Depression, Depressive Disorder, Depressive Disorder, Major, Mental Disorders, Mood Disorders
Conditions
Keywords
OPC-34712, brexpiprazole, Major Depressive Disorder, Adjunctive Treatment
Brief summary
To assess the long-term safety and tolerability of oral OPC-34712 (brexpiprazole), given in addition to an FDA approved antidepressant (ADT) for the treatment of adults with Major Depressive Disorder (MDD)
Interventions
DRUGOPC-34712
Tablet
DRUGEscitalopram
Tablet
DRUGFluoxetine
Capsule
DRUGParoxetine CR
Controlled-release tablets
DRUGSertraline
Tablets
DRUGDuloxetine
Delayed-release capsules
DRUGVenlafaxine XR
Extended-release capsules
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male and Female outpatients 18-65 years of age Eligible subjects from Trials 331-10-227, 331-10-228 or 331-12-282: * Subjects who completed participation in the Double-blind Randomization Phase (i.e. Week 14 visit) in Trial 331-10-227, Trial 331-10-228, or Trial 331-12-282 or * Subjects who met criteria for a response, but did not meet criteria for remission at Week 14 of either trial Eligible subjects from other Phase 3, Double-blind, Brexpiprazole MDD trials: • Subjects who completed the last scheduled visit of the prior Double-blind Randomized Phase 3 trial.
Exclusion criteria
* Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving OPC-34712. * Subjects with a major protocol violation during the course of their participation in the Double-blind Randomization Phase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events (AEs) - All Participants | From screening to week 52/early termination | To assess the frequency and severity of AEs as the variables of safety and tolerability of brexpiprazole. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Clinical Global Impression - Severity (CGI-S) of Illness Score | From screening to week 52/early termination | The severity of illness for each participant was rated using the CGI-S . On the basis of the investigator answer to the question: Considering your total clinical experience with this particular population, how mentally ill was the participant at that time? Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. |
| Change From Baseline in Mean Clinical Global Impression - Improvement (CGI-I) Score | From screening to week 52/early termination | The efficacy of trial treatment was rated for each participant using the CGI-I. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. All responses were compared to the participant's condition at screening. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse and 7 = very much worse. |
| Summary of Mean Change From Baseline in Sheehan Disability Scale (SDS) Mean Score | From screening to week 52/early termination | The SDS was a self-rated instrument used to measure the effect of the participant's symptoms on regular life responsibilities. The SDS was a visual analogue scale that used spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the 3 domains with scores from 0 = not at all, to 10 = extremely. Scores of 5 and above were associated with significant functional impairment. |
| Change From Baseline in the Inventory of Depressive Symptomatology - Self Report (IDS-SR) Total Score | From screening to week 52/early termination | The IDS-SR was a 30-item self-report measure used to assess core diagnostic depressive symptoms as well as atypical and melancholic symptom features of MDD. The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the best rating and 3 being the worst rating. The IDS-SR Total Score is the sum of ratings of 28 item scores. The possible IDS-SR Total Score ranges from 0 (best) to 84 (worst). Under item 9, two sub-items 9A and 9B exist, with possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two sub-items are not included in the calculation of the total score. Item 11 or item 12 should be completed but not both, and similarly, item 13 or item 14 should be completed but not both. If the number of items recorded is at least 23 and at most 27, the IDS-SR Total Score will be the mean of the recorded items multiplied by 28 and then rounded to the first decimal place. |
Countries
Canada, France, Germany, Hungary, Poland, Romania, Russia, Serbia, Slovakia, Ukraine, United States
Participant flow
Recruitment details
This trial was conducted in 2944 participants at 188 sites in 11 countries: Canada, France, Germany, Hungary, Poland, Romania, Russian Federation, Serbia, Slovakia, Ukraine, and United States (US).
Pre-assignment details
The study population consisted of eligible participants who completed one of the double-blind, phase 3 brexpiprazole major depressive disorder (MDD) trials and who, could potentially benefit from adjunctive treatment with oral brexpiprazole for MDD.
