of money: a smaller amount now or a larger amount in the future (ex: ''Would you prefer $27 today or $50 in 21 days?"). The answers provided an estimate of the subject's discounting rate, higher discounting rates indicated impulsivity.

  8. Change From Baseline to Week 6 in Stop Signal Reaction Time Task (SSRT) Task Behavior [ Time Frame: At baseline (Day 0), and Week 6 (Day 42). ]
    Brexpiprazole reduced impulsivity was measured by a change in Stop Signal Reaction Time (SSRT) on the SSRT task (a lower SSRT was suggestive of better inhibition). A white circle was shown for 500ms, followed by a left (<)/right (>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. During scanning, the SSD was dynamically adjusted to yield a 50% successful inhibition rate, so that SSRT could be estimated for each participant. This resulted in approximately equal proportions of stop trials with & without a response

  9. Change From Baseline to Week 3 in SSRT Task Behavior [ Time Frame: During trial visits from Day 0 to Week 3 (Day 21). ]
    Brexpiprazole reduced impulsivity was measured by a change in Stop Signal Reaction Time (SSRT) on the SSRT task (a lower SSRT was suggestive of better inhibition). A white circle was shown for 500ms, followed by a left (<)/right (>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. During scanning, the SSD was dynamically adjusted to yield a 50% successful inhibition rate, so that SSRT could be estimated for each participant. This resulted in approximately equal proportions of stop trials with & without a response

  10. Change From Baseline to Week 6 in Continuous Performance Task (CPT) Behavior [ Time Frame: During trial visits from Day 0 to Week 6 (Day 42). ]
    The AX trials were "target trials" with a valid cue, A followed by a valid probe, X. This feature was intended to encourage participants to "expect" a valid probe to follow a valid cue. A consequence of this manipulation was that participants developed a prepotency to respond with "target" responses on trials for which valid cues were presented. The cue was presented for 1000msec (with a target or nontarget response expected), the inter-stimulus interval was 2000msec, and the target was presented for 500msec with a response window of 1500msec. The ITI was 1200msec. Practice trials were embedded in the task, along with instructions. Participants had to practice until criteria were obtained. The value calculated was the rate of correct response for all the reaction of target trial.

  11. Change From Baseline to Week 3 in CPT Behavior [ Time Frame: During trial visits from Day 0 to Week 3 (Day 21). ]
    The AX trials were "target trials" with a valid cue, A followed by a valid probe, X. This feature was intended to encourage participants to "expect" a valid probe to follow a valid cue. A consequence of this manipulation was that participants developed a prepotency to respond with "target" responses on trials for which valid cues were presented. The cue was presented for 1000msec (with a target or nontarget response expected), the inter-stimulus interval was 2000msec, and the target was presented for 500msec with a response window of 1500msec. The ITI was 1200msec. Practice trials were embedded in the task, along with instructions. Participants had to practice until criteria were obtained. The value calculated was the rate of correct response for all the reaction of target trial.

  12. Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score [ Time Frame: During trial visits from Day 0 to Week 6 (Day 42). ]
    The PANSS consisted of 3 subscales containing 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. PANSS Positive and Negative subscale scores symptom constructs consisted of positive subscale (7 positive symptom constructs), negative subscale (7 negative symptom constructs), and general psychopathology subscale (16 symptom constructs). The possible maximum PANSS total score was 210; 30 indicating no symptoms; 210 indicating extremely severe symptoms.

  13. Change From Baseline to Week 3 in PANSS Total Score [ Time Frame: During trial visits from Day 0 to Week 3 (Day 21). ]
    The PANSS consisted of 3 subscales containing 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. PANSS Positive and Negative subscale scores symptom constructs consisted of positive subscale (7 positive symptom constructs), negative subscale (7 negative symptom constructs), and general psychopathology subscale (16 symptom constructs). The possible maximum PANSS total score was 210; 30 indicating no symptoms; 210 indicating extremely severe symptoms.

  14. Change From Baseline to Week 6 in PANSS Positive Subscale Score [ Time Frame: During trial visits from Day 0 to Week 6 (Day 42). ]
    PANSS consisted of positive subscales with 7 symptom constructs (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity.

  15. Change From Baseline to Week 3 in PANSS Positive Subscale Score [ Time Frame: During trial visits from Day 0 to Week 3 (Day 21). ]
    PANSS consisted of positive subscales with 7 symptom constructs (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity.

  16. Change From Baseline to Week 6 in PANSS Negative Subscale Score [ Time Frame: During trial visits from Day 0 to Week 6 (Day 42). ]
    PANSS consisted of negative subscale with 7 symptom constructs (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity.

  17. Change From Baseline to Week 3 in PANSS Negative Subscale Score [ Time Frame: During trial visits from Day 0 to Week 3 (Day 21). ]
    PANSS consisted of negative subscale with 7 symptom constructs (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity.

  18. Change From Baseline to Week 6 in Clinical Global Impression - Severity of Illness Scale (CGI-S) Score [ Time Frame: During trial visits from Day 0 to Week 6 (Day 42). ]
    The severity of illness for each subject was assessed. The rater or investigator's response choices included: 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 subjects.

