Bipolar I Disorder
Conditions
Keywords
Mixed episode associated with Bipolar I
Brief summary
Whether treatment with olanzapine in combination with mood stabilizer reduces symptoms of both mania and depression more than treatment with mood stabilizer alone, in patients with a mixed episode of bipolar I disorder.
Interventions
DRUGolanzapine
15mg, capsules, by mouth every evening, daily for minimum of one day, followed by 5-20mg, capsules, by mouth every evening, daily for remainder of study (6 weeks total).
DRUGplacebo
placebo, capsules, by mouth every evening, daily, for 6 weeks.
DRUGdivalproex
dose to maintain blood levels of 75-125 ug/mL, by mouth, twice a day, daily for 52 days (Study Period I and Study Period II).
Sponsors
Eli Lilly and Company
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 60 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with a mixed episode of bipolar I disorder. * Have had at least one previous manic or mixed episode associated with bipolar disorder * You must be between 18 and 60 years old. * You must be able to visit the doctor's office three times in the first week and then once every week for the next five weeks. * If you are a female, you must have a negative pregnancy test and be using an effective method of contraception.
Exclusion criteria
* You have a diagnosis of schizophrenia, schizoaffective disorder or substance abuse or dependence. * You have diseases of the intestinal tract, lungs, liver, kidney, nervous or endocrine systems, or blood. * Have required a recent thyroid hormone supplement to treat hypothyroidism (must have been on a stable dose of the medication for at least 2 months prior to Visit 3). * You are allergic to any of the medications involved in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Young Mania Rating Scale (YMRS) Scores From Baseline to Endpoint. | Baseline to endpoint (6 weeks) | The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60. |
| Mean Change in Hamilton Depression Rating Scale-21 (HAMD) Scores From Baseline to Endpoint. | Baseline to endpoint (6 weeks) | The 21-item HAMD measures depression severity. Items are rated on a scale from 0 (symptoms not present) to a maximum of 2 to 4 (symptom extremely severe) for a total score range of 0 to 60. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Clinical Global Impression for Bipolar Illness Severity (CGI-BP) From Baseline to Endpoint | Baseline to endpoint (6 weeks) | CGI-BP Severity is used by the clinician to record the severity of illness at the time of assessment. The score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). |
| Number of Patients Hospitalized Due to Relapse of Mania or Depression. | Baseline to endpoint (6 weeks) | Number of participants hospitalized as a result of relapse of mania or depression. |
| Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | Baseline to endpoint (6 weeks) | Change from Baseline to endpoint in cholesterol: value of cholesterol measure at endpoint minus the value at baseline. |
| Clinically Significant Laboratory Values - Fasting Triglycerides Change From Baseline | Baseline to endpoint (6 weeks) | Change from baseline to endpoint in triglycerides: Value of triglyceride measure at endpoint minus value at baseline. |
| Number of Participants Meeting the Criteria for Mixed Onset of Action | Baseline to endpoint (6 weeks) | The original outcome measure was Time to Mixed Onset of Action (at least a 25% reduction on HAMD and YMRS total scores from baseline); however since upper limit of measure of dispersion could not be computed by observed data, which is not allowed on this system, number of patients with event are presented instead. |
| Clinically Significant Laboratory Values - Bilirubin Total Change From Baseline | Baseline to endpoint (6 weeks) | Change from baseline to endpoint in bilirubin total: Value of bilirubin total measure at endpoint minus value at baseline. |
| Clinically Significant Vital Signs - Body Mass Index Change From Baseline | Baseline to endpoint (6 weeks) | Change from baseline to endpoint in body mass index (an estimate of body fat derived by dividing body weight by height squared): Value of body mass index measure at endpoint minus value at baseline. |
