Major Depressive Disorder
Conditions
Keywords
MDD
Brief summary
The objective of this study is to evaluate the efficacy, safety and tolerability of cariprazine as an adjunctive treatment to antidepressant therapy (ADT) in patients with MDD who have had an inadequate response to antidepressants alone.
Interventions
DRUGCariprazine
Cariprazine supplied in capsules
DRUGPlacebo
Placebo supplied in capsules
ADT as prescribed by the physician per standard of care in clinical practice.
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent has been obtained. * Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable (eg, Written Authorization for Use and Release of Health and Research Study Information \[US sites\] and written Data Protection consent \[EU sites\]). * Participant must be an outpatient at the time of Visit 1 (Screening). * Participant meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for MDD based on Structured Clinical Interview for DSM-5 (SCID-5), with a current major depressive episode of at least 8 weeks and not exceeding 24 months in duration at Visit 1/Screening. A diagnosis of MDD with psychotic features will be acceptable. * Diagnosis of MDD confirmed through a formal adjudication process. * Participant demonstrates ability to follow study instructions and likely to complete all required visits. * Participant must have an inadequate response, as measured by the modified antidepressant treatment response questionnaire (ATRQ), to 1 to 3 antidepressants administered during the current episode at an adequate dose (as per package insert) and for at least 6 weeks duration, with at least one dose escalation during the current depressive episode. * Only one antidepressant (of sufficient dose per package insert and taken for at least 6 weeks) will be allowed at randomization and Participants must agree to continue taking the same ADT dosing regimen through completion of Visit 6/early termination (ET). Participants who are taking more than one antidepressant at Screening, regardless of the indication, will need to discontinue all other antidepressants prior to Visit 2 (Baseline). * Male and female Participants must agree to use a medically acceptable and highly effective method of birth control during the course of the entire study. * Women of childbearing potential (only) must have a negative serum β-human chorionic gonadotropin pregnancy test prior to Visit 2.
Exclusion criteria
* Diagnosis of any current psychiatric diagnosis other than MDD (including those with current intellectual development disability) with the exception of specific phobias. * Participant has a history of intolerance or hypersensitivity to cariprazine or other drugs of the same class or to rescue medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 6 in the MADRS (Montgomery-Åsberg Depression Rating Scale) Total Score | Baseline and Week 6 | The MADRS is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants were rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each item was scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity. The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change from Baseline indicates improvement. Mixed-effects Model for Repeated Measures (MMRM) was used for analyses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 6 in the Clinical Global Impressions-Severity (CGI-S) Score | Baseline and Week 6 | The CGI-S is a clinician-rated scale used to rate the severity of the participant's current state of mental illness compared with MDD population. The participant was rated on a scale from 1 to 7, where 1=normal, not at all ill and 7=among the most extremely ill participants. Higher score indicates worsening of mental illness. A negative change from Baseline indicates improvement. MMRM was used for analyses. |
Countries
Canada, Czechia, Finland, Poland, Puerto Rico, Serbia, Slovakia, United States
Participant flow
Pre-assignment details
A total of 752 participants were enrolled, of which 751 took ≥1 dose of double-blind investigational product and were included in the Safety Population. One participant was randomized but did not receive treatment and was excluded from the study analyses. At the end of treatment in the Double-blind Period, participants continued on their background antidepressant therapy (ADT) and entered the Safety Follow-up Period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + ADT Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6. | 250 |
| Cariprazine 1.5 mg/Day + ADT Cariprazine 1.5 mg capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6. | 250 |
| Cariprazine 3 mg/Day + ADT Cariprazine 1.5 mg capsules, orally, once daily for 2 weeks starting at the Baseline, titrated to 3.0 mg capsules, orally, once daily from Week 2 through Week 6 in addition to their ongoing ADT (same antidepressant and dose of ADT) during the Double-blind Treatment Period, up to Week 6. | 251 |
| Total | 751 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Treatment Period (6 Weeks) | Adverse Event | 6 | 9 | 13 |
| Double-blind Treatment Period (6 Weeks) | Lack of Efficacy | 1 | 0 | 1 |