Participants by arm
| Arm | Count |
|---|---|
| Prior Placebo Participants who received placebo with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment. | 516 |
| Prior Brexpiprazole Participants who received Brexpiprazole with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment. | 707 |
| Prior ADT Participants who received only ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment. | 1,645 |
| Prior Seroquel Participants who received Seroquel with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment. | 76 |
| Total | 2,944 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 56 | 61 | 134 | 6 |
| Overall Study | Lack of Efficacy | 30 | 40 | 30 | 4 |
| Overall Study | Lost to Follow-up | 11 | 28 | 41 | 0 |
| Overall Study | Paticipant met withdrawal criteria | 11 | 28 | 54 | 0 |
| Overall Study | Protocol Deviation | 25 | 33 | 61 | 2 |
| Overall Study | Withdrawal by participant | 79 | 89 | 168 | 8 |
| Overall Study | Withdrawn by Investigator | 9 | 8 | 31 | 2 |
Baseline characteristics
| Characteristic | Total | Prior Placebo | Prior Brexpiprazole | Prior ADT | Prior Seroquel |
|---|---|---|---|---|---|
| Age, Continuous | 45.0 years STANDARD_DEVIATION 12 | 45.0 years STANDARD_DEVIATION 11 | 45.0 years STANDARD_DEVIATION 11 | 44.0 years STANDARD_DEVIATION 12 | 44.0 years STANDARD_DEVIATION 11 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 14 Participants | 0 Participants | 6 Participants | 8 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 21 Participants | 5 Participants | 8 Participants | 8 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 288 Participants | 55 Participants | 76 Participants | 149 Participants | 8 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 6 Participants | 0 Participants | 0 Participants | 6 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 27 Participants | 4 Participants | 8 Participants | 15 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 2588 Participants | 452 Participants | 609 Participants | 1459 Participants | 68 Participants |
| Sex: Female, Male Female | 2005 Participants | 367 Participants | 479 Participants | 1108 Participants | 51 Participants |
| Sex: Female, Male Male | 939 Participants | 149 Participants | 228 Participants | 537 Participants | 25 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 | 2 / 516 | 2 / 706 | 0 / 1,640 | 0 / 76 |
| other Total, other adverse events | 296 / 516 | 323 / 706 | 787 / 1,640 | 33 / 76 |
| serious Total, serious adverse events | 14 / 516 | 23 / 706 | 33 / 1,640 | 1 / 76 |
Outcome results
Primary
Adverse Events (AEs) - All Participants
To assess the frequency and severity of AEs as the variables of safety and tolerability of brexpiprazole.
Time frame: From screening to week 52/early termination
Population: Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prior Placebo | Adverse Events (AEs) - All Participants | Participants with treatment emergent AE (TEAE) | 399 Participants |
| Prior Placebo | Adverse Events (AEs) - All Participants | Participants with adverse events | 400 Participants |
| Prior Placebo | Adverse Events (AEs) - All Participants | Participants with serious TEAE | 14 Participants |
| Prior Placebo | Adverse Events (AEs) - All Participants | Partcipants discontinued due to AEs | 55 Participants |
| Prior Placebo | Adverse Events (AEs) - All Participants | Participants with severe TEAE | 48 Participants |
| Prior Brexpiprazole | Adverse Events (AEs) - All Participants | Participants with severe TEAE | 64 Participants |
| Prior Brexpiprazole | Adverse Events (AEs) - All Participants | Participants with adverse events | 511 Participants |
| Prior Brexpiprazole | Adverse Events (AEs) - All Participants | Participants with treatment emergent AE (TEAE) | 510 Participants |
| Prior Brexpiprazole | Adverse Events (AEs) - All Participants | Participants with serious TEAE | 23 Participants |
| Prior Brexpiprazole | Adverse Events (AEs) - All Participants | Partcipants discontinued due to AEs | 58 Participants |
| Prior ADT | Adverse Events (AEs) - All Participants | Partcipants discontinued due to AEs | 134 Participants |
| Prior ADT | Adverse Events (AEs) - All Participants | Participants with serious TEAE | 33 Participants |
| Prior ADT | Adverse Events (AEs) - All Participants | Participants with severe TEAE | 99 Participants |
| Prior ADT | Adverse Events (AEs) - All Participants | Participants with adverse events | 1165 Participants |
| Prior ADT | Adverse Events (AEs) - All Participants | Participants with treatment emergent AE (TEAE) | 1163 Participants |
| Prior Seroquel | Adverse Events (AEs) - All Participants | Participants with severe TEAE | 4 Participants |
| Prior Seroquel | Adverse Events (AEs) - All Participants | Participants with treatment emergent AE (TEAE) | 51 Participants |
| Prior Seroquel | Adverse Events (AEs) - All Participants | Participants with serious TEAE | 1 Participants |
| Prior Seroquel | Adverse Events (AEs) - All Participants | Participants with adverse events | 51 Participants |
| Prior Seroquel | Adverse Events (AEs) - All Participants | Partcipants discontinued due to AEs | 6 Participants |
Secondary
Change From Baseline in Mean Clinical Global Impression - Improvement (CGI-I) Score
The efficacy of trial treatment was rated for each participant using the CGI-I. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. All responses were compared to the participant's condition at screening. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse and 7 = very much worse.