| Clinically Significant Vital Signs - Weight Change From Baseline | Baseline to endpoint (6 weeks) | Change from baseline to endpoint: Value of weight measure at endpoint minus value at baseline. |
| Clinically Significant Vital Signs - Percentage of Participants With Baseline-to-Endpoint Weight Increase of at Least Seven Percent (7%) | Baseline to endpoint (6 weeks) | Percentages of participants in each group who experienced an increase in weight of at least 7% from baseline to endpoint. |
| Clinically Significant Laboratory Values - Fasting Blood Glucose Change From Baseline | Baseline to endpoint (6 weeks) | Change from baseline to endpoint in fasting blood glucose: Value of fasting blood glucose measure at endpoint minus value at baseline. |
| Number of Participants Meeting the Criteria for Mixed Response | baseline to endpoint (6 weeks) | The original outcome measure was Time to Mixed Response(at least a 50% reduction on HAMD and YMRS total scores from baseline); however since upper limit of measure of dispersion could not be computed by observed data, which is not allowed on this system, number of patients with event are presented instead. |
Countries
United States
Participant flow
Pre-assignment details
Study Period 1 was a 2-28 day day period allowing for screening, divalproex treatment initiation (if appropriate) and washout. Patients meeting diagnostic criteria and having therapeutic serum levels of divalproex in target range of 75 to 125 µg/mL (≥80 µg/mL recommended) during Study Period I, will be randomized into either placebo or olanzapine.
Participants by arm
| Arm | Count |
|---|---|
| Olanzapine Olanzapine: 15mg, capsules, by mouth every evening, daily for minimum of one day, followed by 5-20mg, capsules, by mouth every evening, daily for remainder of study (6 weeks total).
Divalproex: dose to maintain blood levels of 75-125 ug/mL, by mouth, twice a day, daily for 6 weeks (following dose achieved in Study Period I). | 101 |
| Placebo Placebo: placebo capsules, by mouth every evening, daily, for 6 weeks. Divalproex: dose to maintain blood levels of 75-125 ug/mL, by mouth, twice a day, daily for 6 weeks (following dose achieved in Study Period I). | 101 |
| Total | 202 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 4 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lack of Efficacy | 1 | 4 |
| Overall Study | Lost to Follow-up | 11 | 11 |
| Overall Study | Physician Decision | 2 | 4 |
| Overall Study | Protocol Entry Criteria Not Met | 5 | 4 |
| Overall Study | Protocol Violation | 8 | 7 |
| Overall Study | Sponsor Decision | 4 | 5 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Olanzapine |
|---|---|---|---|
| Age Continuous | 38.52 years STANDARD_DEVIATION 11.07 | 38.56 years STANDARD_DEVIATION 11.11 | 38.61 years STANDARD_DEVIATION 11.2 |
| Body Mass Index (BMI) | 31.72 kilograms per square meters STANDARD_DEVIATION 8.29 | 31.23 kilograms per square meters STANDARD_DEVIATION 8.64 | 30.73 kilograms per square meters STANDARD_DEVIATION 8.99 |
| Body Weight | 90.75 kilograms STANDARD_DEVIATION 23.7 | 89.04 kilograms STANDARD_DEVIATION 23.94 | 87.33 kilograms STANDARD_DEVIATION 24.17 |
| Race/Ethnicity African Descent | 29 participants | 67 participants | 38 participants |
| Race/Ethnicity Caucasian | 56 participants | 102 participants | 46 participants |
| Race/Ethnicity East Asian | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity Hispanic | 13 participants | 28 participants | 15 participants |
| Race/Ethnicity Native American | 2 participants | 3 participants | 1 participants |
| Region of Enrollment United States | 101 participants | 202 participants | 101 participants |
| Sex: Female, Male Female | 58 Participants | 119 Participants | 61 Participants |
| Sex: Female, Male Male | 43 Participants | 83 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 80 / — | 63 / — |
| serious Total, serious adverse events | 3 / — | 5 / — |
Outcome results
Primary
Mean Change in Hamilton Depression Rating Scale-21 (HAMD) Scores From Baseline to Endpoint.
The 21-item HAMD measures depression severity. Items are rated on a scale from 0 (symptoms not present) to a maximum of 2 to 4 (symptom extremely severe) for a total score range of 0 to 60.
