Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia

Study Overview
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Brief Summary
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The purpose of this study is to compare the effectiveness, safety and tolerability of three different doses of OPC-34712 with placebo in the treatment of acute schizophrenia in adults.

Detailed Description
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Schizophrenia is a severely debilitating mental illness that affects approximately 1% of the world population. Hallucinations and delusions are the most striking characteristic positive symptoms of schizophrenia; however, more subtle negative symptoms (eg, social withdrawal and lack of emotion, energy, and motivation) may also be present. The first antipsychotics developed for the treatment of schizophrenia were effective against positive symptoms, but showed little efficacy for negative symptoms and were also associated with a high incidence of side effects. Second generation antipsychotics, represent a significant advancement in the treatment of psychotic disorders because they are effective and at the same time exhibit fewer side effects than first generation antipsychotics. Although generally safer than first generation antipsychotics, the second-generation antipsychotics are not devoid of undesirable side effects such as Hyperprolactinemia and weight gain. In addition, the safety of these drugs vary considerably.

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Three Fixed Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia

Conditions
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Acute Schizophrenia

Intervention / Treatment
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* Drug: OPC-34712 [Brexpiprazole] High Dose
* Drug: Experimental: OPC-34712 [Brexpiprazole] Middle Dose
* Drug: Experimental: OPC-34712 [Brexpiprazole] Low Dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between 18 and 65 years of age, with a diagnosis of schizophrenia, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria Subjects who have been recently hospitalized or who would benefit from hospitalization for an acute relapse of schizophrenia Subjects experiencing an acute exacerbation of psychotic symptoms Other protocol specific inclusion criteria may apply Exclusion Criteria: Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving study drug Subjects with a current DSM-IV-TR Axis I diagnosis of: Schizoaffective disorder Major depressive disorder (MDD) Bipolar disorder Delirium, dementia, amnestic or other cognitive disorder Borderline, paranoid, histrionic, schizotypal, schizoid or antisocial personality disorder Subjects presenting with a first episode of schizophrenia Other protocol specific exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OPC-34712 [Brexpiprazole] High Dose<br>Higher Dose, tablet, once daily, for six weeks | Drug: OPC-34712 [Brexpiprazole] High Dose<br>* Higher dose, tablet, once daily, for six weeks<br>|
| Experimental: OPC-34712 [Brexpiprazole] Middle Dose<br>Middle Dose, tablet, once daily, for six weeks | Drug: Experimental: OPC-34712 [Brexpiprazole] Middle Dose<br>* Middle dose, tablet, once daily, for six weeks<br>|
| Experimental: OPC-34712 [Brexpiprazole] Low Dose<br>Lower Dose, tablet, once daily, for six weeks | Drug: Experimental: OPC-34712 [Brexpiprazole] Low Dose<br>* Lower dose, tablet, once daily, for six weeks<br>|
| Placebo Comparator: Placebo<br>Placebo, once daily, for six weeks | Drug: Placebo<br>* Placebo, once daily, for six weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to Week 6 Positive and Negative Syndrome Scale (PANSS) Total Score. | The PANSS consists of 3 subscales (positive subscale, negative subscale and general psychology subscale) containing a total of 30 symptom constructs and was administered using the Structured Clinical Interview (SCI)-PANSS. 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. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome). | Baseline to Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to Week 6 in Clinical Global Impression - Severity of Illness Scale (CGI-S) Score. | The severity of illness was rated using the CGI-S which is the key secondary endpoint. To perform this assessment, the rater or study physician answered the following question: Considering your total clinical experience with this particular population, how mentally ill is the participant at this time? 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 participant. | Baseline to Week 6 | 
| Mean Change From Baseline to Week 1, 2, 3, 4 and 5 Positive and Negative Syndrome Scale (PANSS) Total Score. | The PANSS consists of 3 subscales (positive subscale, negative subscale and general psychology subscale) containing a total of 30 symptom constructs and was administered using the Structured Clinical Interview (SCI)-PANSS. 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. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome). | Baseline to Week 1, 2, 3, 4, 5 | 
| Mean Change From Baseline to Week 1, 2, 3, 4 and 5 in Clinical Global Impression - Severity of Illness Scale (CGI-S) Score. | The severity of illness was rated using the CGI-S. To perform this assessment, the rater or study physician answered the following question: Considering your total clinical experience with this particular population, how mentally ill is the participant at this time? 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 participant. | Baseline to Week 1, 2, 3, 4 and 5 | 
