Major Depressive Disorder
Conditions
Keywords
Brexpiprazole, MDD
Brief summary
Major depressive disorder (MDD) is a serious medical illness associated with significant suicidal risk and marked disability. Despite the availability of numerous treatments, achievement of consistent and favorable long-term outcomes remains challenging. This study will assess the safety, efficacy and tolerability of brexpiprazole as adjunctive therapy to protocol-specific open-label antidepressant therapy.
Interventions
DRUGBrexpiprazole
Administered as tablets.
Protocol-specified oral ADTs included: citalopram hydrobromide (Celexa®) tablets, escitalopram (Lexapro®) tablets, fluoxetine (Prozac®) capsules, paroxetine (Paxil CR®) controlled-release tablets, sertraline (Zoloft®) tablets, duloxetine (Cymbalta®) delayed-release capsules, venlafaxine XR (Effexor XR®) extended-release (XR) capsules.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participants with both a diagnosis of recurrent major depressive disorder, and in a current major depressive episode of ≥ 8 weeks in duration, as defined by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and confirmed by both the Mini International Neuropsychiatric Interview (MINI) and an adequate clinical psychiatric evaluation. * Participants must have reported a history for the current major depressive episode of an inadequate response to 1 or 2 adequate antidepressant treatments, and participants must currently be taking a protocol-mandated antidepressant treatment at an adequate dose and duration, and most not have reported ≥ 50% improvement. For participants who are currently on an adequate dose of protocol-mandated antidepressant therapy (ADT), but for an inadequate duration, can use the screening period to achieve adequate duration. At Phase A baseline visit, all participants must have either 2 or 3 documented inadequate responses to antidepressant treatment in total for the current episode as defined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ). * Participants with a Hamilton Rating Scale for Depression (HAM-D17) total score ≥ 18 at the screening visit, and Phase A baseline visits. * Participants willing to discontinue all prohibited psychotropic medications to meet protocol-required washouts prior to and during the trial period.
Exclusion criteria
* Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving investigational medicinal product (IMP). * Sexually active males or females of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of IMP. * Participants who report treatment with adjunctive antipsychotic medication with an antidepressant for a minimum of 3 weeks during the current major depressive episode. * Participants who report allergies or an intolerability (lifetime treatment history) to trial-provided ADTs that have not been prescribed to the participant during the current major depressive episode. * Participants who have received electroconvulsive therapy (ECT) for the current major depressive episode. * Participants who have had an inadequate response to ECT at any time in the past or who have had a vagus nerve stimulation or deep brain stimulation device implanted at any time for the management of treatment-resistant depression. Participants who have had transcranial magnetic stimulation during the current major depressive episode. * Participants with a current need for involuntary commitment or who have been hospitalized within 4 weeks of screening for the current major depressive episode. * Participants with a primary DSM-5 diagnosis of: 1. Schizophrenia Spectrum and Other Psychotic Disorders 2. Bipolar and Related Disorders 3. Obsessive Compulsive Disorders 4. Feeding and Eating Disorders 5. Neurocognitive Disorders 6. Panic Disorder 7. Post-Traumatic Stress Disorder * Participants with a current DSM-5 diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder or intellectual disability. * Participants experiencing hallucinations, delusions, or any psychotic symptomatology in the current major depressive episode. * Participants receiving new onset psychotherapy (individual, group, marriage or family therapy) within 42 days of screening or at any time during participation in the trial. * Participants who have met DSM-5 criteria for substance use disorder (moderate or severe) within the past 60 days; including alcohol