Depression, Depressive Disorder, Depressive Disorder, Major, Mental Disorders, Mood Disorders
Conditions
Keywords
OPC-34712, brexpiprazole, Major Depressive Disorder, Adjunctive Treatment, Anxious Distress
Brief summary
The purpose of this study is to assess the tolerability, safety, and efficacy of brexpiprazole (2.0 mg/day) as adjunctive therapy in adult subjects with a diagnosis of MDD with and without anxious distress
Detailed description
The introduction of atypical antipsychotics has created a renewed interest in adjunctive therapy for MDD, particularly for treatment-resistant MDD. Several atypical antipsychotics have been shown to enhance the response to ADT. This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, fixed-dose trial designed to assess the safety and efficacy of brexpiprazole (2.0 mg/day) as adjunctive therapy to an assigned open-label ADT in depressed subjects with and without anxious distress.
Interventions
DRUGPlacebo + ADT
Placebo + ADT Placebo + FDA Approved Antidepressant (ADT)
DRUGBrexpiprazole +ADT
Brexpiprazole + ADT Tablet, Oral, 2mg brexpiprazole and FDA Approved Antidepressant (ADT)
Sponsors
H. Lundbeck A/S
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
* Male and Female subjects between 18-65 years of age, with diagnosis of major depressive disorder with or without anxious distress * Current depressive episode must be at least 8 weeks in duration
Exclusion criteria
* Subjects with a history of Neuroleptic Malignant Syndrome or Serotonin Syndrome * Subjects who report an inadequate response to more than 3 antidepressant treatments in the current episode * Subjects with a current Axis I diagnosis of: Delirium, dementia, amnestic or other cognitive disorder, Schizophrenia, schizoaffective disorder, or other psychotic disorder, Bipolar I or II disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Montgomery-Asberg Depression | From baseline (end of Phase A [Week 8]) to week 14 | To assess the change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from Baseline (End of Phase A \[Week 8\]) to Week 14. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The rater decided whether the rating lied on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment | From baseline (end of Phase A [Week 8]) to week 14 | To assess the change in the Sheehan Disability Scale (SDS) Score (the mean of 3 individual item scores) from Baseline (End of Phase A \[Week 8\]) to Week 14 (End of Phase B). SDS was a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life, and family life/home responsibility. Each item was scored using a scale of 0 to 10 (a higher score indicates symptoms have disrupted work, social life, and family life/home responsibility extremely). The maximum total score was 30; 0 = not at all, to 30 = extremely. |
| Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With <25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score | From baseline (end of Phase A [Week 8]) to week 14 | To assess the change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with \< 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected. |
| Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). | From baseline (end of Phase A [Week 8]) to week 14 | To assess the change from end of Phase A (Week 8) to end of Phase B (Week 14) in MADRS Total Score for the subpopulations with anxious distress as specified in DSM-V. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected. |
Countries
Germany, Hungary, Poland, Slovakia, United States
Participant flow
Recruitment details
This trial was conducted in 837 participants at 51 trial sites in the following 5 countries:Germany,Hungary,Poland,Slovakia,andUnited States (US).A total of 1144 participants with major depressive disorder were screened for the trial, 837 enrolled into Phase A,394 were randomized into Phase B and 322 continued treatment with placebo+ADT in Phase A+
Pre-assignment details
Trial consisted of a screening phase and 3 phases. In phase A (8-week single-blind prospective treatment phase) and in phase A+ (Single-blind phase A Responder), there was single treatment group. In phase B (6-week double-blind randomization phase), there were 2 treatment groups. All Outcome Measures were assessed in phase B.
