An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression
Abstract
Objective:
Method:
Results:
Conclusions:
Method
Study Design
Patients
Efficacy Evaluations
Safety Evaluations
Statistical Analysis
Results
Patient Disposition and Demographic Characteristics
Cariprazine | ||||||||
---|---|---|---|---|---|---|---|---|
Characteristic | Placebo | 0.75 mg/day | 1.5 mg/day | 3.0 mg/day | ||||
N | % | N | % | N | % | N | % | |
Female | 89 | 61.4 | 91 | 64.5 | 92 | 63.0 | 88 | 60.3 |
Race | ||||||||
White | 110 | 75.9 | 111 | 78.7 | 109 | 74.7 | 113 | 77.4 |
Black or African American | 30 | 20.7 | 26 | 18.4 | 30 | 20.5 | 26 | 17.8 |
Other | 5 | 3.5 | 4 | 2.8 | 7 | 4.8 | 7 | 4.8 |
Mean | SD | Mean | SD | Mean | SD | Mean | SD | |
Age (years)a | 43.6 | 12.0 | 40.1 | 11.2 | 40.9 | 11.4 | 42.8 | 10.8 |
Weight (kg) | 80.0 | 17.1 | 80.8 | 18.4 | 81.4 | 16.8 | 81.5 | 17.9 |
BMI | 27.8 | 5.3 | 28.4 | 5.7 | 28.4 | 5.4 | 28.3 | 5.6 |
Age at onset of original episode (years) | 28.4 | 11.4 | 26.0 | 10.2 | 25.4 | 10.2 | 28.1 | 11.0 |
Duration of bipolar disorder (years) | 15.3 | 10.2 | 14.1 | 9.7 | 15.5 | 10.3 | 14.6 | 9.5 |
Duration of current depressive episode (months) | 3.3 | 2.3 | 3.8 | 2.6 | 3.7 | 2.7 | 3.5 | 2.4 |
Number of lifetime depressive episodes | 6.2 | 5.8 | 5.7 | 5.2 | 7.2 | 8.0 | 6.8 | 7.0 |
Measure, Model, and Group | Analyses | ||||||||
---|---|---|---|---|---|---|---|---|---|
Baseline score | Change | Difference versus placebo | |||||||
N | Mean | SD | LS mean | SE | LSMD | 95% CI | p | Adjusted p | |
Primary Efficacy Parameter: MADRS | |||||||||
Mixed-effects model for repeated measures | |||||||||
Placebo | 141 | 30.4 | 4.6 | –11.1 | 0.9 | ||||
Cariprazine 0.75 mg/day | 140 | 31.1 | 4.7 | –13.0 | 0.9 | –1.9 | –4.3, 0.5 | 0.129 | 0.129 |
Cariprazine 1.5 mg/day | 145 | 30.3 | 4.4 | –15.1 | 0.8 | –4.0 | –6.3, –1.6 | 0.001 | 0.003 |
Cariprazine 3.0 mg/day | 145 | 30.6 | 4.7 | –13.7 | 0.9 | –2.5 | –4.9, –0.1 | 0.037 | 0.112 |
ANCOVA with last observation carried forward | |||||||||
Placebo | 141 | 30.4 | 4.6 | –10.1 | 0.8 | ||||
Cariprazine 0.75 mg/day | 140 | 31.1 | 4.7 | –12.4 | 0.8 | –2.3 | –4.6, –0.1 | 0.041 | |
Cariprazine 1.5 mg/day | 145 | 30.3 | 4.4 | –14.2 | 0.8 | –4.1 | –6.3, –1.9 | <0.001 | |
Cariprazine 3.0 mg/day | 145 | 30.6 | 4.7 | –12.8 | 0.8 | –2.7 | –4.9, –0.5 | 0.017 | |
Secondary Efficacy Parameter: CGI-S | |||||||||
Mixed-effects model for repeated measures | |||||||||
Placebo | 141 | 4.4 | 0.5 | –1.0 | 0.1 | ||||
Cariprazine 0.75 mg/day | 140 | 4.4 | 0.5 | –1.1 | 0.1 | –0.1 | –0.4, 0.1 | 0.303 | 0.303 |
Cariprazine 1.5 mg/day | 145 | 4.4 | 0.5 | –1.4 | 0.1 | –0.4 | –0.6, –0.1 | 0.004 | 0.013 |
Cariprazine 3.0 mg/day | 145 | 4.4 | 0.5 | –1.3 | 0.1 | –0.3 | –0.5, –0.0 | 0.049 | 0.112 |
ANCOVA with last observation carried forward | |||||||||
Placebo | 141 | 4.4 | 0.5 | –0.9 | 0.1 | ||||
Cariprazine 0.75 mg/day | 140 | 4.4 | 0.5 | –1.0 | 0.1 | –0.2 | –0.4, 0.1 | 0.198 | |
Cariprazine 1.5 mg/day | 145 | 4.4 | 0.5 | –1.3 | 0.1 | –0.4 | –0.6, –0.2 | 0.001 | |
Cariprazine 3.0 mg/day | 145 | 4.4 | 0.5 | –1.2 | 0.1 | –0.3 | –0.5, –0.0 | 0.024 | |
