Acute Schizophrenia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy of brexpiprazole compared with placebo as maintenance treatment in adults with schizophrenia.
Detailed description
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.
Interventions
DRUGBrexpiprazole
Brexpiprazole tablets 1 to 4 mg /day
DRUGPlacebo
Placebo comparator for 52 weeks
Sponsors
Quintiles, Inc.
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients age 18 years or older to less than 65 years, inclusive (at time of informed consent) * Subjects with a current diagnosis of schizophrenia, as defined by DSM-IV-TR criteria and a history of the illness for at least three years prior to screening (as per subject, family, healthcare provider, or by previous medical records). * Subjects with a stable living environment, as demonstrated by the ability to provide contact information for themselves and/or family/friend(s)/caregiver(s). * Subjects who showed previous response to antipsychotic treatment in the past year. * Subjects who are currently treated with oral or depot antipsychotics other than clozapine or who have had a recent lapse in antipsychotic treatment requiring chronic treatment with antipsychotic medication for stabilization. * Subjects who are experiencing a current acute exacerbation of psychotic symptoms requiring stabilization * Subjects with a history of relapse and/or exacerbation of symptoms when they are not receiving antipsychotic treatment.
Exclusion criteria
* Female patients who are breastfeeding or who have a positive pregnancy test (urine) result prior to receiving investigational medicinal product * Patients presenting a first episode of schizophrenia based on the clinical judgment of the investigator * Patients who are diagnosed with a disease other than schizophrenia (schizoaffective disorder, major depressive disorder, bipolar disorder, posttraumatic stress disorder, anxiety disorder, delirium, dementia, amnesia, or other cognitive disorder) based on current DSM-IV-TR Axis Ι criteria, or who are diagnosed with a personality disorder (borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial) * Subjects experiencing acute depressive symptoms within the past 30 days * Subjects with schizophrenia who are considered resistant/refractory to antipsychotic treatment by history * Subjects with a significant risk of violent behavior; who represent a risk of committing suicide * Subjects with clinically significant tardive dyskinesia * Subjects currently treated with insulin for diabetes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to Exacerbation of Psychotic Symptoms/Impending Relapse in Phase C. | From randomization to time of exacerbation of psychotic symptoms/impending relapse - up to 52 weeks | The primary efficacy variable was time to impending relapse from randomization, as assessed by Clinical Global Impression of Improvement (CGI-I) score ≥5, Positive and Negative Syndrome Scale (PANSS) scores for hostility or uncooperativeness ≥5, or ≥20% increase in PANSS Total Score. Impending relapse was defined as meeting any of the following 5 criteria: 1) CGI-I score of ≥ 5 (minimally worse) and increase in individual PANSS items to a score \>4 with an absolute increase of ≥ 2 on that specific item or absolute increase of ≥ 4 on the combined 4 PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content).OR 2) CGI-I score of 6 or 7 (much or very much worse) OR 3) Hospitalization due to worsening of illness OR 4) Any suicidal behavior or answers of yes to Questions 4 or 5 on the suicidal ideation section of the C-SSRS OR 5) Violent or aggressive behavior resulting in clinically significant injury.The measure type, number is Hazard Ratio. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria in the Double-blind Maintenance Phase | Baseline and Week 52/Early Termination | Impending relapse was defined as meeting any of the following 5 criteria: 1) CGI-I score of ≥ 5 (minimally worse) and increase in individual PANSS items to a score \> 4 with an absolute increase of ≥ 2 on that specific item or an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual though content) to a score of \>4 and an absolute increase of ≥ 4 on the combined 4 PANSS items. OR 2) CGI-I score of 6 or 7 (much or very much worse) OR 3) Hospitalization due to worsening of illness OR 4) Current suicidal behavior as assessed by the C-SSRS (ie, an answer of yes to any of the questions on the suicidal behavior section of the C-SSRS 5) Violent or aggressive behavior resulting in clinically significant self-injury to another person, or property damage. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome). |
| Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome). |
| Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome). |
| Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome). |
| Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome). |
| Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Baseline, Weeks 6, 12, 24, 36 and 52 | The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the 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 ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. |
| Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the 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 ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. |
| Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Weeks 6, 12, 24, 36 and 52 | The rater or investigator would rate the participant's total improvement whether or not it is due entirely to study treatment. During Phase B, responses were compared to the participant's condition at Baseline of Phase B (for participants who entered Phase B directly after screening) or to the End of Phase A visit (for participants who participated in Phase A). During Phase C, responses were compared to the participant's condition at the End of Phase B visit. Response choices include: 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. |
| Mean Change From Baseline in Personal and Social Performance (PSP) Scale Score - MMRM Analysis | Baseline and Weeks 24 and 52 | The PSP is a validated clinician-rated scale that measures personal and social functioning in four domains: socially useful activities (e.g., work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains is rated as absent, mild, manifest, marked, severe, or very severe. These ratings are 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 are considered to have mild functional difficulty. Scores of 31 to 70 represent manifest disabilities of various degrees and ratings of 1 to 30 indicate minimal functioning that requires intense support and/or supervision.The PSP score ranges from 0 to 100, with higher scores indicating higher levels of social functioning. |
| Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The disorganized thoughts factor score is the sum of score from the 7 items on the disorganized thoughts subscale (range: 7 - best possible outcome to 49 - worst possible outcome). |
| Mean Change From Baseline in PSP Scale Score - LOCF Analysis | Baseline and Weeks 24 and 52 | The PSP is a validated clinician-rated scale that measures personal and social functioning in four domains: socially useful activities (e.g., work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains is rated as absent, mild, manifest, marked, severe, or very severe. These ratings are 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 are considered to have mild functional difficulty. Scores of 31 to 70 represent manifest disabilities of various degrees and ratings of 1 to 30 indicate minimal functioning that requires intense support and/or supervision.The PSP score ranges from 0 to 100, with higher scores indicating higher levels of social functioning. |
| Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis | Baseline and Weeks 12, 24, 36 and 52 | The GAF is a clinician-rated scale that assesses the participant's psychological, social, and occupational functioning on a hypothetical continuum of mental health-illness using a scale that ranges from 1 to 100 score, where lower values indicate worst outcome. From among 10 descriptive anchors, investigators will choose the anchor which is the most representative of the participant's level of functioning at the time of the assessment and will assign a single score within the point range given for the selected anchor. |
| Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Weeks 6, 12, 24, 36 and 52 | Participants were assessed for stability using the following criteria:1) Outpatient status AND 2) Positive and Negative Syndrome Scale (PANSS) Total Score ≤ 70 AND 3) A score of ≤ 4 (moderate) on each of the following PANSS items (possible scores of 1 to 7 for each item): conceptual disorganization, suspiciousness hallucinatory behavior, unusual thought content, AND 4) Clinical Global Impression - Severity of Illness scale(CGI-S) score ≤ 4 (moderately ill) AND 5) No current suicidal behavior as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), defined as the following: An answer of no to each question on the Suicidal Behavior section of the C-SSRS AND an answer of no to Questions 4 and 5 on the Suicidal Ideation section of the C-SSRS, if completed, AND 6) No evidence of aggressive or violent behavior resulting in clinically significant self-injury, injury to another person, property damage. |
| Percentage of Participants Who Discontinued Due to All Causes | Baseline to Week 52 | Analysis of the percentage of participants who discontinued due to all causes was based on all participants who have been randomized and taken one dose of IMP in the Double-blind Maintenance phase. The trial was completed by sponsor when efficacy was demonstrated at the first pre-specified interim analysis (45 impending relapse events) performed by an independent (unblinded) statistician. |
| Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | The PEC score consisted of five PANSS items: excitement (P4), hostility (P7), tension (G4), uncooperativeness (G8), and poor impulse control (G14). Each of the items were rated on a scale of 1 (absent) to 7 (extreme). The PEC scores ranged from 5 (not present) to 35 (extremely severe). |
| Mean Change From Baseline in PEC Score - LOCF Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | The PEC score consisted of five PANSS items: excitement (P4), hostility (P7), tension (G4), uncooperativeness (G8), and poor impulse control (G14). Each of the items were rated on a scale of 1 (absent) to 7 (extreme). The PEC scores ranged from 5 (not present) to 35 (extremely severe). |
| Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The positive factor score is the sum of the 8 components of the positive symptoms scale (range: 8 - best possible outcome to 56 - worst possible outcome). |
| Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The positive factor score is the sum of the 8 components of the positive symptoms scale (range: 8 - best possible outcome to 56 - worst possible outcome). |
| Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The negative factor score is the sum of the 7 items of the negative subscale (range: 8 - best possible outcome to 56 - worst possible outcome). |
| Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The negative factor score is the sum of the 7 items of the negative subscale (range: 8 - best possible outcome to 56 - worst possible outcome). |
| Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The disorganized thoughts factor score is the sum of score from the 7 items on the disorganized thoughts subscale (range: 7 - best possible outcome to 49 - worst possible outcome). |
| Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The uncontrolled hostility/excitement factor score is the sum of score from the 4 items on the uncontrolled hostility/excitement subscale (range: 4 - best possible outcome to 28 - worst possible outcome). |
| Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The uncontrolled hostility/excitement factor score is the sum of score from the 4 items on the uncontrolled hostility/excitement subscale (range: 4 - best possible outcome to 28 - worst possible outcome). |
| Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The anxiety/depression factor score is the sum of score from the 4 items on the anxiety/depression subscale (range: 4 - best possible outcome to 28 - worst possible outcome). |
| Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The anxiety/depression factor score is the sum of score from the 4 items on the anxiety/depression subscale (range: 4 - best possible outcome to 28 - worst possible outcome). |
| Mean Change From Baseline in GAF Scale Score - LOCF Analysis | Baseline and Weeks 12, 24, 36 and 52 | The GAF is a clinician-rated scale that assesses the participant's psychological, social, and occupational functioning on a hypothetical continuum of mental health-illness using a scale that ranges from 1 to 100 score, where lower values indicate worst outcome. From among 10 descriptive anchors, investigators will choose the anchor which is the most representative of the participant's level of functioning at the time of the assessment and will assign a single score within the point range given for the selected anchor. |
| Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Baseline and Weeks 6, 12, 24, 36 and 52 | The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome). |
Countries
Colombia, Malaysia, Puerto Rico, Romania, Serbia, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
A total of 753 participants were screened at 49 trial sites in the following 7 countries: United States (US, including Puerto Rico), Malaysia, Colombia, Romania, Ukraine, Serbia, and Turkey.
Pre-assignment details
Trial had Phase A (Conversion) (N= 406), Phase B (Oral Stabilization) (N= 464; 346 rolled over from Phase A and 118 entered directly into Phase B ) and Phase C (Double-Blind Maintenance) with (N= 202 rolled over from Phase B). Participants were randomized in to Phase C in a 1:1 ratio (brexpiprazole:placebo) to receive treatment for up to 52 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Participants received maintenance treatment daily with brexpiprazole (at the final dose achieved during the stabilization phase) for up to 52 weeks. | 97 |
| Phase C - Placebo (Double-Blind Maintenance Phase) Participants received placebo orally once daily for 52 weeks. | 105 |
| Total | 202 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase A (Conversion Phase) | Adverse Event Without Impending Relapse | 8 | 0 | 0 | 0 |
| Phase A (Conversion Phase) | Lack of Efficacy | 7 | 0 | 0 | 0 |
| Phase A (Conversion Phase) | Lost to Follow-up | 3 | 0 | 0 | 0 |
| Phase A (Conversion Phase) | Met Withdrawal Criteria | 3 | 0 | 0 | 0 |
| Phase A (Conversion Phase) | Physician Decision | 2 | 0 | 0 | 0 |
| Phase A (Conversion Phase) | Protocol Violation | 2 | 0 | 0 | 0 |
| Phase A (Conversion Phase) | Terminated Study on Interim Analysis | 19 | 0 | 0 | 0 |
| Phase A (Conversion Phase) | Withdrawal by Subject | 16 | 0 | 0 | 0 |
| Phase B (Stabilization Phase) | Adverse Event Without Impending Relapse | 0 | 43 | 0 | 0 |
| Phase B (Stabilization Phase) | Lack of Efficacy | 0 | 21 | 0 | 0 |
| Phase B (Stabilization Phase) | Lost to Follow-up | 0 | 16 | 0 | 0 |
| Phase B (Stabilization Phase) | Met Withdrawal Criteria | 0 | 22 | 0 | 0 |
| Phase B (Stabilization Phase) | Physician Decision | 0 | 11 | 0 | 0 |
| Phase B (Stabilization Phase) | Protocol Violation | 0 | 3 | 0 | 0 |
| Phase B (Stabilization Phase) | Terminated Study on Interim Analysis | 0 | 86 | 0 | 0 |
| Phase B (Stabilization Phase) | Withdrawal by Subject | 0 | 60 | 0 | 0 |
| Phase C (Double-Blind Maintenance Phase) | Adverse Event Without Impending Relapse | 0 | 0 | 4 | 2 |
| Phase C (Double-Blind Maintenance Phase) | Lack of Efficacy | 0 | 0 | 2 | 10 |
| Phase C (Double-Blind Maintenance Phase) | Lack of Efficacy without AE | 0 | 0 | 11 | 30 |
| Phase C (Double-Blind Maintenance Phase) | Lost to Follow-up | 0 | 0 | 4 | 6 |
| Phase C (Double-Blind Maintenance Phase) | Met Withdrawal Criteria | 0 | 0 | 3 | 3 |
| Phase C (Double-Blind Maintenance Phase) | Physician Decision | 0 | 0 | 5 | 2 |
| Phase C (Double-Blind Maintenance Phase) | Protocol Violation | 0 | 0 | 2 | 0 |
| Phase C (Double-Blind Maintenance Phase) | Terminated Study on Interim Analysis | 0 | 0 | 49 | 38 |
| Phase C (Double-Blind Maintenance Phase) | Withdrawal by Subject | 0 | 0 | 3 | 5 |
Baseline characteristics
| Characteristic | Phase C - Brexpiprazole (Double-Blind Maintenance Phase) | Phase C - Placebo (Double-Blind Maintenance Phase) | Total |
|---|---|---|---|
| Age, Continuous | 38.8 years STANDARD_DEVIATION 10.7 | 41.6 years STANDARD_DEVIATION 10.6 | 40.2 years STANDARD_DEVIATION 10.7 |
| Gender Female | 39 Participants | 40 Participants | 79 Participants |
| Gender Male | 58 Participants | 65 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 148 / 464 | 0 / 97 | 0 / 104 |
| serious Total, serious adverse events | 34 / 464 | 3 / 97 | 11 / 104 |
Outcome results
Primary
Time From Randomization to Exacerbation of Psychotic Symptoms/Impending Relapse in Phase C.
