Major Depressive Disorder (MDD)
Conditions
Keywords
Major Depressive Disorder, Depression
Brief summary
The objectives of this exploratory trial are to evaluate the efficacy, safety, and subjects' subjective satisfaction when switching to adjunctive brexpiprazole in subjects with MDD who have responded inadequately to preceding adjunctive drug therapy.
Interventions
DRUGADT
DRUGBrexpiprazole
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of MDD * In current major depressive episode of ≥ 8 weeks in duration and includes an inadequate response to at least 1 adjunctive treatment. * Positive history of at least 1 additional failure to an adequate monotherapy antidepressant treatment. * HAM-D17 total score≥ 18 * Currently receiving SSRI of SNRI with adjunctive treatment for at least 6 weeks before screening. * Willing to discontinue use of all prohibited psychotropic medications * Historical positive serological results for HIV, hepatitis B/C * Able to provide written informed consent prior to the initiation of any protocol-required procedures * Subjects who could potentially benefit from adjunctive treatment with Brexpiprazole
Exclusion criteria
* Sexually active women of childbearing potential * Male subjects not practicing 2 different methods of birth control * Females who are breastfeeding and/or who have a positive pregnancy test result * Subjects who have received ECT for the current major depressive episode. * Subjects who have had an inadequate response to ECT * Current need for involuntary commitment or who have been hospitalized within 4 weeks of screening * Current Axis I (DSM-IV-TR) * Current Axis II (DSM-IV-TR) * Subjects experiencing hallucinations, delusions, or any psychotic symptomatology in the current major depressive episode. * Subjects receiving new onset psychotherapy. * Subjects who answer Yes on the C-SSRS Suicidal Ideation Item 4, Item 5, or on any of the 5 C-SSRS Suicidal Behavior Items * Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the past 180 days * Hypothyroidism or hyperthyroidism * Clinically significant neurological, hepatic, renal, metabolic, haematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders * Currently treated with insulin for diabetes * Uncontrolled hypertension or symptomatic hypotension, or orthostatic hypotension * Known ischemic heart disease or history of myocardial infarction, congestive heart failure, angioplasty, stenting, or coronary artery bypass surgery * Epilepsy or history of seizures * Positive drug screen * The following laboratory test and ECG results are exclusionary: 1. Platelets ≤ 75,000/mm3 2. Hemoglobin ≤ 9 g/dL 3. Neutrophils, absolute ≤ 1000/mm3 4. AST \> 2 × ULN 5. ALT \> 2 × ULN 6. CPK \> 3 × ULN, unless discussed with and approved by the medical monitor 7. Creatinine ≥ 2 mg/dL 8. HbA1c ≥ 7.0% 9. Abnormal free T4 (Note: Free T4 is measured only if result for TSH is abnormal.) 10. QTcF ≥ 470 msec for females and ≥ 450 msec for males * Treatment with an MAOI or EMSAM within 14 days of the Baseline visit. * Use of benzodiazepines and/or hypnotics within 7 days prior to the first dose of IMP * Use of oral neuroleptics within 7 days prior or long-acting approved atypical antipsychotics ≤ 1 full cycle plus ½ cycle prior to the first dose of IMP * Subjects who would be likely to require prohibited concomitant therapy during the trial. * Subjects who previously participated in any prior brexpiprazole trial * History of neuroleptic malignant syndrome or serotonin syndrome * History of true allergic response to more than one class of medications * Prisoners or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness. * Subjects who participated in a clinical trial within the last 180 days or who participated in more than 2 clinical trials within the past year. * Any subject who, in the opinion of the investigator or medical monitor, should not participate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Baseline and Week 6 | The MADRS was used as the primary efficacy assessment of level of depression. The MADRS was administered using the Structured Interview Guide for the MADRS. Detailed instructions were provided.The MADRS consists of 10 items each, with 7 defined grades of severity (ie, 0 to 6, with 0 being the best rating and 6 being the worst rating). The MADRS total score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score least squares (LS) mean changes from baseline to Week 6 is mentioned below. |
Countries
United States
Participant flow
Recruitment details
This trial was conducted in 61 participants in 28 trial sites, all of which were located in the United States.