Time frame: Baseline to endpoint (6 weeks)
Population: Intent to Treat analysis. All randomized patients with baseline \& at least one post-baseline measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Mean Change in Hamilton Depression Rating Scale-21 (HAMD) Scores From Baseline to Endpoint. | -9.37 units on a scale | Standard Error 0.55 |
| Placebo | Mean Change in Hamilton Depression Rating Scale-21 (HAMD) Scores From Baseline to Endpoint. | -7.69 units on a scale | Standard Error 0.54 |
Comparison: The overall power of the two co-primary analyses-the probability of simultaneously rejecting both co-primary null hypotheses-for this sample size under assumed effect sizes of 0.5 and 0.45 is estimated as approximately 85-87% and 77-80%, respectively.p-value: 0.022Mixed Models Analysis
Primary
Mean Change in Young Mania Rating Scale (YMRS) Scores From Baseline to Endpoint.
The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.
Time frame: Baseline to endpoint (6 weeks)
Population: Intent to Treat analysis. All randomized patients with baseline \& at least one post-baseline measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Mean Change in Young Mania Rating Scale (YMRS) Scores From Baseline to Endpoint. | -10.15 units on a scale | Standard Error 0.44 |
| Placebo | Mean Change in Young Mania Rating Scale (YMRS) Scores From Baseline to Endpoint. | -7.68 units on a scale | Standard Error 0.44 |
Comparison: The overall power of the two co-primary analyses-the probability of simultaneously rejecting both co-primary null hypotheses-for this sample size under assumed effect sizes of 0.5 and 0.45 is estimated as approximately 85-87% and 77-80%, respectively.p-value: <0.001Mixed Models Analysis
Secondary
Clinically Significant Laboratory Values - Bilirubin Total Change From Baseline
Change from baseline to endpoint in bilirubin total: Value of bilirubin total measure at endpoint minus value at baseline.
Time frame: Baseline to endpoint (6 weeks)
Population: All randomized participants with both baseline and post-baseline measures. Intention to Treat analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Clinically Significant Laboratory Values - Bilirubin Total Change From Baseline | Baseline | 6.50 micromoles per Liter | Standard Deviation 3.46 |
| Olanzapine | Clinically Significant Laboratory Values - Bilirubin Total Change From Baseline | Change from Baseline | -1.56 micromoles per Liter | Standard Deviation 2.99 |
| Placebo | Clinically Significant Laboratory Values - Bilirubin Total Change From Baseline | Baseline | 6.65 micromoles per Liter | Standard Deviation 3.43 |
| Placebo | Clinically Significant Laboratory Values - Bilirubin Total Change From Baseline | Change from Baseline | -0.74 micromoles per Liter | Standard Deviation 3.03 |
p-value: 0.046ANOVA
Secondary
Clinically Significant Laboratory Values - Fasting Blood Glucose Change From Baseline
Change from baseline to endpoint in fasting blood glucose: Value of fasting blood glucose measure at endpoint minus value at baseline.
Time frame: Baseline to endpoint (6 weeks)
Population: All randomized participants with both baseline and post-baseline measures. Intention to Treat analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Clinically Significant Laboratory Values - Fasting Blood Glucose Change From Baseline | Baseline | 91.81 milligrams per deciliter | Standard Deviation 11.98 |
| Olanzapine | Clinically Significant Laboratory Values - Fasting Blood Glucose Change From Baseline | Change from Baseline | 6.93 milligrams per deciliter | Standard Deviation 23.72 |
| Placebo | Clinically Significant Laboratory Values - Fasting Blood Glucose Change From Baseline | Baseline | 91.90 milligrams per deciliter | Standard Deviation 10.13 |
| Placebo | Clinically Significant Laboratory Values - Fasting Blood Glucose Change From Baseline | Change from Baseline | -0.55 milligrams per deciliter | Standard Deviation 14 |
p-value: 0.007ANOVA
Secondary
Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline
Change from Baseline to endpoint in cholesterol: value of cholesterol measure at endpoint minus the value at baseline.