The primary efficacy variable was time to impending relapse from randomization, as assessed by Clinical Global Impression of Improvement (CGI-I) score ≥5, Positive and Negative Syndrome Scale (PANSS) scores for hostility or uncooperativeness ≥5, or ≥20% increase in PANSS Total Score. Impending relapse was defined as meeting any of the following 5 criteria: 1) CGI-I score of ≥ 5 (minimally worse) and increase in individual PANSS items to a score \>4 with an absolute increase of ≥ 2 on that specific item or absolute increase of ≥ 4 on the combined 4 PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content).OR 2) CGI-I score of 6 or 7 (much or very much worse) OR 3) Hospitalization due to worsening of illness OR 4) Any suicidal behavior or answers of yes to Questions 4 or 5 on the suicidal ideation section of the C-SSRS OR 5) Violent or aggressive behavior resulting in clinically significant injury.The measure type, number is Hazard Ratio.
Time frame: From randomization to time of exacerbation of psychotic symptoms/impending relapse - up to 52 weeks
Population: Based on the Intent-to-Treat (ITT) principle, the full analysis set of this trial was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brexpiprazole | Time From Randomization to Exacerbation of Psychotic Symptoms/Impending Relapse in Phase C. | 0.292 Days |
| Placebo | Time From Randomization to Exacerbation of Psychotic Symptoms/Impending Relapse in Phase C. | 3.420 Days |
Comparison: The total number of exacerbation of psychotic symptoms/impending relapse was estimated using a 1:1 (brexpiprazole:placebo) randomization ratio.p-value: <0.0001Log Rank
Secondary
Percentage of Participants Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria in the Double-blind Maintenance Phase
Impending relapse was defined as meeting any of the following 5 criteria: 1) CGI-I score of ≥ 5 (minimally worse) and increase in individual PANSS items to a score \> 4 with an absolute increase of ≥ 2 on that specific item or an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual though content) to a score of \>4 and an absolute increase of ≥ 4 on the combined 4 PANSS items. OR 2) CGI-I score of 6 or 7 (much or very much worse) OR 3) Hospitalization due to worsening of illness OR 4) Current suicidal behavior as assessed by the C-SSRS (ie, an answer of yes to any of the questions on the suicidal behavior section of the C-SSRS 5) Violent or aggressive behavior resulting in clinically significant self-injury to another person, or property damage.
Time frame: Baseline and Week 52/Early Termination
Population: Based on ITT principle, the full analysis set of this trial was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brexpiprazole | Percentage of Participants Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria in the Double-blind Maintenance Phase | 13.54 percentage of participants |
| Placebo | Percentage of Participants Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria in the Double-blind Maintenance Phase | 38.46 percentage of participants |
Comparison: The percentage of participants with impending relapse in treatment groups (Brexpiprazole and placebo) in final analysis for participants meeting at least one of the criteria.p-value: <0.0001Chi-squared
Other Pre-specified
Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis
The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the 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 ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 12 | -0.04 Units on a scale | Standard Error 0.11 |
| Brexpiprazole | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 36 | -0.00 Units on a scale | Standard Error 0.11 |
| Brexpiprazole | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 24 | -0.03 Units on a scale | Standard Error 0.11 |
| Brexpiprazole | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 52 | 0.02 Units on a scale | Standard Error 0.11 |
| Brexpiprazole | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 6 | -0.08 Units on a scale | Standard Error 0.09 |
| Placebo | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 52 | 0.55 Units on a scale | Standard Error 0.11 |
| Placebo | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 6 | 0.17 Units on a scale | Standard Error 0.09 |
| Placebo | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 12 | 0.32 Units on a scale | Standard Error 0.1 |
| Placebo | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 24 | 0.47 Units on a scale | Standard Error 0.1 |
| Placebo | Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis | Week 36 | 0.56 Units on a scale | Standard Error 0.1 |
Comparison: Statistical analysis at Week 6.p-value: 0.028495% CI: [-0.47, -0.03]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.005695% CI: [-0.62, -0.11]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.000295% CI: [-0.76, -0.24]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: <0.000195% CI: [-0.82, -0.3]ANCOVA
Comparison: Statistical analysis at Week 52p-value: 0.000295% CI: [-0.79, -0.26]ANCOVA
Other Pre-specified
Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis
The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the 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 ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
Time frame: Baseline, Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 12 (N= 73, 68) | -0.01 Units on a scale | Standard Error 0.11 |
| Brexpiprazole | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 36 (N= 33, 24) | -0.31 Units on a scale | Standard Error 0.11 |
| Brexpiprazole | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 24 (N= 50, 36) | -0.16 Units on a scale | Standard Error 0.1 |
| Brexpiprazole | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 52 (N= 15, 9) | -0.23 Units on a scale | Standard Error 0.17 |
| Brexpiprazole | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 6 (N= 81, 84) | -0.01 Units on a scale | Standard Error 0.09 |
| Placebo | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 52 (N= 15, 9) | 0.28 Units on a scale | Standard Error 0.22 |
| Placebo | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 6 (N= 81, 84) | 0.26 Units on a scale | Standard Error 0.09 |
| Placebo | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 12 (N= 73, 68) | 0.37 Units on a scale | Standard Error 0.11 |
| Placebo | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 24 (N= 50, 36) | 0.21 Units on a scale | Standard Error 0.1 |
| Placebo | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis | Week 36 (N= 33, 24) | 0.25 Units on a scale | Standard Error 0.12 |
Comparison: Statistical analysis at Week 6.p-value: 0.027995% CI: [-0.53, -0.03]Mixed Models Analysis
Comparison: Statistical analysis at Week 12.p-value: 0.011795% CI: [-0.68, -0.09]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.010595% CI: [-0.64, -0.09]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.000795% CI: [-0.87, -0.25]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.07895% CI: [-1.09, 0.06]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.000695% CI: [-0.54, -0.15]Mixed Models Analysis
Other Pre-specified
Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis
The rater or investigator would rate the participant's total improvement whether or not it is due entirely to study treatment. During Phase B, responses were compared to the participant's condition at Baseline of Phase B (for participants who entered Phase B directly after screening) or to the End of Phase A visit (for participants who participated in Phase A). During Phase C, responses were compared to the participant's condition at the End of Phase B visit. Response choices include: 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.