Additional Efficacy Parameters | |||||||||
HAM-D | |||||||||
Mixed-effects model for repeated measures | |||||||||
Placebo | 141 | 24.1 | 2.8 | –9.1 | 0.6 | ||||
Cariprazine 0.75 mg/day | 140 | 24.6 | 3.4 | –10.3 | 0.6 | –1.1 | –2.9, 0.6 | 0.199 | |
Cariprazine 1.5 mg/day | 145 | 23.9 | 3.2 | –11.8 | 0.6 | –2.7 | –4.4, –1.0 | 0.002 | |
Cariprazine 3.0 mg/day | 145 | 24.0 | 3.1 | –11.3 | 0.6 | –2.2 | –3.9, –0.5 | 0.013 | |
ANCOVA with last observation carried forward | |||||||||
Placebo | 141 | 24.1 | 2.8 | –8.4 | 0.6 | ||||
Cariprazine 0.75 mg/day | 140 | 24.6 | 3.4 | –9.7 | 0.6 | –1.4 | –3.1, 0.3 | 0.098 | |
Cariprazine 1.5 mg/day | 145 | 23.9 | 3.2 | –11.2 | 0.6 | –2.9 | –4.5, –1.2 | 0.001 | |
Cariprazine 3.0 mg/day | 145 | 24.0 | 3.1 | –10.6 | 0.6 | –2.2 | –3.9, –0.6 | 0.007 | |
Odds Ratio Versus Placebo | |||||||||
n | % | Odds Ratio | 95% CI | p | |||||
Response at week 6 (≥50% score reduction on MADRS)b | |||||||||
Placebo | 45 | 31.9 | |||||||
Cariprazine 0.75 mg/day | 54 | 38.6 | 1.35 | 0.83, 2.22 | 0.227 | ||||
Cariprazine 1.5 mg/day | 72 | 49.7 | 2.10 | 1.30, 3.41 | 0.002 | ||||
Cariprazine 3.0 mg/day | 65 | 44.8 | 1.74 | 1.07, 2. 82 | 0.024 | ||||
Remission at week 6 (score ≤10 on MADRS)b | |||||||||
Placebo | 28 | 19.9 | |||||||
Cariprazine 0.75 mg/day | 33 | 23.6 | 1.32 | 0.74, 2.36 | 0.340 | ||||
Cariprazine 1.5 mg/day | 53 | 36.6 | 2.38 | 1.38, 4.09 | 0.002 | ||||
Cariprazine 3.0 mg/day | 40 | 27.6 | 1.59 | 0.91, 2.78 | 0.105 | ||||
HAM-D remitters (score ≤7)b | |||||||||
Placebo | 22 | 15.6 | |||||||
Cariprazine 0.75 mg/day | 28 | 20.0 | 1.44 | 0.77, 2.67 | 0.254 | ||||
Cariprazine 1.5 mg/day | 44 | 30.3 | 2.34 | 1.31, 4.18 | 0.004 | ||||
Cariprazine 3.0 mg/day | 31 | 21.4 | 1.46 | 0.80, 2.69 | 0.219 |
Efficacy Outcomes
Primary, secondary, and additional efficacy outcomes.
Post hoc efficacy analyses.
Safety Outcomes
Extent of exposure.
Adverse events.
Cariprazine | ||||||||
---|---|---|---|---|---|---|---|---|
Placebo (N=145) | 0.75 mg/day (N=141) | 1.5 mg/day (N=146) | 3.0 mg/day (N=146) | |||||
Measure | N | % | N | % | N | % | N | % |
Overall adverse event summary | ||||||||
Patients with any treatment-emergent adverse event | 79 | 54.5 | 80 | 56.7 | 91 | 62.3 | 91 | 62.3 |
Patients with serious adverse event | 5 | 3.4 | 1 | 0.7 | 2 | 1.4 | 2 | 1.4 |
Deaths | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Patients who discontinued due to adverse events | 15 | 10.3 | 12 | 8.5 | 12 | 8.2 | 17 | 11.6 |
Patients with newly emergent adverse eventsa | 6 | 4.1 | 2 | 1.4 | 5 | 3.4 | 3 | 2.1 |
Adverse events during double-blind treatment period (≥5% in any treatment group) | ||||||||
Akathisia | 2 | 1.4 | 4 | 2.8 | 7 | 4.8 | 21 | 14.4 |
Insomnia | 12 | 8.3 | 16 | 11.3 | 10 | 6.8 | 17 | 11.6 |
Nausea | 7 | 4.8 | 12 | 8.5 | 12 | 8.2 | 12 | 8.2 |
Headache | 16 | 11.0 | 11 | 7.8 | 10 | 6.8 | 10 | 6.8 |
Somnolence | 6 | 4.1 | 6 | 4.3 | 9 | 6.2 | 10 | 6.8 |
Restlessness | 5 | 3.4 | 4 | 2.8 | 4 | 2.7 | 9 | 6.2 |
Diarrhea | 8 | 5.5 | 2 | 1.4 | 9 | 6.2 | 3 | 2.1 |
Irritability | 1 | 0.7 | 7 | 5.0 | 3 | 2.1 | 2 | 1.4 |
Laboratory values, vital signs, and other safety parameters.
