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Safety, Tolerability, and Efficacy of Cariprazine in Participants With Bipolar Depression

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ClinicalTrials.gov Identifier: NCT01396447
Recruitment Status : Completed
First Posted : July 18, 2011
Results First Posted : May 1, 2018
Last Update Posted : May 1, 2018
Sponsor:
Collaborator:
Gedeon Richter Ltd.
Information provided by (Responsible Party):
Forest Laboratories

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Depression, Bipolar
Interventions Drug: Placebo
Drug: Cariprazine
Enrollment 584
Recruitment Details Adult participants with a diagnosis of bipolar I disorder with a current major depressive episode were considered for participation in the study.
Pre-assignment Details  
Arm/Group Title Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
Hide Arm/Group Description Participants received placebo orally once a day for 8 weeks. Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period. Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period. Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.
Period Title: Overall Study
Started 148 143 147 146
Received Treatment 145 141 146 146
Completed 105 103 117 94
Not Completed 43 40 30 52
Reason Not Completed
Did Not Receive Treatment             3             2             1             0
Adverse Event             15             12             12             17
Insufficient Therapeutic Response             5             5             2             4
Protocol Violation             5             2             3             7
Withdrawal of Consent             11             9             4             15
Lost to Follow-up             4             8             7             9
Other Miscellaneous Reasons             0             2             1             0
Arm/Group Title Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg Total
Hide Arm/Group Description Participants received placebo orally once a day for 8 weeks. Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period. Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period. Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period. Total of all reporting groups
Overall Number of Baseline Participants 145 141 146 146 578
Hide Baseline Analysis Population Description
Safety population: All randomized participants who received at least 1 dose of investigational product.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 145 participants 141 participants 146 participants 146 participants 578 participants
43.6  (12.0) 40.1  (11.2) 40.9  (11.4) 42.8  (10.8) 41.9  (11.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 145 participants 141 participants 146 participants 146 participants 578 participants
Female
89
  61.4%
91
  64.5%
92
  63.0%
88
  60.3%
360
  62.3%
Male
56
  38.6%
50
  35.5%
54
  37.0%
58
  39.7%
218
  37.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 145 participants 141 participants 146 participants 146 participants 578 participants
Hispanic or Latino
12
   8.3%
13
   9.2%
11
   7.5%
12
   8.2%
48
   8.3%
Not Hispanic or Latino
133
  91.7%
128
  90.8%
135
  92.5%
134
  91.8%
530
  91.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 145 participants 141 participants 146 participants 146 participants 578 participants
White
110
  75.9%
111
  78.7%
109
  74.7%
113
  77.4%
443
  76.6%
Black or African-American
30
  20.7%
26
  18.4%
30
  20.5%
26
  17.8%
112
  19.4%
Asian
1
   0.7%
1
   0.7%
2
   1.4%
0
   0.0%
4
   0.7%
American Indian or Alaska Native
2
   1.4%
1
   0.7%
1
   0.7%
3
   2.1%
7
   1.2%
Other
2
   1.4%
2
   1.4%
4
   2.7%
4
   2.7%
12
   2.1%
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 145 participants 141 participants 146 participants 146 participants 578 participants
79.98  (17.08) 80.81  (18.36) 81.43  (16.79) 81.45  (17.86) 80.92  (17.49)
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 145 participants 141 participants 146 participants 146 participants 578 participants
27.81  (5.27) 28.42  (5.71) 28.44  (5.39) 28.28  (5.64) 28.24  (5.50)
Waist circumference  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 145 participants 141 participants 146 participants 146 participants 578 participants
91.40  (14.24) 93.32  (15.45) 93.38  (14.55) 93.24  (15.40) 92.83  (14.90)
1.Primary Outcome
Title Change From Baseline in the Montgomery-Åsberg Depression Rating Scale Total Score at Week 6
Hide Description The Montgomery-Åsberg Depression Rating Scale is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants are 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 is 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 scores on the 10 items are summed for a total score that can range from 0 to 60. A higher score indicates greater depression. A negative change score indicates improvement.
Time Frame Baseline to Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who took at least 1 dose of investigational product and had at least 1 post-Baseline assessment of the Montgomery-Åsberg Depression Rating Scale.
Arm/Group Title Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
Hide Arm/Group Description:
Participants received placebo orally once a day for 8 weeks.
Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.
Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.
Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.
Overall Number of Participants Analyzed 141 140 145 145
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-11.1  (0.9) -13.0  (0.9) -15.1  (0.8) -13.7  (0.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Cariprazine 0.75 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1292
Comments The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
Method Repeated measures mixed-effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.9
Confidence Interval (2-Sided) 95%
-4.3 to 0.5
Estimation Comments Cariprazine 0.75 mg vs Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Cariprazine 1.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0010
Comments The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
Method Repeated measures mixed-effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.0
Confidence Interval (2-Sided) 95%
-6.3 to -1.6
Estimation Comments Cariprazine 1.5 mg vs Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Cariprazine 3.0 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0374
Comments The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
Method Repeated measures mixed-effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.5
Confidence Interval (2-Sided) 95%
-4.9 to -0.1
Estimation Comments Cariprazine 3.0 mg vs Placebo
2.Secondary Outcome
Title Change From Baseline in the Clinical Global Impressions-Severity Total Score at Week 6
Hide Description The Clinical Global Impressions-Severity scale is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of illness in other participants the physician has observed. The participant is rated on a scale from 1 to 7 with 1 indicating a "normal state" and 7 indicating "among the most extremely ill participants." A higher score indicates greater illness. A negative change score indicates improvement.
Time Frame Baseline to Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who took at least 1 dose of investigational product and had at least 1 post-Baseline assessment of the Montgomery-Åsberg Depression Rating Scale.
Arm/Group Title Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
Hide Arm/Group Description:
Participants received placebo orally once a day for 8 weeks.
Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.
Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.
Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.
Overall Number of Participants Analyzed 141 140 145 145
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.0  (0.1) -1.1  (0.1) -1.4  (0.1) -1.3  (0.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Cariprazine 0.75 mg
Comments The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3025
Comments [Not Specified]
Method Repeated measures mixed-effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-0.4 to 0.1
Estimation Comments Cariprazine 0.75 mg vs Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Cariprazine 1.5 mg
Comments The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0044
Comments [Not Specified]
Method Repeated measures mixed-effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.4
Confidence Interval (2-Sided) 95%
-0.6 to -0.2
Estimation Comments Cariprazine 1.5 mg vs Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Cariprazine 3.0 mg
Comments The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0489
Comments [Not Specified]
Method Repeated measures mixed-effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-0.5 to -0.0
Estimation Comments Cariprazine 3.0 mg vs Placebo
Time Frame Adverse Events were collected and recorded from the time the participant signs the informed consent form until 30 days after the last dose of treatment.
Adverse Event Reporting Description Safety population: All randomized participants who took at least 1 dose of investigational product.
 