and benzodiazepines, but excluding nicotine. * Participants with hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications for at least the past 90 days) and/or an abnormal result for free T4 at screening. * Participants who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders such as any history of myocardial infarction, congestive heart failure, HIV seropositive status/acquired immunodeficiency syndrome, chronic hepatitis B or C. * Participants with diabetes mellitus (IDDM and non-IDDM) are ineligible for the trial unless their condition is stable and well-controlled. * Participants with uncontrolled hypertension (DBP \> 95 millimetres of mercury \[mmHg\]) or symptomatic hypotension, or orthostatic hypotension which is defined as a decrease of ≥ 30 mmHg in systolic blood pressure (SBP) and/or decrease of ≥ 20 mmHg in diastolic blood pressure (DBP) after at least 3 minutes standing compared to the previous supine blood pressure OR development of symptoms. * Participants with known ischemic heart disease or history of myocardial infarction-or congestive heart failure (whether controlled or uncontrolled). * Participants with epilepsy or a history of seizures, except for a single seizure episode. * Participants with a positive drug screen for cocaine or other drugs of abuse (excluding known prescription stimulants and other medications and marijuana). Detectable levels of alcohol, marijuana, barbiturates, or opiates in the drug screen are not exclusionary if, in the investigator's documented opinion, the participant does not meet DSM-5 criteria for moderate to severe substance use disorder and the positive test does not signal a clinical condition that would impact the safety of the participant or interpretation of the trial results, and participation is agreed to by the medical monitor prior to treatment. * Treatment with a monoamine oxidase inhibitor (MAOI) within 14 day prior to the first dose of IMP in Phase A. * Use of benzodiazepines and/or hypnotics (including non-benzodiazepine sleep aids) within 7 days prior to first dose of IMP in Phase A. * Use of varenicline within 5 days prior to the first dose of IMP in Phase A. * Use of oral (or immediate release intramuscular) neuroleptics within 7 days prior or long-acting approved neuroleptics ≤ 1 full cycle plus 1/2 cycle prior to the first dose of IMP in Phase A. * Participants who would be likely to require prohibited concomitant therapy during the trial. * Participants who have been exposed to brexpiprazole in any prior clinical trial or has received commercial brexpiprazole (Rexulti). * Participants with a history of neuroleptic malignant syndrome or serotonin syndrome. * Participants with a history of true allergic response to more than one class of medications. * Prisoners or participants who are compulsorily detained for treatment of either a psychiatric or physical illness. * Participants who participated in any clinical trial within the last 60 days or who participated in more than 2 clinical trials within the past year.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase C: Time-to-Relapse by Any Criteria as Defined in Blinded Addendum | Up to 14 days post last dose in Phase C (up to 28 weeks) | Relapse criteria included:At same visit, increase in Montgomery Asberg Depression Rating Scale\[MADRS\] total score(10 items, 0=no symptoms to 6=severe symptoms,total score=0 to 60)of 50% from randomization and Clinical Global Impression-Severity of Illness \[CGI-\](8-point scale of 0=not assessed to 7=most extremely ill)score ≥4,hospitalization for depression, discontinuation for lack of efficacy/worsening of depression, active suicidality(score of ≥4 on MADRS item10 of suicidality)or yes answered on question 4 or 5 of Columbia-Suicide Severity Rating Scale\[C-SSRS\](Suicidal Ideation \[SI\] has 5 questions: wish to be dead,non-specific active suicidal thoughts,active SI with any methods \[not plan\]without intent to act,active SI with some intent to act without specific plan,active SI with specific plan,intent)or yes answered to any question in suicidal behavior section (5 questions:preparatory acts/behavior,aborted attempt,interrupted attempt,actual attempt\[non-fatal\],completed suicide). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase C: Time-to-functional Relapse Based on SDS Criteria | Up to 14 days post last dose in Phase C (up to 28 weeks) | Time-to-functional relapse was based on a 30% increase in the SDS mean total score from Phase C Baseline, at least one SDS sub-score at 4 or greater, and an SDS total score ≥7 when all 3 sub-scores were available. The SDS is a self-rated instrument used to measure the effect of the participant's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0=not at all, to 10=extremely. Higher scores of 5 and above are associated with significant functional impairment. |
