Bipolar I Disorder, Depression, Mania
Conditions
Brief summary
1\) To evaluate the efficacy and safety of cariprazine at a target dose of 3.0 mg/day compared with placebo in prevention of relapse in patients with bipolar I disorder whose current episode (i.e. index episode) is manic or depressive, with or without mixed features; 2) To evaluate the efficacy and safety of cariprazine at a target dose of 1.5 mg/day compared with placebo in prevention of relapse in patients with bipolar I disorder whose current episode (i.e. index episode) is manic or depressive, with or without mixed features who were initially stabilized on a target dose of 3.0 mg/day
Interventions
DRUGCariprazine
Cariprazine capsules, oral administration, once daily
DRUGPlacebo
Matching placebo capsules, oral administration, once daily
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
* Currently meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for bipolar I disorder, and at least one of the following two criteria: * Current episode manic, with or without mixed features, having a total Young Mania Rating Scale (YMRS) total score ≥ 20 and a score of at least 4 on 2 YMRS items (irritability, speech, content, or disruptive/aggressive behavior); * OR current episode depressive, with or without mixed features, having a Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 23 and a score of at least 3 on 2 MADRS items (apparent sadness, reported sadness, inner tension or inability to feel).
Exclusion criteria
* Four or more episodes of a mood disturbance within the 12 months before Visit 1; * Diagnosis of another psychiatric disorder other than bipolar disorder with the exception of specific phobias.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | From Week 16 to Week 55 | Relapse was defined as the occurrence of any 1 of the following: * Young Mania Rating Score (YMRS) total score ≥ 17 (range 0-60; higher score indicates a worse outcome); * Montgomery Asberg Depression Rating Scale; (MADRS) total score ≥ 20 (range 0-60; higher score indicates more depressive symptoms); * Clinical Global Impression-Improvement scale (CGI-S) ≥ 4 (range from 1 \[normal, not at all ill\] to 7 \[extremely ill\]); * Initiation of additional psychiatric medication; * Psychiatric hospitalization; * Exacerbation of illness as judged by clinical impression of the Investigator. Time to first relapse (days) was calculated as the date of the first relapse - the date of randomization + 1. Participants who did not meet the relapse criteria were considered censored at the time of completion or discontinuation from the Double-Blind Treatment Period (DBTP) of the study. Percentiles (95% Confidence Intervals \[CI\]) are based on Kaplan-Meier estimates. |
Countries
Bulgaria, Malaysia, Poland, Puerto Rico, Russia, Serbia, South Korea, Taiwan, Thailand, Ukraine, United States
Participant flow
Pre-assignment details
A total of 901 participants were enrolled; 5 participants did not enter the open label treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Open Label Treatment Period Participants started on cariprazine 1.5 mg QD, with a target dose of 3.0 mg QD, for up to 16 weeks. | 896 |
| Total | 896 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Treatment Period | Adverse Event | 0 | 1 | 5 | 1 |
| Double-Blind Treatment Period | Lack of Efficacy | 0 | 1 | 0 | 0 |
| Double-Blind Treatment Period | Lost to Follow-up | 0 | 4 | 4 | 9 |
| Double-Blind Treatment Period | Non-Compliance With Study Drug | 0 | 0 | 4 | 4 |
| Double-Blind Treatment Period | Other, Not Specified | 0 | 5 | 8 | 6 |
| Double-Blind Treatment Period | Protocol Violation | 0 | 3 | 8 | 4 |
| Double-Blind Treatment Period | Relapse Event during Double-blind Treatment Period | 0 | 29 | 25 | 26 |
| Double-Blind Treatment Period | Withdrawal by Subject | 0 | 23 | 11 | 14 |
| Open Label Treatment Period | Adverse Event | 67 | 0 | 0 | 0 |
| Open Label Treatment Period | Failure to Meet Randomization Criteria | 143 | 0 | 0 | 0 |
| Open Label Treatment Period | Lack of Efficacy | 35 | 0 | 0 | 0 |
| Open Label Treatment Period | Lost to Follow-up | 55 | 0 | 0 | 0 |
| Open Label Treatment Period | Non-Compliance With Study Drug | 25 | 0 | 0 | 0 |
| Open Label Treatment Period | Other, Not Specified | 7 | 0 | 0 | 0 |
| Open Label Treatment Period | Pregnancy | 1 | 0 | 0 | 0 |
| Open Label Treatment Period | Protocol Violation | 17 | 0 | 0 | 0 |
| Open Label Treatment Period | Study Terminated by Sponsor | 2 | 0 | 0 | 0 |
| Open Label Treatment Period | Withdrawal by Subject | 104 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Open Label Treatment Period |
|---|---|
| Age, Customized < 45 years | 539 Participants |
| Age, Customized ≥ 45 years | 357 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 89 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 806 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 32 Participants |
| Race (NIH/OMB) Black or African American | 258 Participants |
| Race (NIH/OMB) More than one race | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 591 Participants |
| Sex: Female, Male Female | 542 Participants |
| Sex: Female, Male Male | 354 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 | 1 / 901 | 1 / 145 | 0 / 147 | 0 / 148 |
| other Total, other adverse events | 256 / 896 | 27 / 145 | 34 / 144 | 34 / 147 |
| serious Total, serious adverse events | 19 / 896 | 5 / 145 | 7 / 144 | 3 / 147 |
Outcome results
Primary
Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period
Relapse was defined as the occurrence of any 1 of the following: * Young Mania Rating Score (YMRS) total score ≥ 17 (range 0-60; higher score indicates a worse outcome); * Montgomery Asberg Depression Rating Scale; (MADRS) total score ≥ 20 (range 0-60; higher score indicates more depressive symptoms); * Clinical Global Impression-Improvement scale (CGI-S) ≥ 4 (range from 1 \[normal, not at all ill\] to 7 \[extremely ill\]); * Initiation of additional psychiatric medication; * Psychiatric hospitalization; * Exacerbation of illness as judged by clinical impression of the Investigator. Time to first relapse (days) was calculated as the date of the first relapse - the date of randomization + 1. Participants who did not meet the relapse criteria were considered censored at the time of completion or discontinuation from the Double-Blind Treatment Period (DBTP) of the study. Percentiles (95% Confidence Intervals \[CI\]) are based on Kaplan-Meier estimates.
Time frame: From Week 16 to Week 55
Population: Double-Blind Intent-to-Treat Population: All participants who took at least 1 dose of DB IP and had at least 1 post-randomization assessment of the YMRS, MADRS or CGI-S scores or relapsed during the 39-week DBTP of the study.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Double-Blind Placebo QD | Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | 50% percentile | NA days |
| Double-Blind Placebo QD | Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | 25% percentile | NA days |
| Double-Blind Placebo QD | Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | 75% percentile | NA days |
| Double-Blind Cariprazine 1.5 mg QD | Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | 50% percentile | NA days |
| Double-Blind Cariprazine 1.5 mg QD | Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | 25% percentile | NA days |
| Double-Blind Cariprazine 1.5 mg QD | Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | 75% percentile | NA days |
| Double-Blind Cariprazine 3.0 mg QD | Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | 25% percentile | NA days |
| Double-Blind Cariprazine 3.0 mg QD | Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | 75% percentile | NA days |
| Double-Blind Cariprazine 3.0 mg QD | Time to First Relapse of Any Mood Episode During the Double-Blind Treatment Period | 50% percentile | NA days |
p-value: 0.574595% CI: [0.48, 1.43]Log Rank
p-value: 0.630895% CI: [0.52, 1.51]Log Rank