| Mean Change From Baseline to Week 6 in Personal and Social Performance Scale (PSP) | The PSP is a clinician-rated scale that measures 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 in each of these domains was rated as absent, mild, manifest, marked, severe, or very severe. These ratings were then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval, and the rater's judgment to determine the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 were considered to have mild functional difficulty. Scores of 31 to 70 represented manifest disabilities of various degrees and ratings of 1 to 30 indicated minimal functioning that required intense support and/or supervision. | Baseline to Week 6 | 
| Mean Change From Baseline to Week 6 in PANSS Positive Subscale Score | For each symptom construct of the PANSS Positive Subscale, 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. The symptom constructs were as follows: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS Positive Subscale Score for each participant was calculated as the sum of the rating assigned to each of the 7 subscale items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. | Baseline to Week 6 | 
| Mean Change From Baseline to Week 6 in PANSS Negative Subscale Score | For each symptom construct of the PANSS Negative Subscale, 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. The symptom constructs were as follows: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Subscale Score for each participant was calculated as the sum of the rating assigned to each of the 7 subscale items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. | Baseline to Week 6 | 
| Clinical Global Impression- Improvement Scale (CGI-I) Score at Week 6 | The participant's overall improvement was rated using the CGI-I. The rater or study physician rated the participant's total improvement whether or not it was due entirely to drug treatment. All responses were compared with the participant's condition at screening/baseline. Response choices were: 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. | Week 6 | 
| Response Rate at Week 6 | Response rate was defined as improvement in mean change of ≥30% from baseline in PANSS Total Score at Week 6 or CGI-I score of 1 (very much improved) or 2 (much improved) at Week 6. | Week 6 | 
| Mean Change From Baseline to Week 6 in PANSS Excited Component (PEC) Score | The PEC consists of 5 PANSS items (excitement [P4], hostility [P7], tension [G4], uncooperativeness [G8], and poor impulse control [G14]). Each rated on a scale of 1 (absent) to 7 (extreme). The PEC for participants was calculated as the sum of the rating assigned to each of the 5 items, and ranged from 5 to 35 with a higher score indicating greater severity of symptoms. | Baseline to Week 6 | 
| Discontinuation Rate for Lack of Efficacy at Week 6 |  | Week 6 | 
| Change From Baseline to Week 6 in PANSS Marder Factor Score - Positive Symptoms Score | The PANSS Marder Factor score - Positive Symptoms Score consists of 8 PANSS items (delusions [P1], hallucinatory behaviour [P3], grandiosity [P5], suspiciousness [P6], stereotyped thinking [N7], somatic concern [G1], unusual thought content [G9], lack of judgment and insight [G10]. Each was rated on a scale of 1 (absent) to 7 (extreme). The PANSS Marder Factor score - Positive Symptoms Score for participants was calculated as the sum of the rating assigned to each of the 8 items, and ranged from 8 to 42 with a higher score indicating greater severity of symptoms. | Baseline to Week 6 | 
| Change From Baseline to Week 6 in PANSS Marder Factor Score - Negative Symptoms Score | The PANSS Marder Factor score - Negative Symptoms Score consists of 7 PANSS items (blunted effect [N1], emotional withdrawal [N2], poor rapport [N3], passive/apathetic social withdrawal [N4], lack of spontaneity and conversation flow [N6], motor retardation [G7], active social avoidance [G16]). The PANSS Marder Factor score - Negative Symptoms Score for participants was calculated as the sum of the rating assigned to each of the 7 items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. | Baseline to Week 6 | 
| Change From Baseline to Week 6 in PANSS Marder Disorganised Thought Score | The PANSS Marder Factor score -Disorganized Thought Score consists of 7 PANSS items (conceptual disorganization [P2], difficulty in abstract thinking [N5], mannerisms and posturing [G5], disorientation [G10], poor attention [G11], disturbance of violation [G13], preoccupation [G15]). The PANSS Marder Factor score - Disorganized Thought Score for participants was calculated as the sum of the rating assigned to each of the 7 items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. | Baseline to Week 6 | 
| Change From Baseline to Week 6 in PANSS Marder Uncontrolled Hostility/Excitement Score | The PANSS Marder Factor score - Uncontrolled Hostility/Excitement Score consists of 4 PANSS items (excitement [P4], hostility [P7], uncooperativeness [G8], poor impulse control [G14]). The PANSS Marder Factor score - Uncontrolled Hostility/Excitement Score for participants was calculated as the sum of the rating assigned to each of the 4 items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. | Baseline to Week 6 | 
| Change From Baseline to Week 6 in PANSS Marder Anxiety Depression Score | The PANSS Marder Factor score - Anxiety/Depression Score consists of 4 PANSS items (anxiety [G2], guilt feelings [G3], tension [G4], depression [G6]). The PANSS Marder Factor score - Anxiety/Depression Score for participants was calculated as the sum of the rating assigned to each of the 4 items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. | Baseline to Week 6 |