Major Depressive Disorder
Conditions
Keywords
Major depressive disorder, Depression
Brief summary
An outpatient study to evaluate the safety and efficacy of cariprazine as adjunct to antidepressant therapy (ADT) in participants with major depressive disorder (MDD) who have an inadequate response to ADT alone. This clinical study compared cariprazine + ADT with placebo + ADT in outpatients with a diagnosis of MDD and an inadequate response to ADT. The study consisted of approximately 2 weeks of screening and washout followed by 8 weeks of double-blind treatment followed by a 1 week safety follow-up.
Interventions
DRUGPlacebo
Placebo was supplied in capsules
DRUGCariprazine
Cariprazine was supplied in capsules.
Sponsors
Gedeon Richter Ltd.
Forest Laboratories
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 or female outpatients 18 to 65 years of age, inclusive. * Currently meet the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for moderate to severe major depressive disorder (MDD). * Current major depressive episode of at least 8 weeks and not exceeding 24 months in duration. * Ongoing inadequate response to protocol allowed antidepressant therapy (ADT).
Exclusion criteria
* Principal DSM-IV-TR-based diagnosis of an axis I disorder, other than MDD, * Women who are pregnant, or planning to become pregnant or breastfeed during the study or not practicing reliable contraception that will continue through out the study. * History of meeting DSM-IV-TR criteria for: 1. Depressive episode with psychotic or catatonic features. 2. Manic, hypomanic or mixed episode, including bipolar disorder and substance induced manic, hypomanic or mixed episode. 3. Schizophrenia, schizoaffective, or other psychotic disorder. 4. Obsessive-compulsive disorder. 5. Bulimia or anorexia nervosa. 6. Dementia, amnesic, or other cognitive disorder. 7. Mental retardation. * Participants considered a suicide risk.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 8 | Baseline to Week 8 | The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and 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 negative change score indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at Week 8 | Baseline to Week 8 | The SDS measures an individual's perception of the extent to which his or her emotional symptoms are disrupting his or her functioning in 3 domains, work/school, social life/leisure activities, and family life/home responsibilities. The participant is asked to rate the degree to which their functioning is impaired on an 11-point scale, ranging from 0 (not at all) to 10 (extremely). Scores of 0 to 3 indicate mild functional impairment, 4 to 6 indicate moderate functional impairment, and 7 to 9 indicate marked functional impairment. The scores for the 3 domains are summed into a total score that ranges from 0 (unimpaired) to 30 (highly impaired). A higher score indicates greater impairment. A negative change score indicates improvement. |
Countries
Estonia, Finland, Slovakia, Sweden, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment. | 266 |
| Cariprazine 1-2 mg Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment. | 273 |
| Cariprazine 2-4.5 mg Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment. | 273 |
| Total | 812 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 18 | 36 |
| Overall Study | Insufficient Therapeutic Response | 3 | 4 | 0 |
| Overall Study | Lost to Follow-up | 3 | 2 | 5 |
| Overall Study | Other Miscellaneous Reasons | 2 | 0 | 0 |
| Overall Study | Protocol Deviation | 7 | 10 | 10 |
| Overall Study | Withdrawal of Consent | 12 | 14 | 15 |
Baseline characteristics
| Characteristic | Placebo | Cariprazine 1-2 mg | Cariprazine 2-4.5 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 46.4 years STANDARD_DEVIATION 11.6 | 45.5 years STANDARD_DEVIATION 11.9 | 45.1 years STANDARD_DEVIATION 11.4 | 45.7 years STANDARD_DEVIATION 11.6 |
| Body Mass Index (BMI) | 28.93 kg/m^2 STANDARD_DEVIATION 5.09 | 28.21 kg/m^2 STANDARD_DEVIATION 5.51 | 29.05 kg/m^2 STANDARD_DEVIATION 5.59 | 28.73 kg/m^2 STANDARD_DEVIATION 5.41 |
| Race/Ethnicity, Customized All other races | 36 participants | 39 participants | 31 participants | 106 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants | 1 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 4 participants | 4 participants | 9 participants |
| Race/Ethnicity, Customized Black or African American | 32 participants | 31 participants | 24 participants | 87 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 14 participants | 17 participants | 22 participants | 53 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 252 participants | 256 participants | 251 participants | 759 participants |
| Race/Ethnicity, Customized Other | 1 participants | 3 participants | 2 participants | 6 participants |
| Race/Ethnicity, Customized White | 230 participants | 234 participants | 242 participants | 706 participants |
| Sex: Female, Male Female | 190 Participants | 187 Participants | 201 Participants | 578 Participants |
| Sex: Female, Male Male | 76 Participants | 86 Participants | 72 Participants | 234 Participants |
| Waist Circumference | 94.32 cm STANDARD_DEVIATION 13.44 | 93.36 cm STANDARD_DEVIATION 14.2 | 94.91 cm STANDARD_DEVIATION 14.66 | 94.20 cm STANDARD_DEVIATION 14.12 |
| Weight | 81.53 kg STANDARD_DEVIATION 16.19 | 79.69 kg STANDARD_DEVIATION 16.31 | 82.17 kg STANDARD_DEVIATION 17.37 | 81.13 kg STANDARD_DEVIATION 16.65 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 266 | 0 / 273 | 0 / 273 |
| other Total, other adverse events | 102 / 266 | 121 / 273 | 179 / 273 |
| serious Total, serious adverse events | 1 / 266 | 0 / 273 | 3 / 273 |
Outcome results
Primary
Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 8
The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and 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 negative change score indicates improvement.
Time frame: Baseline to Week 8
Population: Intent-to-treat population consisted of all patients in the Safety Population who had at least 1 post-baseline assessment of the MADRS total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 8 | -12.5 Units on a scale | Standard Error 0.5 |
| Cariprazine 1-2 mg | Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 8 | -13.4 Units on a scale | Standard Error 0.5 |
| Cariprazine 2-4.5 mg | Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 8 | -14.6 Units on a scale | Standard Error 0.6 |
p-value: 0.240495% CI: [-2.4, 0.6]Mixed-effect model for repeated measures
p-value: 0.011495% CI: [-3.7, -0.6]Mixed-effect model for repeated measures
Secondary
Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at Week 8
The SDS measures an individual's perception of the extent to which his or her emotional symptoms are disrupting his or her functioning in 3 domains, work/school, social life/leisure activities, and family life/home responsibilities. The participant is asked to rate the degree to which their functioning is impaired on an 11-point scale, ranging from 0 (not at all) to 10 (extremely). Scores of 0 to 3 indicate mild functional impairment, 4 to 6 indicate moderate functional impairment, and 7 to 9 indicate marked functional impairment. The scores for the 3 domains are summed into a total score that ranges from 0 (unimpaired) to 30 (highly impaired). A higher score indicates greater impairment. A negative change score indicates improvement.
Time frame: Baseline to Week 8
Population: Intent-to-treat population consisted of all patients in the Safety Population who had at least 1 post-baseline assessment of the MADRS total score. Only participants with scores for all 3 domains were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at Week 8 | -6.6 Units on a scale | Standard Error 0.5 |
| Cariprazine 1-2 mg | Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at Week 8 | -7.7 Units on a scale | Standard Error 0.5 |
| Cariprazine 2-4.5 mg | Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at Week 8 | -8.0 Units on a scale | Standard Error 0.5 |
p-value: 0.240495% CI: [-2.5, 0.3]Mixed-effect model for repeated measures
p-value: 0.11495% CI: [-2.8, 0]Mixed-effect model for repeated measures