Time frame: Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 12 | 3.66 Units on a scale | Standard Deviation 1.19 |
| Brexpiprazole | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 36 | 3.71 Units on a scale | Standard Deviation 1.27 |
| Brexpiprazole | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 24 | 3.67 Units on a scale | Standard Deviation 1.27 |
| Brexpiprazole | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 52 | 3.77 Units on a scale | Standard Deviation 1.26 |
| Brexpiprazole | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 6 | 3.68 Units on a scale | Standard Deviation 0.98 |
| Placebo | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 52 | 4.40 Units on a scale | Standard Deviation 1.32 |
| Placebo | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 6 | 4.00 Units on a scale | Standard Deviation 1.14 |
| Placebo | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 12 | 4.10 Units on a scale | Standard Deviation 1.3 |
| Placebo | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 24 | 4.30 Units on a scale | Standard Deviation 1.32 |
| Placebo | Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis | Week 36 | 4.39 Units on a scale | Standard Deviation 1.3 |
Comparison: Statistical analysis at Week 6.p-value: 0.038795% CI: [-0.6, -0.2]Cochran-Mantel-Haenszel
Comparison: Statistical analysis at Week 12.p-value: 0.018595% CI: [-0.75, -0.07]Cochran-Mantel-Haenszel
Comparison: Statistical analysis at Week 24.p-value: 0.00195% CI: [-0.97, -0.24]Cochran-Mantel-Haenszel
Comparison: Statistical analysis at Week 36.p-value: 0.000495% CI: [-1.02, -0.3]Cochran-Mantel-Haenszel
Comparison: Statistical analysis at Week 52.p-value: 0.000995% CI: [-0.96, -0.25]Cochran-Mantel-Haenszel
Other Pre-specified
Mean Change From Baseline in GAF Scale Score - LOCF Analysis
The GAF is a clinician-rated scale that assesses the participant's psychological, social, and occupational functioning on a hypothetical continuum of mental health-illness using a scale that ranges from 1 to 100 score, where lower values indicate worst outcome. From among 10 descriptive anchors, investigators will choose the anchor which is the most representative of the participant's level of functioning at the time of the assessment and will assign a single score within the point range given for the selected anchor.
Time frame: Baseline and Weeks 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in GAF Scale Score - LOCF Analysis | Week 12 | 0.44 Units on a scale | Standard Error 1.26 |
| Brexpiprazole | Mean Change From Baseline in GAF Scale Score - LOCF Analysis | Week 24 | 0.85 Units on a scale | Standard Error 1.37 |
| Brexpiprazole | Mean Change From Baseline in GAF Scale Score - LOCF Analysis | Week 36 | 0.97 Units on a scale | Standard Error 1.35 |
| Brexpiprazole | Mean Change From Baseline in GAF Scale Score - LOCF Analysis | Week 52 | 0.55 Units on a scale | Standard Error 1.38 |
| Placebo | Mean Change From Baseline in GAF Scale Score - LOCF Analysis | Week 52 | -6.01 Units on a scale | Standard Error 1.28 |
| Placebo | Mean Change From Baseline in GAF Scale Score - LOCF Analysis | Week 12 | -3.44 Units on a scale | Standard Error 1.17 |
| Placebo | Mean Change From Baseline in GAF Scale Score - LOCF Analysis | Week 36 | -5.84 Units on a scale | Standard Error 1.25 |
| Placebo | Mean Change From Baseline in GAF Scale Score - LOCF Analysis | Week 24 | -4.51 Units on a scale | Standard Error 1.27 |
Comparison: Statistical analysis at Week 12.p-value: 0.011195% CI: [0.9, 6.86]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.001495% CI: [2.1, 8.62]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: <0.000195% CI: [3.61, 10]ANCOVA
Comparison: Statistical analysis at Week 52.p-value: 0.000195% CI: [3.28, 9.83]ANCOVA
Other Pre-specified
Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis
The GAF is a clinician-rated scale that assesses the participant's psychological, social, and occupational functioning on a hypothetical continuum of mental health-illness using a scale that ranges from 1 to 100 score, where lower values indicate worst outcome. From among 10 descriptive anchors, investigators will choose the anchor which is the most representative of the participant's level of functioning at the time of the assessment and will assign a single score within the point range given for the selected anchor.
Time frame: Baseline and Weeks 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis | Week 12 (N= 73, 68) | 1.59 Units on a scale | Standard Error 1.27 |
| Brexpiprazole | Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis | Week 24 (N= 50, 36) | 3.74 Units on a scale | Standard Error 1.42 |
| Brexpiprazole | Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis | Week 36 (N= 33, 24) | 4.71 Units on a scale | Standard Error 1.5 |
| Brexpiprazole | Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis | Week 52 (N= 15, 9) | 5.72 Units on a scale | Standard Error 1.87 |
| Placebo | Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis | Week 52 (N= 15, 9) | -0.16 Units on a scale | Standard Error 2.37 |
| Placebo | Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis | Week 12 (N= 73, 68) | -0.03 Units on a scale | Standard Error 1.29 |
| Placebo | Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.21 Units on a scale | Standard Error 1.67 |
| Placebo | Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis | Week 24 (N= 50, 36) | 1.09 Units on a scale | Standard Error 1.57 |
Comparison: Statistical analysis at Week 12.p-value: 0.32995% CI: [-1.65, 4.88]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.176595% CI: [-1.22, 6.54]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.033195% CI: [0.38, 8.63]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.052295% CI: [-0.06, 11.82]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.028195% CI: [0.41, 6.92]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis
The PEC score consisted of five PANSS items: excitement (P4), hostility (P7), tension (G4), uncooperativeness (G8), and poor impulse control (G14). Each of the items were rated on a scale of 1 (absent) to 7 (extreme). The PEC scores ranged from 5 (not present) to 35 (extremely severe).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The last-observation-carried-forward (LOCF) data set included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data (eg.the last visit prior to the first dosing of Phase C) were not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 12 (N= 73, 68) | 0.50 Units on a scale | Standard Error 0.34 |
| Brexpiprazole | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.10 Units on a scale | Standard Error 0.33 |
| Brexpiprazole | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 24 (N= 50, 36) | -0.06 Units on a scale | Standard Error 0.31 |
| Brexpiprazole | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 52 (N= 15, 9) | -0.04 Units on a scale | Standard Error 0.46 |
| Brexpiprazole | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.32 Units on a scale | Standard Error 0.23 |
| Placebo | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 52 (N= 15, 9) | 1.00 Units on a scale | Standard Error 0.59 |
| Placebo | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.74 Units on a scale | Standard Error 0.22 |
| Placebo | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 12 (N= 73, 68) | 1.16 Units on a scale | Standard Error 0.35 |
| Placebo | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 24 (N= 50, 36) | 0.45 Units on a scale | Standard Error 0.36 |
| Placebo | Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis | Week 36 (N= 33, 24) | 1.25 Units on a scale | Standard Error 0.4 |
Comparison: Statistical analysis at Week 6.p-value: 0.157795% CI: [-1.02, 0.17]Mixed Models Analysis
Comparison: Statistical analysis at Week 12.p-value: 0.168595% CI: [-1.61, 0.28]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.281595% CI: [-1.43, 0.42]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.028695% CI: [-2.16, -0.12]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.180395% CI: [-2.58, 0.51]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.007795% CI: [-1.12, -0.17]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The anxiety/depression factor score is the sum of score from the 4 items on the anxiety/depression subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 12 | 0.86 Units on a scale | Standard Error 0.32 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 36 | 1.09 Units on a scale | Standard Error 0.32 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 24 | 1.07 Units on a scale | Standard Error 0.32 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 52 | 1.17 Units on a scale | Standard Error 0.31 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 6 | 0.19 Units on a scale | Standard Error 0.27 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 52 | 1.88 Units on a scale | Standard Error 0.29 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 6 | 0.85 Units on a scale | Standard Error 0.25 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 12 | 1.41 Units on a scale | Standard Error 0.3 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 24 | 1.64 Units on a scale | Standard Error 0.3 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis | Week 36 | 1.79 Units on a scale | Standard Error 0.3 |