  19. Change From Baseline to Week 3 in CGI-S Score [ Time Frame: During trial visits from Day 0 to Week 3 (Day 21). ]
    The severity of illness for each subject was assessed. The rater or investigator's response choices included: 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 subjects.

  20. Clinical Global Impression - Improvement Scale (CGI-I) Score at Week 6 [ Time Frame: During trial visits from Day 0 to Week 6 (Day 42). ]
    To assess whether the total improvement was entirely due to drug treatment. The rater or investigator's response choices included: 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 response at a given week was compared to the subject's condition at baseline (last available measurement at the baseline/Day 0 visit before the first dose of IMP).

  21. CGI-I Score at Week 3 [ Time Frame: During trial visits from Day 0 to Week 3 (Day 21). ]
    To assess whether the total improvement was entirely due to drug treatment. The rater or investigator's response choices included: 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 response at a given week was compared to the subject's condition at baseline (last available measurement at the baseline/Day 0 visit before the first dose of IMP).

  22. Change From Baseline to Week 6 in Personal and Social Performance Scale (PSP) [ Time Frame: During trial visits from Day 0 to Week 6 (Day 42). ]
    A validated clinician-rated scale that measured personal and social functioning in 4 domains: socially useful activities (eg, work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment was rated as absent, mild, manifest, marked, severe, or very severe and were converted to a total score on a 100-point scale: 71 to 100 - mild functional difficulty, 31 to 70 - manifest disabilities of various degrees and 1 to 30 - minimal functioning that required intense support and/or supervision.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Are 18 to 65 years of age, inclusive, at the time of informed consent (outpatients only), with a diagnosis of schizophrenia as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria and confirmed by both the M.I.N.I. for Schizophrenia and Psychotic Disorders Studies, and an adequate clinical psychiatric evaluation.
  • Have a CGI-S score of ≤ 4 (moderately ill) at screening and baseline.
  • Have a score of ≤ 4 (moderate) on PANSS item G8 (uncooperativeness) at screening and baseline.
  • Have a BIS-11 score of ≥ 50 at screening and baseline.
  • Willing to discontinue all prohibited psychotropic medications to meet protocol-required washouts prior to and during the trial period.
  • Are stable on their current oral antipsychotic medication (no changes within the last month) and are able to meet protocol-required washouts of their current antipsychotic medication.
  • Have received previous outpatient antipsychotic treatment at an adequate dose (at least minimal recommended dose for the treatment of schizophrenia according to the manufacturer labeling) for an adequate duration (at least 6 weeks) and showed a previous good response to such antipsychotic treatment (other than clozapine) in the last 12 months, according to the investigator's opinion.
  • Subjects with eyesight that is sufficient to be able to see visual displays, or correctable with magnet-compatible glasses or contact lenses.
  • Subjects fluent in English

Exclusion Criteria:

  • Are presenting with schizophreniform or with a first episode of schizophrenia based on the clinical judgment of the investigator.
  • Have been hospitalized for psychotic symptoms within the previous 6 months.
  • Have a current DSM-IV-TR Axis I primary diagnosis other than schizophrenia, including, but not limited to, schizoaffective disorder, major depressive disorder, bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder (OCD) or panic disorder, delirium, dementia, amnestic, or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, antisocial personality disorders, or mental retardation.
  • Have worsening of ≥ 20% in total PANSS score between the screening and baseline assessments.
  • Experiencing a deterioration in clinical status or an acute exacerbation of schizophrenia in the opinion of the Investigator.
  • Experiencing acute onset of clinically significant depressive symptoms within the past 30 days, according to the investigator's opinion.
  • Answer "Yes" on the Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) and whose most recent episode meeting criteria for this C-SSRS Item 4 occurred within the last 6 months, OR Answer "Yes" on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) and whose most recent episode meeting criteria for this C-SSRS Item 5 occurred within the last 6 months OR Answer "Yes" on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent episode meeting criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred within the last 2 years, OR who, in the opinion of the investigator, present a serious risk of suicide.
  • Have a history of stroke.
  • Contraindications to magnetic resonance imaging (MRI) such as metal prostheses, pacemakers, claustrophobia, movement disorders, waist circumference more than 56 inches or head circumference more than 29 inches, color blindness, significant tremors, or history of head injury or prolonged unconsciousness

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02194933


Locations
United States, California
University of California at Irvine Medical Center
Orange, California, United States, 92868
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Otsuka Pharmaceutical Co., Ltd.

Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT02194933     History of Changes
Other Study ID Numbers: 331-13-009
First Posted: July 21, 2014    Key Record Dates
Results First Posted: September 11, 2018
Last Update Posted: September 11, 2018
Last Verified: August 2018

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Schizophrenia
Mental Disorders, Antipsychotic,
Psychotic disorder, Impulsivity

Additional relevant MeSH terms:
Schizophrenia
Impulsive Behavior
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Brexpiprazole
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Dopamine Agonists
Dopamine Agents