| Phase C: Percentage of Participants Meeting Any Relapse Criteria | Up to 26 weeks in Phase C | Relapse criteria included: At the same visit, increase in MADRS total score (10 items,7-point scale of 0=no symptoms to 6=severe symptoms, total score of 0 to 60) of 50% from randomization and CGI-S (8-point scale ranging from 0=not assessed to 7=most extremely ill) score ≥4, hospitalization for depression, discontinuation for lack of efficacy/worsening of depression, active suicidality (score of ≥4 on MADRS item 10 of suicidality) or answer of yes on question 4 or 5 of C-SSRS (SI has 5 questions: wish to be dead, non-specific active suicidal thoughts, active SI with any methods \[not plan\] without intent to act, active SI with some intent to act without specific plan, active SI with specific plan, intent) or answer of yes to any question in suicidal behavior section (5 questions: preparatory acts/behavior, aborted attempt, interrupted attempt, actual attempt \[non-fatal\], completed suicide). Percentage of participants were rounded off to single decimal point. |
| Phase C: Percentage of Participants Maintaining Remission | Weeks 21, 23, 25, 29, 33, 37, 41, 45, and 46 | Participants maintaining remission was defined as MADRS total score ≤10. The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants were rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. |
| Phase C: Change From Baseline for Randomization Phase in Sheehan Disability Scale (SDS) Mean Total Score at Week 46 | Baseline and Week 46 | The SDS is a self-rated instrument used to measure the effect of the participant's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0=not at all, to 10=extremely. The SDS total score is the mean of the 3 item responses. The SDS total score ranges from 0 to 10, with higher scores indicating greater functional impairment. Baseline was defined as the last available assessment value between Week 14 and Week 20 in Phase B for this outcome measure. Analysis of covariance (ANCOVA) model was used for analysis. |
| Phase C: Change From Baseline for Randomization Phase in CGI-S Score at Week 46 | Baseline and Week 46 | The CGI -S was used to rate the severity of illness for each participant on an 8-point scale ranging from 0 to 7 where 0=not assessed, 1=normal, not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=among the most extremely ill participants. A positive change from Baseline indicates worsening of illness. Baseline was defined as the last available assessment value in Phase B for this outcome measure. ANCOVA model was used for analysis. |
| Phase C: Change From Baseline for Randomization Phase in Each of the SDS Individual Item Scores at Week 46 | Baseline and Week 46 | The SDS is a self-rated instrument used to measure the effect of the participant's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0=not at all, to 10=extremely. Higher scores of 5 and above are associated with significant functional impairment. A positive change from Baseline indicates worsening of symptoms impacting each area. Baseline was defined as the last available assessment value between Week 14 and Week 20 in Phase B for this outcome measure. ANCOVA model was used for analysis. |
| Phase C: Change From Baseline for Randomization Phase in MADRS Total Score at Week 46 | Baseline and Week 46 | The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants were rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A positive change from Baseline indicates worsening of symptoms. Baseline was defined as the last available assessment value in Phase B for this outcome measure. ANCOVA model was used for analysis. |
Countries
United States
Participant flow
Recruitment details
A total of 1149 participants with major depressive disorder (MDD) participated in the study from 13 July 2018 to 29 July 2022.