Comparison: Statistical analysis at Week 6.p-value: 0.046795% CI: [-1.32, -0.06]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.159995% CI: [-1.33, 0.22]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.141795% CI: [-1.35, 0.19]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: 0.072495% CI: [-1.47, 0.06]ANCOVA
Comparison: Statistical analysis at Week 52.p-value: 0.060895% CI: [-1.47, 0.03]ANCOVA
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The anxiety/depression factor score is the sum of score from the 4 items on the anxiety/depression subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 12 (N= 73, 68) | 0.54 Units on a scale | Standard Error 0.29 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.46 Units on a scale | Standard Error 0.33 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 24 (N= 50, 36) | 0.61 Units on a scale | Standard Error 0.28 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 52 (N= 15, 9) | 0.04 Units on a scale | Standard Error 0.43 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.19 Units on a scale | Standard Error 0.25 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 52 (N= 15, 9) | 0.28 Units on a scale | Standard Error 0.56 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.66 Units on a scale | Standard Error 0.24 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 12 (N= 73, 68) | 0.78 Units on a scale | Standard Error 0.29 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 24 (N= 50, 36) | 0.58 Units on a scale | Standard Error 0.32 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.71 Units on a scale | Standard Error 0.39 |
Comparison: Statistical analysis at Week 6.p-value: 0.16495% CI: [-1.14, 0.19]Mixed Models Analysis
Comparison: Statistical analysis at Week 12.p-value: 0.546695% CI: [-1.04, 0.55]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.941795% CI: [-0.81, 0.87]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.625795% CI: [-1.25, 0.76]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.743795% CI: [-1.68, 1.21]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.450695% CI: [-0.62, 0.28]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The disorganized thoughts factor score is the sum of score from the 7 items on the disorganized thoughts subscale (range: 7 - best possible outcome to 49 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 12 | -0.19 Units on a scale | Standard Error 0.41 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 36 | 0.00 Units on a scale | Standard Error 0.45 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 24 | -0.29 Units on a scale | Standard Error 0.44 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 52 | 0.29 Units on a scale | Standard Error 0.48 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 6 | -0.32 Units on a scale | Standard Error 0.34 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 52 | 1.97 Units on a scale | Standard Error 0.45 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 6 | 0.33 Units on a scale | Standard Error 0.31 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 12 | 1.19 Units on a scale | Standard Error 0.38 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 24 | 1.76 Units on a scale | Standard Error 0.41 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis | Week 36 | 1.95 Units on a scale | Standard Error 0.42 |
Comparison: Statistical analysis at Week 6.p-value: 0.106295% CI: [-1.44, 0.14]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.005195% CI: [-2.33, -0.42]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.000195% CI: [-3.08, -1.01]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: 0.000495% CI: [-3, -0.89]ANCOVA
Comparison: Statistical analysis at Week 52.p-value: 0.003595% CI: [-2.81, -0.56]ANCOVA
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The disorganized thoughts factor score is the sum of score from the 7 items on the disorganized thoughts subscale (range: 7 - best possible outcome to 49 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 12 (N= 73, 68) | -0.44 Units on a scale | Standard Error 0.38 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 36 (N= 33, 24) | -1.31 Units on a scale | Standard Error 0.44 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 24 (N= 50, 36) | -1.26 Units on a scale | Standard Error 0.34 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 52 (N= 15, 9) | -0.37 Units on a scale | Standard Error 0.99 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 6 (N= 81, 84) | -0.18 Units on a scale | Standard Error 0.31 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 52 (N= 15, 9) | -0.30 Units on a scale | Standard Error 1.24 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.32 Units on a scale | Standard Error 0.3 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 12 (N= 73, 68) | 0.69 Units on a scale | Standard Error 0.39 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 24 (N= 50, 36) | 0.27 Units on a scale | Standard Error 0.38 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.17 Units on a scale | Standard Error 0.5 |
Comparison: Statistical analysis at Week 6.p-value: 0.225195% CI: [-1.33, 0.31]Mixed Models Analysis
Comparison: Statistical analysis at Week 12.p-value: 0.036895% CI: [-2.19, -0.07]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.002495% CI: [-2.51, -0.56]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.029395% CI: [-2.8, -0.15]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.963295% CI: [-3.32, 3.17]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.002995% CI: [-1.63, -0.34]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The negative factor score is the sum of the 7 items of the negative subscale (range: 8 - best possible outcome to 56 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 12 | -0.15 Units on a scale | Standard Error 0.48 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 36 | -0.07 Units on a scale | Standard Error 0.52 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 24 | -0.09 Units on a scale | Standard Error 0.49 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 52 | 0.34 Units on a scale | Standard Error 0.56 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 6 | -0.24 Units on a scale | Standard Error 0.4 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 52 | 1.57 Units on a scale | Standard Error 0.5 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 6 | 0.61 Units on a scale | Standard Error 0.36 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 12 | 1.09 Units on a scale | Standard Error 0.43 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 24 | 1.50 Units on a scale | Standard Error 0.44 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis | Week 36 | 1.56 Units on a scale | Standard Error 0.47 |
Comparison: Statistical analysis at Week 6.p-value: 0.070795% CI: [-1.78, 0.07]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.027695% CI: [-2.35, -0.14]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.006595% CI: [-2.72, -0.45]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: 0.008595% CI: [-2.84, -0.42]ANCOVA
Comparison: Statistical analysis at Week 52.p-value: 0.06395% CI: [-2.52, 0.07]ANCOVA
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The negative factor score is the sum of the 7 items of the negative subscale (range: 8 - best possible outcome to 56 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 12 (N= 73, 68) | -0.01 Units on a scale | Standard Error 0.45 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 36 (N= 33, 24) | -0.80 Units on a scale | Standard Error 0.5 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 24 (N= 50, 36) | -0.71 Units on a scale | Standard Error 0.4 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 52 (N= 15, 9) | 1.37 Units on a scale | Standard Error 1.39 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.02 Units on a scale | Standard Error 0.38 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 52 (N= 15, 9) | 1.06 Units on a scale | Standard Error 1.77 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.68 Units on a scale | Standard Error 0.36 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 12 (N= 73, 68) | 0.80 Units on a scale | Standard Error 0.45 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 24 (N= 50, 36) | 0.46 Units on a scale | Standard Error 0.43 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.70 Units on a scale | Standard Error 0.56 |
Comparison: Statistical analysis at Week 6.p-value: 0.196995% CI: [-1.66, 0.35]Mixed Models Analysis