| Double-blind Treatment Period (6 Weeks) | Lost to Follow-up | 1 | 1 | 2 |
| Double-blind Treatment Period (6 Weeks) | Non-compliance With Study Drug | 1 | 3 | 1 |
| Double-blind Treatment Period (6 Weeks) | Protocol Deviation | 1 | 0 | 1 |
| Double-blind Treatment Period (6 Weeks) | Reason not Specified | 1 | 0 | 1 |
| Double-blind Treatment Period (6 Weeks) | Withdrawal by Subject | 4 | 4 | 6 |
| Safety Follow-Up Period (4 Weeks) | Death | 1 | 0 | 0 |
| Safety Follow-Up Period (4 Weeks) | Lost to Follow-up | 0 | 0 | 2 |
| Safety Follow-Up Period (4 Weeks) | Reason not Specified | 0 | 0 | 2 |
| Safety Follow-Up Period (4 Weeks) | Withdrawal by Subject | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo + ADT | Total | Cariprazine 3 mg/Day + ADT | Cariprazine 1.5 mg/Day + ADT |
|---|---|---|---|---|
| Age, Continuous | 46.2 years STANDARD_DEVIATION 12.12 | 45.7 years STANDARD_DEVIATION 12.51 | 45.8 years STANDARD_DEVIATION 12.45 | 45.0 years STANDARD_DEVIATION 12.95 |
| Clinical Global Impression-Severity (CGI-S) Scale Score | 4.67 score on a scale STANDARD_DEVIATION 0.599 | 4.64 score on a scale STANDARD_DEVIATION 0.614 | 4.65 score on a scale STANDARD_DEVIATION 0.654 | 4.61 score on a scale STANDARD_DEVIATION 0.586 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 30 Participants | 102 Participants | 34 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 220 Participants | 649 Participants | 217 Participants | 212 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | 32.99 score on a scale STANDARD_DEVIATION 4.789 | 32.41 score on a scale STANDARD_DEVIATION 4.593 | 32.25 score on a scale STANDARD_DEVIATION 4.688 | 32.00 score on a scale STANDARD_DEVIATION 4.246 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 9 Participants | 5 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants | 83 Participants | 22 Participants | 32 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 217 Participants | 654 Participants | 221 Participants | 216 Participants |
| Sex: Female, Male Female | 191 Participants | 573 Participants | 197 Participants | 185 Participants |
| Sex: Female, Male Male | 59 Participants | 178 Participants | 54 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 250 | 0 / 250 | 0 / 251 |
| other Total, other adverse events | 54 / 250 | 70 / 250 | 85 / 251 |
| serious Total, serious adverse events | 2 / 250 | 3 / 250 | 1 / 251 |
Outcome results
Primary
Change From Baseline to Week 6 in the MADRS (Montgomery-Åsberg Depression Rating Scale) Total Score
The MADRS is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants were rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each item was scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity. The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change from Baseline indicates improvement. Mixed-effects Model for Repeated Measures (MMRM) was used for analyses.
Time frame: Baseline and Week 6
Population: mITT Population included all randomized participants who had ≥1 postbaseline assessment of the MADRS total score. Overall number of participants analyzed are the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + ADT | Change From Baseline to Week 6 in the MADRS (Montgomery-Åsberg Depression Rating Scale) Total Score | -13.4 score on a scale | Standard Error 0.7 |
| Cariprazine 1.5 mg/Day + ADT | Change From Baseline to Week 6 in the MADRS (Montgomery-Åsberg Depression Rating Scale) Total Score | -13.8 score on a scale | Standard Error 0.69 |
| Cariprazine 3 mg/Day + ADT | Change From Baseline to Week 6 in the MADRS (Montgomery-Åsberg Depression Rating Scale) Total Score | -14.8 score on a scale | Standard Error 0.7 |
p-value: 0.679895% CI: [-2.1, 1.37]MMRM
p-value: 0.124595% CI: [-3.11, 0.38]MMRM
Secondary
Change From Baseline to Week 6 in the Clinical Global Impressions-Severity (CGI-S) Score
The CGI-S is a clinician-rated scale used to rate the severity of the participant's current state of mental illness compared with MDD population. The participant was rated on a scale from 1 to 7, where 1=normal, not at all ill and 7=among the most extremely ill participants. Higher score indicates worsening of mental illness. A negative change from Baseline indicates improvement. MMRM was used for analyses.
Time frame: Baseline and Week 6
Population: mITT Population included all randomized participants who had ≥1 postbaseline assessment of the MADRS total score. Overall number of participants analyzed are the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + ADT | Change From Baseline to Week 6 in the Clinical Global Impressions-Severity (CGI-S) Score | -1.4 score on a scale | Standard Error 0.09 |
| Cariprazine 1.5 mg/Day + ADT | Change From Baseline to Week 6 in the Clinical Global Impressions-Severity (CGI-S) Score | -1.4 score on a scale | Standard Error 0.09 |
| Cariprazine 3 mg/Day + ADT | Change From Baseline to Week 6 in the Clinical Global Impressions-Severity (CGI-S) Score | -1.6 score on a scale | Standard Error 0.09 |
p-value: 0.515295% CI: [-0.29, 0.15]MMRM
p-value: 0.057395% CI: [-0.43, 0.01]MMRM