Pre-assignment details
Of the 1149 participants enrolled in Phase A (Acute Treatment) of the study, 766 eligible participants continued to Phase B (Stabilization). Eligible participants who completed the Phase B were randomized into Phase C (Double-blind Randomized Withdrawal) to receive brexpiprazole or placebo along with open-label antidepressant therapy (ADT) in a 1:1 ratio for up to 26 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Phase A: Brexpiprazole + ADT Participants received brexpiprazole 2 or 3 mg/day along with protocol-specified ADT, orally, for 6 to 8 weeks during Phase A. Participants were initially titrated to a target dose of brexpiprazole 2 mg over a 2 to 4-week period. Thereafter, participants who had not met response criteria as defined in the blinded addendum, did not have potentially dose-related AEs, and had not achieved the maximum dose of medication had their dose increased up to 3 mg. | 1,149 |
| Total | 1,149 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase A: Acute Treatment (up to 8 Weeks) | Adverse Event | 82 | 0 | 0 | 0 |
| Phase A: Acute Treatment (up to 8 Weeks) | Death | 1 | 0 | 0 | 0 |
| Phase A: Acute Treatment (up to 8 Weeks) | Lack of Efficacy | 185 | 0 | 0 | 0 |
| Phase A: Acute Treatment (up to 8 Weeks) | Lost to Follow-up | 24 | 0 | 0 | 0 |
| Phase A: Acute Treatment (up to 8 Weeks) | Non-Compliance With Study Drug | 9 | 0 | 0 | 0 |
| Phase A: Acute Treatment (up to 8 Weeks) | Physician Decision | 1 | 0 | 0 | 0 |
| Phase A: Acute Treatment (up to 8 Weeks) | Protocol Deviation | 12 | 0 | 0 | 0 |
| Phase A: Acute Treatment (up to 8 Weeks) | Reason not Specified (not due to Coronavirus Disease 2019 [COVID-19] Restriction) | 15 | 0 | 0 | 0 |
| Phase A: Acute Treatment (up to 8 Weeks) | Subject Withdrew Consent | 54 | 0 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Adverse Event | 0 | 52 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Due to COVID-19 Restriction | 0 | 1 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Lack of Efficacy | 0 | 136 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Lost to Follow-up | 0 | 5 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Non-Compliance With Study Drug | 0 | 9 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Physician Decision | 0 | 6 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Pregnancy | 0 | 1 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Protocol Deviation | 0 | 9 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Reason not Specified (not due to COVID-19 Restriction) | 0 | 11 | 0 | 0 |
| Phase B: Stabilization (12 Weeks) | Subject Withdrew Consent | 0 | 47 | 0 | 0 |
| Phase C:Randomized Withdrawal (26 Weeks) | Adverse Event | 0 | 0 | 6 | 6 |
| Phase C:Randomized Withdrawal (26 Weeks) | Lack of Efficacy (Phase C MDD Relapse) | 0 | 0 | 54 | 52 |
| Phase C:Randomized Withdrawal (26 Weeks) | Lost to Follow-up | 0 | 0 | 16 | 4 |
| Phase C:Randomized Withdrawal (26 Weeks) | Non-Compliance With Study Drug | 0 | 0 | 1 | 2 |
| Phase C:Randomized Withdrawal (26 Weeks) | Non-compliant Participants | 0 | 0 | 32 | 28 |
| Phase C:Randomized Withdrawal (26 Weeks) | Physician Decision | 0 | 0 | 0 | 1 |
| Phase C:Randomized Withdrawal (26 Weeks) | Pregnancy | 0 | 0 | 1 | 0 |
| Phase C:Randomized Withdrawal (26 Weeks) | Reason not Specified (not due to COVID-19 Restriction) | 0 | 0 | 4 | 6 |
| Phase C:Randomized Withdrawal (26 Weeks) | Subject Withdrew Consent | 0 | 0 | 6 | 19 |
Baseline characteristics
| Characteristic | Phase A: Brexpiprazole + ADT |
|---|---|
| Age, Continuous | 42.3 years STANDARD_DEVIATION 13.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 110 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 968 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 71 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants |
| Race (NIH/OMB) Asian | 22 Participants |
| Race (NIH/OMB) Black or African American | 159 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 90 Participants |