Comparison: Statistical analysis at Week 12.p-value: 0.200795% CI: [-2.04, 0.43]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.043695% CI: [-2.3, -0.03]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.044495% CI: [-2.97, -0.04]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.892795% CI: [-4.4, 5.02]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.215495% CI: [-1.34, 0.31]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The positive factor score is the sum of the 8 components of the positive symptoms scale (range: 8 - best possible outcome to 56 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 12 | 0.10 Units on a scale | Standard Error 0.61 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 36 | 0.60 Units on a scale | Standard Error 0.66 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 24 | 0.25 Units on a scale | Standard Error 0.66 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 52 | 0.58 Units on a scale | Standard Error 0.66 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 6 | 0.05 Units on a scale | Standard Error 0.5 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 52 | 4.02 Units on a scale | Standard Error 0.6 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 6 | 1.13 Units on a scale | Standard Error 0.46 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 12 | 2.03 Units on a scale | Standard Error 0.56 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 24 | 3.08 Units on a scale | Standard Error 0.61 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis | Week 36 | 3.69 Units on a scale | Standard Error 0.6 |
Comparison: Statistical analysis at Week 6.p-value: 0.069595% CI: [-2.26, 0.09]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.008995% CI: [-3.38, -0.49]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.000495% CI: [-4.39, -1.27]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: 0.000195% CI: [-4.63, -1.54]ANCOVA
Comparison: Statistical analysis at Week 52.p-value: <0.000195% CI: [-4.99, -1.89]ANCOVA
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The positive factor score is the sum of the 8 components of the positive symptoms scale (range: 8 - best possible outcome to 56 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 12 (N= 73, 68) | -0.18 Units on a scale | Standard Error 0.58 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 36 (N= 33, 24) | -1.35 Units on a scale | Standard Error 0.57 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 24 (N= 50, 36) | -0.82 Units on a scale | Standard Error 0.54 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 52 (N= 15, 9) | -1.62 Units on a scale | Standard Error 0.83 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 6 (N= 81, 84) | -0.10 Units on a scale | Standard Error 0.45 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 52 (N= 15, 9) | 1.78 Units on a scale | Standard Error 1.05 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 6 (N= 81, 84) | 1.24 Units on a scale | Standard Error 0.44 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 12 (N= 73, 68) | 1.83 Units on a scale | Standard Error 0.58 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 24 (N= 50, 36) | 0.77 Units on a scale | Standard Error 0.6 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.93 Units on a scale | Standard Error 0.63 |
Comparison: Statistical analysis at Week 6.p-value: 0.028895% CI: [-2.54, -0.14]Mixed Models Analysis
Comparison: Statistical analysis at Week 12.p-value: 0.012895% CI: [-3.6, -0.44]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.046295% CI: [-3.15, 0.03]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.007495% CI: [-3.94, -0.64]Mixed Models Analysis
Comparison: Statistical analysis at Week 52p-value: 0.013695% CI: [-6.05, -0.75]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.000195% CI: [-2.84, -0.97]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The uncontrolled hostility/excitement factor score is the sum of score from the 4 items on the uncontrolled hostility/excitement subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 12 | 0.52 Units on a scale | Standard Error 0.3 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 52 | 0.49 Units on a scale | Standard Error 0.37 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 36 | 0.57 Units on a scale | Standard Error 0.36 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 24 | 0.50 Units on a scale | Standard Error 0.36 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 6 | 0.32 Units on a scale | Standard Error 0.22 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 52 | 1.75 Units on a scale | Standard Error 0.34 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 6 | 0.65 Units on a scale | Standard Error 0.21 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 12 | 0.94 Units on a scale | Standard Error 0.28 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 24 | 1.31 Units on a scale | Standard Error 0.33 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis | Week 36 | 1.63 Units on a scale | Standard Error 0.33 |
Comparison: Statistical analysis at Week 6.p-value: 0.213595% CI: [-0.86, 0.19]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.243795% CI: [-1.13, 0.29]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.063595% CI: [-1.66, 0.05]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: 0.014495% CI: [-1.92, -0.22]ANCOVA
Comparison: Statistical analysis at Week 52.p-value: 0.004695% CI: [-2.12, -0.39]ANCOVA
Other Pre-specified
Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis
Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The uncontrolled hostility/excitement factor score is the sum of score from the 4 items on the uncontrolled hostility/excitement subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 12 (N= 73, 68) | 0.33 Units on a scale | Standard Error 0.28 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 36 (N= 33, 24) | -0.13 Units on a scale | Standard Error 0.29 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 24 (N= 50, 36) | -0.26 Units on a scale | Standard Error 0.27 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 52 (N= 15, 9) | -0.20 Units on a scale | Standard Error 0.4 |
| Brexpiprazole | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.19 Units on a scale | Standard Error 0.19 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 52 (N= 15, 9) | 0.94 Units on a scale | Standard Error 0.5 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.55 Units on a scale | Standard Error 0.18 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 12 (N= 73, 68) | 0.82 Units on a scale | Standard Error 0.29 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 24 (N= 50, 36) | 0.81 Units on a scale | Standard Error 0.31 |
| Placebo | Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.94 Units on a scale | Standard Error 0.34 |
Comparison: Statistical analysis at Week 6.p-value: 0.146595% CI: [-0.85, 0.13]Mixed Models Analysis
Comparison: Statistical analysis at Week 12.p-value: 0.215495% CI: [-1.27, 0.29]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.269695% CI: [-1.23, 0.35]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.017995% CI: [-1.95, -0.19]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.087595% CI: [-2.46, 0.18]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.002195% CI: [-1.08, -0.24]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis
The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 12 | -0.17 Units on a scale | Standard Error 0.46 |
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 36 | -0.14 Units on a scale | Standard Error 0.51 |
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 24 | -0.08 Units on a scale | Standard Error 0.49 |
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 52 | 0.39 Units on a scale | Standard Error 0.54 |
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 6 | -0.12 Units on a scale | Standard Error 0.39 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 52 | 1.63 Units on a scale | Standard Error 0.49 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 6 | 0.63 Units on a scale | Standard Error 0.35 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 12 | 1.06 Units on a scale | Standard Error 0.42 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 24 | 1.47 Units on a scale | Standard Error 0.44 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis | Week 36 | 1.44 Units on a scale | Standard Error 0.46 |
Comparison: Statistical analysis at Week 6.p-value: 0.098195% CI: [-1.65, 0.14]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.026495% CI: [-2.3, -0.15]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.007895% CI: [-2.69, -0.42]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: 0.010195% CI: [-2.77, -0.38]ANCOVA
Comparison: Statistical analysis at Week 52p-value: 0.051695% CI: [-2.5, 0.01]ANCOVA
Other Pre-specified
Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis
The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 12 (N= 73, 68) | -0.22 Units on a scale | Standard Error 0.43 |
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 36 (N= 33, 24) | -1.03 Units on a scale | Standard Error 0.47 |