Cariprazine | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Parameter | Placebo | 0.75 mg/day | 1.5 mg/day | 3.0 mg/day | ||||||||
N | Mean | SD | N | Mean | SD | N | Mean | SD | N | Mean | SD | |
Liver function | ||||||||||||
ALT (U/L) | 131 | 0.4 | 11.1 | 120 | 0.1 | 16.8 | 132 | 1.4 | 9.4 | 125 | 1.7 | 21.6 |
AST (U/L) | 131 | –0.8 | 7.1 | 120 | –0.1 | 11.1 | 132 | 0.6 | 7.1 | 124 | 0.2 | 6.9 |
Total bilirubin (mg/dL) | 131 | –0.03 | 0.24 | 119 | –0.01 | 0.20 | 132 | 0.00 | 0.24 | 125 | –0.02 | 0.25 |
Metabolic parameters | ||||||||||||
Cholesterol | ||||||||||||
HDL (mg/dL) | 131 | 0.73 | 13.69 | 120 | 0.88 | 12.10 | 132 | 0.46 | 10.33 | 124 | –1.64 | 9.49 |
LDL (mg/dL)a | 131 | –3.41 | 23.48 | 120 | –2.78 | 21.96 | 132 | –3.18 | 23.40 | 124 | –6.40 | 23.86 |
Total (mg/dL) | 131 | –2.50 | 30.12 | 120 | –3.93 | 29.13 | 132 | –2.56 | 28.83 | 125 | –6.76 | 27.00 |
Triglycerides (mg/dL) | 115 | 1.97 | 64.38 | 105 | –5.27 | 90.14 | 119 | –2.36 | 61.26 | 106 | 7.51 | 74.44 |
Fasting glucose (mg/dL) | 115 | 3.63 | 13.91 | 105 | 1.97 | 18.90 | 119 | 1.45 | 13.17 | 106 | 8.08 | 20.31 |
Chemistry parameters | ||||||||||||
Prolactin (ng/mL) | 131 | –1.00 | 15.50 | 119 | 0.59 | 8.35 | 131 | 0.25 | 14.29 | 123 | 1.54 | 15.22 |
Creatine kinase (U/L) | 131 | –2.3 | 94.9 | 120 | 13.0 | 66.2 | 132 | 27.3 | 191.6 | 124 | 9.4 | 70.8 |
Vital signs | ||||||||||||
Blood pressureb | ||||||||||||
Systolic (mmHg) | 142 | –0.7 | 10.4 | 140 | –1.4 | 8.3 | 145 | 1.3 | 8.7 | 145 | –0.6 | 12.0 |
Diastolic (mmHg) | 142 | –0.1 | 8.0 | 140 | –0.7 | 7.8 | 145 | 0.8 | 6.5 | 145 | –0.4 | 7.5 |
Pulseb | 142 | 0.2 | 10.4 | 140 | –0.6 | 10.0 | 145 | 1.4 | 10.8 | 145 | 2.2 | 10.2 |
Body weight (kg) | 142 | 0.10 | 2.28 | 140 | 0.84 | 2.50 | 145 | 1.10 | 2.64 | 145 | 0.63 | 2.26 |
Waist circumference (cm) | 142 | 0.08 | 4.07 | 140 | 0.77 | 3.48 | 145 | 0.23 | 3.33 | 145 | 0.53 | 3.54 |
N | n | % | N | n | % | N | n | % | N | n | % | |
Other safety outcomes | ||||||||||||
Orthostatic hypotensionc | 142 | 17 | 12.0 | 139 | 19 | 13.7 | 145 | 12 | 8.3 | 143 | 13 | 9.1 |
Treatment-emergent parkinsonismd | 142 | 0 | 0 | 140 | 2 | 1.4 | 145 | 2 | 1.4 | 145 | 3 | 2.1 |
Treatment-emergent akathisiae | 142 | 6 | 4.2 | 140 | 8 | 5.7 | 145 | 12 | 8.3 | 145 | 25 | 17.2 |
Treatment-emergent maniaf | 142 | 5 | 3.5 | 140 | 6 | 4.3 | 145 | 4 | 2.8 | 145 | 4 | 2.8 |
Suicidality.
Discussion
Acknowledgments
Footnotes
Supplementary Material
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