| Race (NIH/OMB) White | 868 Participants |
| Sex: Female, Male Female | 734 Participants |
| Sex: Female, Male Male | 415 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1,149 | 0 / 766 | 0 / 240 | 0 / 249 |
| other Total, other adverse events | 398 / 1,136 | 163 / 765 | 25 / 240 | 13 / 248 |
| serious Total, serious adverse events | 10 / 1,136 | 12 / 765 | 1 / 240 | 3 / 248 |
Outcome results
Primary
Phase C: Time-to-Relapse by Any Criteria as Defined in Blinded Addendum
Relapse criteria included:At same visit, increase in Montgomery Asberg Depression Rating Scale\[MADRS\] total score(10 items, 0=no symptoms to 6=severe symptoms,total score=0 to 60)of 50% from randomization and Clinical Global Impression-Severity of Illness \[CGI-\](8-point scale of 0=not assessed to 7=most extremely ill)score ≥4,hospitalization for depression, discontinuation for lack of efficacy/worsening of depression, active suicidality(score of ≥4 on MADRS item10 of suicidality)or yes answered on question 4 or 5 of Columbia-Suicide Severity Rating Scale\[C-SSRS\](Suicidal Ideation \[SI\] has 5 questions: wish to be dead,non-specific active suicidal thoughts,active SI with any methods \[not plan\]without intent to act,active SI with some intent to act without specific plan,active SI with specific plan,intent)or yes answered to any question in suicidal behavior section (5 questions:preparatory acts/behavior,aborted attempt,interrupted attempt,actual attempt\[non-fatal\],completed suicide).
Time frame: Up to 14 days post last dose in Phase C (up to 28 weeks)
Population: Phase C Efficacy Sample included all participants randomized to the double-blind treatment who had taken at least one dose of investigational medicinal product (IMP) in Phase C. Overall number of participants analyzed for median time to relapse is the number of participants with impending relapse.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase C: Brexpiprazole + ADT | Phase C: Time-to-Relapse by Any Criteria as Defined in Blinded Addendum | 63.0 days |
| Phase C: Placebo + ADT | Phase C: Time-to-Relapse by Any Criteria as Defined in Blinded Addendum | 63.0 days |
p-value: 0.5195% CI: [0.776, 1.669]Log Rank
Secondary
Phase C: Change From Baseline for Randomization Phase in CGI-S Score at Week 46
The CGI -S was used to rate the severity of illness for each participant on an 8-point scale ranging from 0 to 7 where 0=not assessed, 1=normal, not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=among the most extremely ill participants. A positive change from Baseline indicates worsening of illness. Baseline was defined as the last available assessment value in Phase B for this outcome measure. ANCOVA model was used for analysis.
Time frame: Baseline and Week 46
Population: Phase C Efficacy Sample included all participants randomized to the double-blind treatment who had taken at least one dose of IMP in Phase C. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase C: Brexpiprazole + ADT | Phase C: Change From Baseline for Randomization Phase in CGI-S Score at Week 46 | 0.56 score on a scale | Standard Error 0.1 |
| Phase C: Placebo + ADT | Phase C: Change From Baseline for Randomization Phase in CGI-S Score at Week 46 | 0.53 score on a scale | Standard Error 0.09 |
p-value: 0.795695% CI: [-0.18, 0.24]ANCOVA
Secondary
Phase C: Change From Baseline for Randomization Phase in Each of the SDS Individual Item Scores at Week 46
The SDS is a self-rated instrument used to measure the effect of the participant's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0=not at all, to 10=extremely. Higher scores of 5 and above are associated with significant functional impairment. A positive change from Baseline indicates worsening of symptoms impacting each area. Baseline was defined as the last available assessment value between Week 14 and Week 20 in Phase B for this outcome measure. ANCOVA model was used for analysis.