Time frame: Baseline to endpoint (6 weeks)
Population: All randomized participants with both baseline and at least one post-baseline measure. Intention to Treat analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | Total Cholesterol Baseline | 191.37 milligrams per deciliter | Standard Deviation 41.23 |
| Olanzapine | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | Total Cholesterol Change from Baseline | -7.80 milligrams per deciliter | Standard Deviation 31.77 |
| Olanzapine | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | Low Density Lipoprotein Baseline (N=62,N=64) | 115.32 milligrams per deciliter | Standard Deviation 38.82 |
| Olanzapine | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | Low Density Lipoprotein Change (N=62,N=64) | -9.22 milligrams per deciliter | Standard Deviation 27.31 |
| Olanzapine | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | High Density Lipoprotein Baseline | 53.76 milligrams per deciliter | Standard Deviation 12.03 |
| Olanzapine | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | High Density Lipoprotein Change from Baseline | -3.24 milligrams per deciliter | Standard Deviation 10.02 |
| Placebo | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | High Density Lipoprotein Baseline | 51.48 milligrams per deciliter | Standard Deviation 11.64 |
| Placebo | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | Total Cholesterol Baseline | 192.25 milligrams per deciliter | Standard Deviation 44.45 |
| Placebo | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | Low Density Lipoprotein Change (N=62,N=64) | -9.77 milligrams per deciliter | Standard Deviation 28.05 |
| Placebo | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | Total Cholesterol Change from Baseline | -8.72 milligrams per deciliter | Standard Deviation 28.8 |
| Placebo | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | High Density Lipoprotein Change from Baseline | -1.22 milligrams per deciliter | Standard Deviation 8.9 |
| Placebo | Clinically Significant Laboratory Values - Fasting Cholesterol Change From Baseline | Low Density Lipoprotein Baseline (N=62,N=64) | 111.01 milligrams per deciliter | Standard Deviation 36.74 |
p-value: 0.657ANOVA
p-value: 0.924ANOVA
p-value: 0.122ANOVA
Secondary
Clinically Significant Laboratory Values - Fasting Triglycerides Change From Baseline
Change from baseline to endpoint in triglycerides: Value of triglyceride measure at endpoint minus value at baseline.
Time frame: Baseline to endpoint (6 weeks)
Population: All randomized participants with both baseline and post-baseline measures. Intention to Treat analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Clinically Significant Laboratory Values - Fasting Triglycerides Change From Baseline | Baseline | 111.46 milligrams per deciliter | Standard Deviation 61.54 |
| Olanzapine | Clinically Significant Laboratory Values - Fasting Triglycerides Change From Baseline | Change from Baseline | 22.91 milligrams per deciliter | Standard Deviation 67.7 |
| Placebo | Clinically Significant Laboratory Values - Fasting Triglycerides Change From Baseline | Baseline | 139.75 milligrams per deciliter | Standard Deviation 77.22 |
| Placebo | Clinically Significant Laboratory Values - Fasting Triglycerides Change From Baseline | Change from Baseline | 16.80 milligrams per deciliter | Standard Deviation 73.25 |
p-value: 0.293ANOVA
Secondary
Clinically Significant Vital Signs - Body Mass Index Change From Baseline
Change from baseline to endpoint in body mass index (an estimate of body fat derived by dividing body weight by height squared): Value of body mass index measure at endpoint minus value at baseline.
Time frame: Baseline to endpoint (6 weeks)
Population: All randomized participants with both baseline and post-baseline measures. Intention to Treat analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Clinically Significant Vital Signs - Body Mass Index Change From Baseline | 1.18 kilograms per square meters | Standard Error 0.12 |
| Placebo | Clinically Significant Vital Signs - Body Mass Index Change From Baseline | 0.26 kilograms per square meters | Standard Error 0.12 |
p-value: <0.001ANCOVA
Secondary
Clinically Significant Vital Signs - Percentage of Participants With Baseline-to-Endpoint Weight Increase of at Least Seven Percent (7%)
Percentages of participants in each group who experienced an increase in weight of at least 7% from baseline to endpoint.