Participants by arm
| Arm | Count |
|---|---|
| Brexpiprazole + ADT Phase B: Brexpiprazole +Antidepressant therapy (ADT):
Participants received brexpiprazole 2mg and ADT orally once daily for 6 weeks. | 192 |
| Placebo + ADT Phase B: Placebo + Antidepressant therapy (ADT):
Participants received matching placebo and ADT orally once daily for 6 weeks | 202 |
| Total | 394 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase A | Adverse Event | 22 | 0 | 0 | 0 |
| Phase A | Lost to Follow-up | 9 | 0 | 0 | 0 |
| Phase A | Participant Met Withdrawal Criteria | 34 | 0 | 0 | 0 |
| Phase A | Participant withdrawn by investigator | 10 | 0 | 0 | 0 |
| Phase A | Protocol deviation | 12 | 0 | 0 | 0 |
| Phase A | Withdrawal by Subject | 34 | 0 | 0 | 0 |
| Phase A+ | Adverse Event | 0 | 0 | 0 | 1 |
| Phase A+ | Lost to Follow-up | 0 | 0 | 0 | 6 |
| Phase A+ | Participant Met Withdrawal Criteria | 0 | 0 | 0 | 1 |
| Phase A+ | Participant withdrawn by investigator | 0 | 0 | 0 | 1 |
| Phase A+ | Withdrawal by Participant | 0 | 0 | 0 | 5 |
| Phase B | Adverse Event | 0 | 4 | 1 | 0 |
| Phase B | Lack of Efficacy | 0 | 1 | 2 | 0 |
| Phase B | Lost to Follow-up | 0 | 2 | 1 | 0 |
| Phase B | Participant Met Withdrawal Criteria | 0 | 0 | 1 | 0 |
| Phase B | Withdrawal by Participant | 0 | 8 | 1 | 0 |
Baseline characteristics
| Characteristic | Brexpiprazole + ADT | Placebo + ADT | Total |
|---|---|---|---|
| Age, Continuous | 43.0 years STANDARD_DEVIATION 12.7 | 42.7 years STANDARD_DEVIATION 12.5 | 42.9 years STANDARD_DEVIATION 12.6 |
| Race/Ethnicity, Customized Hispanic or Latino | 11 Participants | 9 Participants | 20 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 181 Participants | 192 Participants | 373 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Germany | 27 participants | 29 participants | 56 participants |
| Region of Enrollment Hungary | 16 participants | 16 participants | 32 participants |
| Region of Enrollment Poland | 26 participants | 26 participants | 52 participants |
| Region of Enrollment Slovakia | 23 participants | 25 participants | 48 participants |
| Region of Enrollment United States | 100 participants | 106 participants | 206 participants |
| Sex: Female, Male Female | 147 Participants | 144 Participants | 291 Participants |
| Sex: Female, Male Male | 45 Participants | 58 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 192 | 0 / 202 |
| other Total, other adverse events | 49 / 192 | 35 / 202 |
| serious Total, serious adverse events | 1 / 192 | 0 / 202 |
Outcome results
Primary
Change in the Montgomery-Asberg Depression
To assess the change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from Baseline (End of Phase A \[Week 8\]) to Week 14. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The rater decided whether the rating lied on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.
Time frame: From baseline (end of Phase A [Week 8]) to week 14
Population: The primary analysis was performed on Efficacy Sample which included all randomized participants who took at least one dose of trial medication in Phase B and who have both an end of Phase A (Week 8) and at least one post-randomization MADRS Total Score during Phase B.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole + ADT | Change in the Montgomery-Asberg Depression | -10.4 Units on a scale | Standard Error 0.63 |
| Placebo + ADT | Change in the Montgomery-Asberg Depression | -8.07 Units on a scale | Standard Error 0.61 |
Comparison: Statistical Analysis at Week 14p-value: 0.007495% CI: [-3.97, -0.62]Mixed Models Analysis
Secondary
Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V).
To assess the change from end of Phase A (Week 8) to end of Phase B (Week 14) in MADRS Total Score for the subpopulations with anxious distress as specified in DSM-V. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.
Time frame: From baseline (end of Phase A [Week 8]) to week 14
Population: Subpopulation of Anxious Distress Sample: Comprised of all participants in the Efficacy Sample who had anxious distress as specified in DSM-V.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole + ADT | Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). | -11.8 Units on a scale | Standard Error 0.81 |
| Placebo + ADT | Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). | -8.87 Units on a scale | Standard Error 0.81 |
Comparison: Statistical Analysis at Week 14p-value: 0.009995% CI: [-5.24, -0.72]Mixed Models Analysis
Secondary
Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With <25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score
To assess the change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with \< 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.
Time frame: From baseline (end of Phase A [Week 8]) to week 14
Population: Subpopulation of \<25% Improvement Sample: Comprised of all participants in the Efficacy Sample who had \<25% improvement at the end of Phase A in MADRS Total Score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole + ADT | Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With <25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score | -11.1 Units on a scale | Standard Error 0.71 |
| Placebo + ADT | Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With <25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score | -8.87 Units on a scale | Standard Error 0.71 |
Comparison: Statistical Analysis at Week 14p-value: 0.026395% CI: [-4.23, -0.27]Mixed Models Analysis
Secondary
Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment
To assess the change in the Sheehan Disability Scale (SDS) Score (the mean of 3 individual item scores) from Baseline (End of Phase A \[Week 8\]) to Week 14 (End of Phase B). SDS was a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life, and family life/home responsibility. Each item was scored using a scale of 0 to 10 (a higher score indicates symptoms have disrupted work, social life, and family life/home responsibility extremely). The maximum total score was 30; 0 = not at all, to 30 = extremely.
Time frame: From baseline (end of Phase A [Week 8]) to week 14
Population: The primary analysis was performed on Efficacy Sample which included all randomized participants who took at least one dose of trial medication in Phase B and who have both an end of Phase A (Week 8) and at least one post-randomization MADRS Total Score during Phase B.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole + ADT | Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment | -1.63 Units on a scale | Standard Error 0.18 |
| Placebo + ADT | Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment | -1.41 Units on a scale | Standard Error 0.17 |
Comparison: Statistical Analysis at Week 14p-value: 0.333195% CI: [-0.66, 0.23]Mixed Models Analysis