Time frame: Baseline and Week 46
Population: Phase C Efficacy Sample included all participants randomized to the double-blind treatment who had taken at least one dose of IMP in Phase C. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis for the specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase C: Brexpiprazole + ADT | Phase C: Change From Baseline for Randomization Phase in Each of the SDS Individual Item Scores at Week 46 | Work/School | 0.46 score on a scale | Standard Error 0.22 |
| Phase C: Brexpiprazole + ADT | Phase C: Change From Baseline for Randomization Phase in Each of the SDS Individual Item Scores at Week 46 | Social Life | 0.91 score on a scale | Standard Error 0.19 |
| Phase C: Brexpiprazole + ADT | Phase C: Change From Baseline for Randomization Phase in Each of the SDS Individual Item Scores at Week 46 | Family Life | 0.78 score on a scale | Standard Error 0.19 |
| Phase C: Placebo + ADT | Phase C: Change From Baseline for Randomization Phase in Each of the SDS Individual Item Scores at Week 46 | Work/School | 0.31 score on a scale | Standard Error 0.23 |
| Phase C: Placebo + ADT | Phase C: Change From Baseline for Randomization Phase in Each of the SDS Individual Item Scores at Week 46 | Social Life | 0.56 score on a scale | Standard Error 0.19 |
| Phase C: Placebo + ADT | Phase C: Change From Baseline for Randomization Phase in Each of the SDS Individual Item Scores at Week 46 | Family Life | 0.52 score on a scale | Standard Error 0.19 |
Comparison: SDS Individual Item: Work/Schoolp-value: 0.522395% CI: [-0.31, 0.61]ANCOVA
Comparison: SDS Individual Item: Social Lifep-value: 0.090495% CI: [-0.06, 0.77]ANCOVA
Comparison: SDS Individual Item: Family Lifep-value: 0.228995% CI: [-0.16, 0.67]ANCOVA
Secondary
Phase C: Change From Baseline for Randomization Phase in MADRS Total Score at Week 46
The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants were rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A positive change from Baseline indicates worsening of symptoms. Baseline was defined as the last available assessment value in Phase B for this outcome measure. ANCOVA model was used for analysis.
Time frame: Baseline and Week 46
Population: Phase C Efficacy Sample included all participants randomized to the double-blind treatment who had taken at least one dose of IMP in Phase C. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase C: Brexpiprazole + ADT | Phase C: Change From Baseline for Randomization Phase in MADRS Total Score at Week 46 | 4.09 score on a scale | Standard Error 0.75 |
| Phase C: Placebo + ADT | Phase C: Change From Baseline for Randomization Phase in MADRS Total Score at Week 46 | 4.21 score on a scale | Standard Error 0.73 |
p-value: 0.880695% CI: [-1.73, 1.49]ANCOVA
Secondary
Phase C: Change From Baseline for Randomization Phase in Sheehan Disability Scale (SDS) Mean Total Score at Week 46
The SDS is a self-rated instrument used to measure the effect of the participant's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0=not at all, to 10=extremely. The SDS total score is the mean of the 3 item responses. The SDS total score ranges from 0 to 10, with higher scores indicating greater functional impairment. Baseline was defined as the last available assessment value between Week 14 and Week 20 in Phase B for this outcome measure. Analysis of covariance (ANCOVA) model was used for analysis.
Time frame: Baseline and Week 46
Population: Phase C Efficacy Sample included all participants randomized to the double-blind treatment who had taken at least one dose of IMP in Phase C. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase C: Brexpiprazole + ADT | Phase C: Change From Baseline for Randomization Phase in Sheehan Disability Scale (SDS) Mean Total Score at Week 46 | 0.72 score on a scale | Standard Error 0.18 |
| Phase C: Placebo + ADT | Phase C: Change From Baseline for Randomization Phase in Sheehan Disability Scale (SDS) Mean Total Score at Week 46 | 0.48 score on a scale | Standard Error 0.18 |
p-value: 0.239395% CI: [-0.16, 0.62]ANCOVA
Secondary
Phase C: Percentage of Participants Maintaining Remission
Participants maintaining remission was defined as MADRS total score ≤10. The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants were rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression.