Time frame: From screening to week 52/early termination
Population: Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs and had at least one post-baseline efficacy evaluation of CGI-S.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prior Placebo | Change From Baseline in Mean Clinical Global Impression - Improvement (CGI-I) Score | 2.60 units on a scale | Standard Deviation 1.3 |
| Prior Brexpiprazole | Change From Baseline in Mean Clinical Global Impression - Improvement (CGI-I) Score | 2.63 units on a scale | Standard Deviation 1.34 |
| Prior ADT | Change From Baseline in Mean Clinical Global Impression - Improvement (CGI-I) Score | 2.63 units on a scale | Standard Deviation 1.39 |
| Prior Seroquel | Change From Baseline in Mean Clinical Global Impression - Improvement (CGI-I) Score | 2.40 units on a scale | Standard Deviation 1.17 |
Secondary
Change From Baseline in the Inventory of Depressive Symptomatology - Self Report (IDS-SR) Total Score
The IDS-SR was a 30-item self-report measure used to assess core diagnostic depressive symptoms as well as atypical and melancholic symptom features of MDD. The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the best rating and 3 being the worst rating. The IDS-SR Total Score is the sum of ratings of 28 item scores. The possible IDS-SR Total Score ranges from 0 (best) to 84 (worst). Under item 9, two sub-items 9A and 9B exist, with possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two sub-items are not included in the calculation of the total score. Item 11 or item 12 should be completed but not both, and similarly, item 13 or item 14 should be completed but not both. If the number of items recorded is at least 23 and at most 27, the IDS-SR Total Score will be the mean of the recorded items multiplied by 28 and then rounded to the first decimal place.
Time frame: From screening to week 52/early termination
Population: Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs and had at least one post-baseline efficacy evaluation of CGI-S.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prior Placebo | Change From Baseline in the Inventory of Depressive Symptomatology - Self Report (IDS-SR) Total Score | -5.25 units on a scale | Standard Deviation 12.21 |
| Prior Brexpiprazole | Change From Baseline in the Inventory of Depressive Symptomatology - Self Report (IDS-SR) Total Score | -4.76 units on a scale | Standard Deviation 11.79 |
| Prior ADT | Change From Baseline in the Inventory of Depressive Symptomatology - Self Report (IDS-SR) Total Score | -3.94 units on a scale | Standard Deviation 10.57 |
| Prior Seroquel | Change From Baseline in the Inventory of Depressive Symptomatology - Self Report (IDS-SR) Total Score | -7.44 units on a scale | Standard Deviation 8.89 |
Secondary
Mean Change From Baseline in Clinical Global Impression - Severity (CGI-S) of Illness Score
The severity of illness for each participant was rated using the CGI-S . On the basis of the investigator answer to the question: Considering your total clinical experience with this particular population, how mentally ill was the participant at that time? Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
Time frame: From screening to week 52/early termination
Population: Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs and had at least one post-baseline efficacy evaluation of CGI-S.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prior Placebo | Mean Change From Baseline in Clinical Global Impression - Severity (CGI-S) of Illness Score | -0.77 units on a scale | Standard Deviation 1.11 |
| Prior Brexpiprazole | Mean Change From Baseline in Clinical Global Impression - Severity (CGI-S) of Illness Score | -0.63 units on a scale | Standard Deviation 1.16 |
| Prior ADT | Mean Change From Baseline in Clinical Global Impression - Severity (CGI-S) of Illness Score | -0.48 units on a scale | Standard Deviation 1.04 |
| Prior Seroquel | Mean Change From Baseline in Clinical Global Impression - Severity (CGI-S) of Illness Score | -0.93 units on a scale | Standard Deviation 0.85 |
Secondary
Summary of Mean Change From Baseline in Sheehan Disability Scale (SDS) Mean Score
The SDS was a self-rated instrument used to measure the effect of the participant's symptoms on regular life responsibilities. The SDS was a visual analogue scale that used spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the 3 domains with scores from 0 = not at all, to 10 = extremely. Scores of 5 and above were associated with significant functional impairment.
Time frame: From screening to week 52/early termination
Population: Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs and had at least one post-baseline efficacy evaluation of CGI-S.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prior Placebo | Summary of Mean Change From Baseline in Sheehan Disability Scale (SDS) Mean Score | -0.80 units on a scale | Standard Deviation 2.8 |
| Prior Brexpiprazole | Summary of Mean Change From Baseline in Sheehan Disability Scale (SDS) Mean Score | -0.70 units on a scale | Standard Deviation 2.6 |
| Prior ADT | Summary of Mean Change From Baseline in Sheehan Disability Scale (SDS) Mean Score | -0.40 units on a scale | Standard Deviation 2.3 |
| Prior Seroquel | Summary of Mean Change From Baseline in Sheehan Disability Scale (SDS) Mean Score | -1.00 units on a scale | Standard Deviation 1.7 |