Pre-assignment details
The trial consisted of a continuous 6-week open-label treatment period including an initial 2-week titration period with a 30-day (+2 days) follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| Group 1A Participants who had received a prescribed number of tablets of aripiprazole (baseline/primary antidepressant therapy \[ADT\]) and adjunctive therapy were switched to ADT plus one tablet of brexpiprazole as adjunctive therapy daily throughout the 6-week treatment period. | 12 |
| Group 1B Participants who had received a prescribed number of tablets of quetiapine IR (immediate release) or XR (extended release) (baseline/primary ADT) and adjunctive therapy were switched to ADT plus one tablet of brexpiprazole as adjunctive therapy daily throughout the 6-week treatment period. | 11 |
| Group 2 Participants who had received a prescribed number of tablets of any Selective Serotonin Reuptake Inhibitors (SSRI), any Serotonin-norepinephrine Reuptake Inhibitors (SNRI), any tricyclic antidepressant, or Oleptro (trazodone hydrochloride) IR or XR (baseline/primary ADT) and adjunctive therapy were switched to ADT plus one tablet of brexpiprazole as adjunctive therapy daily throughout the 6-week treatment period. | 13 |
| Group 3 Participants who had received a prescribed number of tablets of bupropion (baseline/primary ADT) and adjunctive therapy were switched to ADT plus one tablet of brexpiprazole as adjunctive therapy daily throughout the 6-week treatment period. | 19 |
| Group 4 Participants who had received a prescribed number of tablets of stimulants such as modafinil, methylphenidate, or psychostimulant (baseline/primary ADT) and adjunctive therapy were switched to ADT plus one tablet of brexpiprazole as adjunctive therapy daily throughout the 6-week treatment period. | 6 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Protocol Deviation | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Specified | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Group 1A | Group 1B | Group 2 | Group 3 | Group 4 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 50.2 Years STANDARD_DEVIATION 8.13 | 41.8 Years STANDARD_DEVIATION 13.57 | 48.5 Years STANDARD_DEVIATION 12.2 | 44.1 Years STANDARD_DEVIATION 13.64 | 41.7 Years STANDARD_DEVIATION 13.59 | 45.6 Years STANDARD_DEVIATION 12.44 |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 11 Participants | 15 Participants | 3 Participants | 43 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 2 Participants | 4 Participants | 3 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 12 | 8 / 11 | 6 / 13 | 15 / 19 | 5 / 6 |
| serious Total, serious adverse events | 0 / 12 | 1 / 11 | 0 / 13 | 0 / 19 | 0 / 6 |
Outcome results
Primary
Mean Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
The MADRS was used as the primary efficacy assessment of level of depression. The MADRS was administered using the Structured Interview Guide for the MADRS. Detailed instructions were provided.The MADRS consists of 10 items each, with 7 defined grades of severity (ie, 0 to 6, with 0 being the best rating and 6 being the worst rating). The MADRS total score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score least squares (LS) mean changes from baseline to Week 6 is mentioned below.
Time frame: Baseline and Week 6
Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid post-baseline efficacy assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1A | Mean Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -12.8 Units on a scale | Standard Error 2.26 |
| Group 1B | Mean Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -18.4 Units on a scale | Standard Error 2.1 |
| Group 2 | Mean Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -19.5 Units on a scale | Standard Error 1.99 |
| Group 3 | Mean Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -19.2 Units on a scale | Standard Error 1.59 |
| Group 4 | Mean Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -16.8 Units on a scale | Standard Error 2.97 |
Comparison: The null hypothesis of zero in mean change from baseline in MADRS total score at Week 6 was tested for each treatment group at significance level of 0.05 (2-sided).p-value: <0.0001Mixed Models Analysis