Time frame: Weeks 21, 23, 25, 29, 33, 37, 41, 45, and 46
Population: Phase C Efficacy Sample included all participants randomized to the double-blind treatment who had taken at least one dose of IMP in Phase C. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 23 | 85.22 percentage of participants |
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 37 | 87.92 percentage of participants |
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 29 | 79.89 percentage of participants |
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 41 | 84.78 percentage of participants |
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 25 | 84.79 percentage of participants |
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 45 | 88.14 percentage of participants |
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 33 | 88.55 percentage of participants |
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 46 | 90.91 percentage of participants |
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 21 | 90.34 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 46 | 91.7 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 21 | 91.3 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 23 | 82.7 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 25 | 82.6 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 29 | 85.5 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 33 | 88.4 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 37 | 89.0 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 41 | 89.4 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Maintaining Remission | Week 45 | 89.0 percentage of participants |
Comparison: Week 21p-value: 0.7081Chi-squared
Comparison: Week 23p-value: 0.4589Chi-squared
Comparison: Week 25p-value: 0.5314Chi-squared
Comparison: Week 29p-value: 0.1433Chi-squared
Comparison: Week 33p-value: 0.9636Chi-squared
Comparison: Week 37p-value: 0.7596Chi-squared
Comparison: Week 41p-value: 0.2402Chi-squared
Comparison: Week 45p-value: 0.8363Chi-squared
Comparison: Week 46p-value: 0.8308Chi-squared
Secondary
Phase C: Percentage of Participants Meeting Any Relapse Criteria
Relapse criteria included: At the same visit, increase in MADRS total score (10 items,7-point scale of 0=no symptoms to 6=severe symptoms, total score of 0 to 60) of 50% from randomization and CGI-S (8-point scale ranging from 0=not assessed to 7=most extremely ill) score ≥4, hospitalization for depression, discontinuation for lack of efficacy/worsening of depression, active suicidality (score of ≥4 on MADRS item 10 of suicidality) or answer of yes on question 4 or 5 of C-SSRS (SI has 5 questions: wish to be dead, non-specific active suicidal thoughts, active SI with any methods \[not plan\] without intent to act, active SI with some intent to act without specific plan, active SI with specific plan, intent) or answer of yes to any question in suicidal behavior section (5 questions: preparatory acts/behavior, aborted attempt, interrupted attempt, actual attempt \[non-fatal\], completed suicide). Percentage of participants were rounded off to single decimal point.
Time frame: Up to 26 weeks in Phase C
Population: Phase C Efficacy Sample included all participants randomized to the double-blind treatment who had taken at least one dose of IMP in Phase C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase C: Brexpiprazole + ADT | Phase C: Percentage of Participants Meeting Any Relapse Criteria | 22.5 percentage of participants |
| Phase C: Placebo + ADT | Phase C: Percentage of Participants Meeting Any Relapse Criteria | 20.6 percentage of participants |
p-value: 0.603Chi-squared
Secondary
Phase C: Time-to-functional Relapse Based on SDS Criteria
Time-to-functional relapse was based on a 30% increase in the SDS mean total score from Phase C Baseline, at least one SDS sub-score at 4 or greater, and an SDS total score ≥7 when all 3 sub-scores were available. The SDS is a self-rated instrument used to measure the effect of the participant's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0=not at all, to 10=extremely. Higher scores of 5 and above are associated with significant functional impairment.
Time frame: Up to 14 days post last dose in Phase C (up to 28 weeks)
Population: Phase C Efficacy Sample included all participants randomized to the double-blind treatment who had taken at least one dose of IMP in Phase C. Overall number of participants analyzed for median time to functional relapse is the number of participants with impending functional relapse.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase C: Brexpiprazole + ADT | Phase C: Time-to-functional Relapse Based on SDS Criteria | 36.0 days |
| Phase C: Placebo + ADT | Phase C: Time-to-functional Relapse Based on SDS Criteria | 35.0 days |
p-value: 0.308695% CI: [0.857, 1.615]Log Rank