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 24 (N= 50, 36) | -0.78 Units on a scale | Standard Error 0.39 |
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 52 (N= 15, 9) | 1.30 Units on a scale | Standard Error 1.37 |
| Brexpiprazole | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 6 (N= 81, 84) | -0.04 Units on a scale | Standard Error 0.37 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 52 (N= 15, 9) | 0.87 Units on a scale | Standard Error 1.71 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.65 Units on a scale | Standard Error 0.35 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 12 (N= 73, 68) | 0.55 Units on a scale | Standard Error 0.44 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 24 (N= 50, 36) | 0.18 Units on a scale | Standard Error 0.42 |
| Placebo | Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.02 Units on a scale | Standard Error 0.53 |
Comparison: Statistical analysis at Week 6.p-value: 0.16595% CI: [-1.66, 0.29]Mixed Models Analysis
Comparison: Statistical analysis at Week 12.p-value: 0.200195% CI: [-1.97, 0.42]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.093995% CI: [-2.07, 0.16]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.139695% CI: [-2.44, 0.35]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.84795% CI: [-4.14, 5]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.225895% CI: [-1.24, 0.3]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis
PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 12 | 0.38 Units on a scale | Standard Error 0.59 |
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 36 | 0.97 Units on a scale | Standard Error 0.63 |
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 24 | 0.49 Units on a scale | Standard Error 0.64 |
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 52 | 0.99 Units on a scale | Standard Error 0.64 |
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 6 | 0.30 Units on a scale | Standard Error 0.49 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 52 | 4.17 Units on a scale | Standard Error 0.59 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 6 | 1.25 Units on a scale | Standard Error 0.45 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 12 | 2.24 Units on a scale | Standard Error 0.54 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 24 | 3.23 Units on a scale | Standard Error 0.59 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis | Week 36 | 3.91 Units on a scale | Standard Error 0.58 |
Comparison: Statistical analysis at Week 6.p-value: 0.109395% CI: [-2.1, 0.21]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.008995% CI: [-3.25, -0.47]ANOVA
Comparison: Statistical analysis at Week 24.p-value: 0.000595% CI: [-4.26, -1.22]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: 0.000195% CI: [-4.43, -1.44]ANCOVA
Comparison: Statistical analysis at Week 52p-value: <0.000195% CI: [-4.7, -1.66]ANCOVA
Other Pre-specified
Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis
PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 12 (N= 73, 68) | -0.06 Units on a scale | Standard Error 0.5 |
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 36 (N= 33, 24) | -0.97 Units on a scale | Standard Error 0.44 |
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 24 (N= 50, 36) | -0.84 Units on a scale | Standard Error 0.46 |
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 52 (N= 15, 9) | -1.21 Units on a scale | Standard Error 0.73 |
| Brexpiprazole | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.17 Units on a scale | Standard Error 0.42 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 52 (N= 15, 9) | 1.50 Units on a scale | Standard Error 0.99 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 6 (N= 81, 84) | 1.28 Units on a scale | Standard Error 0.41 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 12 (N= 73, 68) | 1.81 Units on a scale | Standard Error 0.51 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 24 (N= 50, 36) | 0.72 Units on a scale | Standard Error 0.51 |
| Placebo | Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis | Week 36 (N= 33, 24) | 0.91 Units on a scale | Standard Error 0.51 |
Comparison: Statistical analysis at Week 6.p-value: 0.050795% CI: [-2.23, 0]Mixed Models Analysis
Comparison: Statistical analysis at Week 12.p-value: 0.00895% CI: [-3.24, -0.5]Mixed Models Analysis
Comparison: Statistical analysis at Week 24.p-value: 0.021595% CI: [-2.89, -0.24]Mixed Models Analysis
Comparison: Statistical analysis at Week 36.p-value: 0.005395% CI: [-3.19, -0.58]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.33995% CI: [-5.2, -0.22]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: <0.000195% CI: [-2.32, -0.88]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis
The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 12 | 1.55 Units on a scale | Standard Error 1.77 |
| Brexpiprazole | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 36 | 2.49 Units on a scale | Standard Error 1.89 |
| Brexpiprazole | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 24 | 1.58 Units on a scale | Standard Error 1.88 |
| Brexpiprazole | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 52 | 3.25 Units on a scale | Standard Error 1.94 |
| Brexpiprazole | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 6 | 0.51 Units on a scale | Standard Error 1.4 |
| Placebo | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 52 | 11.20 Units on a scale | Standard Error 1.77 |
| Placebo | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 6 | 3.56 Units on a scale | Standard Error 1.28 |
| Placebo | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 12 | 6.60 Units on a scale | Standard Error 1.62 |
| Placebo | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 24 | 9.17 Units on a scale | Standard Error 1.72 |
| Placebo | Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis | Week 36 | 10.51 Units on a scale | Standard Error 1.73 |
Comparison: Statistical analysis at Week 6.p-value: 0.068395% CI: [-6.31, 0.23]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.017495% CI: [-9.2, -0.9]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.000895% CI: [-12, -3.18]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: 0.000595% CI: [-12.4, -3.59]ANCOVA
Comparison: Statistical analysis at Week 52.p-value: 0.000795% CI: [-12.5, -3.41]ANCOVA
Other Pre-specified
Mean Change From Baseline in PEC Score - LOCF Analysis
The PEC score consisted of five PANSS items: excitement (P4), hostility (P7), tension (G4), uncooperativeness (G8), and poor impulse control (G14). Each of the items were rated on a scale of 1 (absent) to 7 (extreme). The PEC scores ranged from 5 (not present) to 35 (extremely severe).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 6 | 0.38 Units on a scale | Standard Error 0.27 |
| Brexpiprazole | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 24 | 0.78 Units on a scale | Standard Error 0.42 |
| Brexpiprazole | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 12 | 0.73 Units on a scale | Standard Error 0.36 |
| Brexpiprazole | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 36 | 0.89 Units on a scale | Standard Error 0.41 |
| Brexpiprazole | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 52 | 0.82 Units on a scale | Standard Error 0.41 |
| Placebo | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 36 | 2.23 Units on a scale | Standard Error 0.38 |
| Placebo | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 52 | 2.35 Units on a scale | Standard Error 0.38 |
| Placebo | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 6 | 0.81 Units on a scale | Standard Error 0.25 |
| Placebo | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 12 | 1.36 Units on a scale | Standard Error 0.33 |
| Placebo | Mean Change From Baseline in PEC Score - LOCF Analysis | Week 24 | 1.86 Units on a scale | Standard Error 0.38 |
Comparison: Statistical analysis at Week 6.p-value: 0.185295% CI: [-1.06, 0.21]ANCOVA
Comparison: Statistical analysis at Week 12.p-value: 0.14395% CI: [-1.47, 0.21]ANCOVA
Comparison: Statistical analysis at Week 24.p-value: 0.032395% CI: [-2.06, -0.09]ANCOVA
Comparison: Statistical analysis at Week 36.p-value: 0.007195% CI: [-2.31, -0.37]ANCOVA
Comparison: Statistical analysis at Week 52.p-value: 0.002395% CI: [-2.52, -0.56]ANCOVA
Other Pre-specified
Mean Change From Baseline in Personal and Social Performance (PSP) Scale Score - MMRM Analysis
The PSP is a validated clinician-rated scale that measures personal and social functioning in four domains: socially useful activities (e.g., work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains is rated as absent, mild, manifest, marked, severe, or very severe. These ratings are 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 are considered to have mild functional difficulty. Scores of 31 to 70 represent manifest disabilities of various degrees and ratings of 1 to 30 indicate minimal functioning that requires intense support and/or supervision.The PSP score ranges from 0 to 100, with higher scores indicating higher levels of social functioning.