Time frame: Baseline to endpoint (6 weeks)
Population: All randomized participants with both baseline and post-baseline measures. Intention to Treat analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine | Clinically Significant Vital Signs - Percentage of Participants With Baseline-to-Endpoint Weight Increase of at Least Seven Percent (7%) | 22 percentage of participants |
| Placebo | Clinically Significant Vital Signs - Percentage of Participants With Baseline-to-Endpoint Weight Increase of at Least Seven Percent (7%) | 3 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Clinically Significant Vital Signs - Weight Change From Baseline
Change from baseline to endpoint: Value of weight measure at endpoint minus value at baseline.
Time frame: Baseline to endpoint (6 weeks)
Population: All randomized participants with both baseline and post-baseline measures. Intention to Treat analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Clinically Significant Vital Signs - Weight Change From Baseline | 3.34 kilograms | Standard Error 0.34 |
| Placebo | Clinically Significant Vital Signs - Weight Change From Baseline | 0.70 kilograms | Standard Error 0.34 |
p-value: <0.001ANCOVA
Secondary
Mean Change in Clinical Global Impression for Bipolar Illness Severity (CGI-BP) From Baseline to Endpoint
CGI-BP Severity is used by the clinician to record the severity of illness at the time of assessment. The score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).
Time frame: Baseline to endpoint (6 weeks)
Population: Intent to Treat analysis. Number of randomized patients with baseline and at least one nonmissing postbaseline value. Last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Mean Change in Clinical Global Impression for Bipolar Illness Severity (CGI-BP) From Baseline to Endpoint | -1.34 units on a scale | Standard Error 0.11 |
| Placebo | Mean Change in Clinical Global Impression for Bipolar Illness Severity (CGI-BP) From Baseline to Endpoint | -1.06 units on a scale | Standard Error 0.11 |
p-value: 0.056ANCOVA
Secondary
Number of Participants Meeting the Criteria for Mixed Onset of Action
The original outcome measure was Time to Mixed Onset of Action (at least a 25% reduction on HAMD and YMRS total scores from baseline); however since upper limit of measure of dispersion could not be computed by observed data, which is not allowed on this system, number of patients with event are presented instead.
Time frame: Baseline to endpoint (6 weeks)
Population: All randomized participants with both baseline and post-baseline measures. Intention to Treat analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine | Number of Participants Meeting the Criteria for Mixed Onset of Action | 81 participants |
| Placebo | Number of Participants Meeting the Criteria for Mixed Onset of Action | 71 participants |
p-value: 0.1Fisher Exact
Secondary
Number of Participants Meeting the Criteria for Mixed Response
The original outcome measure was Time to Mixed Response(at least a 50% reduction on HAMD and YMRS total scores from baseline); however since upper limit of measure of dispersion could not be computed by observed data, which is not allowed on this system, number of patients with event are presented instead.
Time frame: baseline to endpoint (6 weeks)
Population: All randomized participants with both baseline and post-baseline measures. Intention to Treat analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine | Number of Participants Meeting the Criteria for Mixed Response | 54 participants |
| Placebo | Number of Participants Meeting the Criteria for Mixed Response | 40 participants |
p-value: 0.048Fisher Exact
Secondary
Number of Patients Hospitalized Due to Relapse of Mania or Depression.
Number of participants hospitalized as a result of relapse of mania or depression.
Time frame: Baseline to endpoint (6 weeks)
Population: Intent to Treat analysis. All randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine | Number of Patients Hospitalized Due to Relapse of Mania or Depression. | 1 participants |
| Placebo | Number of Patients Hospitalized Due to Relapse of Mania or Depression. | 0 participants |