Arm/Group Title Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
Hide Arm/Group Description Participants received placebo orally once a day for 8 weeks. Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period. Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period. Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.
All-Cause Mortality
Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/145 (0.00%)   0/141 (0.00%)   0/146 (0.00%)   0/146 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/145 (3.45%)   1/141 (0.71%)   2/146 (1.37%)   2/146 (1.37%) 
Injury, poisoning and procedural complications         
Fall  1  0/145 (0.00%)  0/141 (0.00%)  1/146 (0.68%)  1/146 (0.68%) 
Lower limb fracture  2  0/145 (0.00%)  0/141 (0.00%)  0/146 (0.00%)  1/146 (0.68%) 
Injury  2  0/145 (0.00%)  0/141 (0.00%)  1/146 (0.68%)  0/146 (0.00%) 
Nervous system disorders         
Vertigo CNS origin  1  0/145 (0.00%)  0/141 (0.00%)  0/146 (0.00%)  1/146 (0.68%) 
Hemiparesis  2  1/145 (0.69%)  0/141 (0.00%)  0/146 (0.00%)  0/146 (0.00%) 
Psychiatric disorders         
Depression  2  1/145 (0.69%)  1/141 (0.71%)  0/146 (0.00%)  0/146 (0.00%) 
Hypomania  2  0/145 (0.00%)  0/141 (0.00%)  1/146 (0.68%)  0/146 (0.00%) 
Mania  2  1/145 (0.69%)  0/141 (0.00%)  0/146 (0.00%)  0/146 (0.00%) 
Suicidal ideation  2  1/145 (0.69%)  0/141 (0.00%)  0/146 (0.00%)  0/146 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Chronic obstructive pulmonary disease  2  1/145 (0.69%)  0/141 (0.00%)  0/146 (0.00%)  0/146 (0.00%) 
1
Term from vocabulary, MedDRA (Unspecified)
2
Term from vocabulary, MedDRA, Version 16.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   42/145 (28.97%)   43/141 (30.50%)   51/146 (34.93%)   56/146 (38.36%) 
Gastrointestinal disorders         
Nausea  1  7/145 (4.83%)  12/141 (8.51%)  12/146 (8.22%)  12/146 (8.22%) 
Diarrhoea  2  10/145 (6.90%)  2/141 (1.42%)  9/146 (6.16%)  3/146 (2.05%) 
Nervous system disorders         
Akathisia  2  2/145 (1.38%)  4/141 (2.84%)  7/146 (4.79%)  21/146 (14.38%) 
Headache  2  17/145 (11.72%)  11/141 (7.80%)  11/146 (7.53%)  10/146 (6.85%) 
Somnolence  2  7/145 (4.83%)  6/141 (4.26%)  10/146 (6.85%)  10/146 (6.85%) 
Psychiatric disorders         
Insomnia  2  12/145 (8.28%)  16/141 (11.35%)  10/146 (6.85%)  17/146 (11.64%) 
Restlessness  2  5/145 (3.45%)  4/141 (2.84%)  4/146 (2.74%)  9/146 (6.16%) 
1
Term from vocabulary, MedDRA (Unspecified)
2
Term from vocabulary, MedDRA, Version 16.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
All data generated in this study will be the property of Forest Research Institute, Inc. An integrated clinical and statistical report will be prepared at the completion of the study. Publication of the results by the Investigator will be subject to mutual agreement between the Investigator and Forest Research Institute, Inc.
Results Point of Contact
Name/Title: Therapeutic Area Head
Organization: Allergan
Phone: 714-246-4500
Responsible Party: Forest Laboratories
ClinicalTrials.gov Identifier: NCT01396447     History of Changes
Other Study ID Numbers: RGH-MD-56
2011-002334-39 ( EudraCT Number )
First Submitted: July 15, 2011
First Posted: July 18, 2011
Results First Submitted: March 29, 2018
Results First Posted: May 1, 2018
Last Update Posted: May 1, 2018