Time frame: Baseline and Weeks 24 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in Personal and Social Performance (PSP) Scale Score - MMRM Analysis | Week 24 (N= 50, 36) | 18.85 Units on a scale | Standard Error 1.51 |
| Brexpiprazole | Mean Change From Baseline in Personal and Social Performance (PSP) Scale Score - MMRM Analysis | Week 52 (N= 15, 9) | 18.63 Units on a scale | Standard Error 2.76 |
| Placebo | Mean Change From Baseline in Personal and Social Performance (PSP) Scale Score - MMRM Analysis | Week 24 (N= 50, 36) | 17.84 Units on a scale | Standard Error 1.82 |
| Placebo | Mean Change From Baseline in Personal and Social Performance (PSP) Scale Score - MMRM Analysis | Week 52 (N= 15, 9) | 12.55 Units on a scale | Standard Error 3.48 |
Comparison: Statistical analysis at Week 24.p-value: 0.652595% CI: [-3.47, 5.49]Mixed Models Analysis
Comparison: Statistical analysis at Week 52.p-value: 0.167795% CI: [-2.71, 14.87]Mixed Models Analysis
Comparison: Statistical analysis at across visits.p-value: 0.234795% CI: [-2.41, 9.5]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis
The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
Time frame: Baseline and Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 12 (N= 73, 68) | 0.84 Units on a scale | Standard Error 1.73 |
| Brexpiprazole | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 36 (N= 33, 24) | -2.71 Units on a scale | Standard Error 1.48 |
| Brexpiprazole | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 24 (N= 50, 36) | -1.88 Units on a scale | Standard Error 1.39 |
| Brexpiprazole | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 52 (N= 15, 9) | 0.61 Units on a scale | Standard Error 3.34 |
| Brexpiprazole | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 6 (N= 81, 84) | 0.79 Units on a scale | Standard Error 1.31 |
| Placebo | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 52 (N= 15, 9) | 6.92 Units on a scale | Standard Error 4.53 |
| Placebo | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 6 (N= 81, 84) | 4.09 Units on a scale | Standard Error 1.27 |
| Placebo | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 12 (N= 73, 68) | 6.15 Units on a scale | Standard Error 1.74 |
| Placebo | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 24 (N= 50, 36) | 2.89 Units on a scale | Standard Error 1.55 |
| Placebo | Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis | Week 36 (N= 33, 24) | 3.33 Units on a scale | Standard Error 1.7 |
Comparison: Statistical analysis of treatment comparisons at Week 6.p-value: 0.066495% CI: [-6.82, 0.23]Mixed Models Analysis
Comparison: Statistical analysis of treatment comparisons at Week 12.p-value: 0.030195% CI: [-10.1, -0.52]Mixed Models Analysis
Comparison: Statistical analysis of treatment comparisons at Week 24.p-value: 0.022695% CI: [-8.86, -0.68]Mixed Models Analysis
Comparison: Statistical analysis of treatment comparisons at Week 36.p-value: 0.008695% CI: [-10.5, -1.59]Mixed Models Analysis
Comparison: Statistical analysis of treatment comparisons at Week 52.p-value: 0.2895% CI: [-18.1, 5.46]Mixed Models Analysis
Comparison: Statistical analysis at across visitsp-value: 0.001195% CI: [-7.01, -1.82]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in PSP Scale Score - LOCF Analysis
The PSP is a validated clinician-rated scale that measures personal and social functioning in four domains: socially useful activities (e.g., work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains is rated as absent, mild, manifest, marked, severe, or very severe. These ratings are 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 are considered to have mild functional difficulty. Scores of 31 to 70 represent manifest disabilities of various degrees and ratings of 1 to 30 indicate minimal functioning that requires intense support and/or supervision.The PSP score ranges from 0 to 100, with higher scores indicating higher levels of social functioning.
Time frame: Baseline and Weeks 24 and 52
Population: The LOCF data set for Phase C included data recorded at a given Phase C visit or, if no observation is recorded at that visit, data carried forward from the previous Phase C visit. Baseline data was not be carried forward to impute missing values for the LOCF data set.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline in PSP Scale Score - LOCF Analysis | Week 24 | 15.20 Units on a scale | Standard Error 1.41 |
| Brexpiprazole | Mean Change From Baseline in PSP Scale Score - LOCF Analysis | Week 52 | 15.06 Units on a scale | Standard Error 1.43 |
| Placebo | Mean Change From Baseline in PSP Scale Score - LOCF Analysis | Week 24 | 11.41 Units on a scale | Standard Error 1.32 |
| Placebo | Mean Change From Baseline in PSP Scale Score - LOCF Analysis | Week 52 | 10.31 Units on a scale | Standard Error 1.34 |
Comparison: Statistical analysis at Week 24.p-value: 0.028595% CI: [0.4, 7.17]ANCOVA
Comparison: Statistical analysis at Week 52.p-value: 0.007195% CI: [1.31, 8.18]ANCOVA
Other Pre-specified
Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase
Participants were assessed for stability using the following criteria:1) Outpatient status AND 2) Positive and Negative Syndrome Scale (PANSS) Total Score ≤ 70 AND 3) A score of ≤ 4 (moderate) on each of the following PANSS items (possible scores of 1 to 7 for each item): conceptual disorganization, suspiciousness hallucinatory behavior, unusual thought content, AND 4) Clinical Global Impression - Severity of Illness scale(CGI-S) score ≤ 4 (moderately ill) AND 5) No current suicidal behavior as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), defined as the following: An answer of no to each question on the Suicidal Behavior section of the C-SSRS AND an answer of no to Questions 4 and 5 on the Suicidal Ideation section of the C-SSRS, if completed, AND 6) No evidence of aggressive or violent behavior resulting in clinically significant self-injury, injury to another person, property damage.
Time frame: Weeks 6, 12, 24, 36 and 52
Population: Based on ITT principle, the full analysis set of this trial was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brexpiprazole | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 6 (N= 81, 84) | 92.59 percentage of participants |
| Brexpiprazole | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 12 (N= 73, 68) | 93.15 percentage of participants |
| Brexpiprazole | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 24 (N= 50, 36) | 96.00 percentage of participants |
| Brexpiprazole | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 36 (N= 33, 24) | 93.94 percentage of participants |
| Brexpiprazole | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 52 (N= 15, 9) | 86.67 percentage of participants |
| Brexpiprazole | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Last Visit (N= 96, 104) | 79.17 percentage of participants |
| Placebo | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 52 (N= 15, 9) | 88.89 percentage of participants |
| Placebo | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 6 (N= 81, 84) | 86.90 percentage of participants |
| Placebo | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 36 (N= 33, 24) | 83.33 percentage of participants |
| Placebo | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 12 (N= 73, 68) | 86.76 percentage of participants |
| Placebo | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Last Visit (N= 96, 104) | 56.73 percentage of participants |
| Placebo | Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase | Week 24 (N= 50, 36) | 94.44 percentage of participants |
Comparison: Statistical analysis at Week 36.p-value: 0.1977Chi-squared
Comparison: Statistical analysis at Week 52.p-value: 0.8734Chi-squared
Comparison: Statistical analysis at Week 6.p-value: 0.2296Chi-squared
Comparison: Statistical analysis at Week 12.p-value: 0.2051Chi-squared
Comparison: Statistical analysis at Week 24.p-value: 0.7354Chi-squared
Comparison: Statistical analysis at Last Visit.p-value: 0.0007Chi-squared
Other Pre-specified
Percentage of Participants Who Discontinued Due to All Causes
Analysis of the percentage of participants who discontinued due to all causes was based on all participants who have been randomized and taken one dose of IMP in the Double-blind Maintenance phase. The trial was completed by sponsor when efficacy was demonstrated at the first pre-specified interim analysis (45 impending relapse events) performed by an independent (unblinded) statistician.
Time frame: Baseline to Week 52
Population: Based on ITT principle, the full analysis set was composed of all participants randomized to the double-blind treatment who took at least one dose of study medication in Phase C and who had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brexpiprazole | Percentage of Participants Who Discontinued Due to All Causes | 34.38 Percentage of particpants |
| Placebo | Percentage of Participants Who Discontinued Due to All Causes | 54.81 Percentage of particpants |
p-value: 0.0014Log Rank