Bipolar Depression
Conditions
Keywords
Bipolar I Depression
Brief summary
The main goal of this study is to help answer the following research question(s) and not to treat the child's illness. * Can this study drug make children with bipolar depression feel better? * Does this study drug work better than a placebo (sugar pill)? * Does this study drug cause side effects in children who take it? * Is this drug safe to use in children? (The study drug is a mixture of olanzapine and fluoxetine)
Interventions
DRUGOlanzapine Fluoxetine Combination (OFC)
OFC doses are capsules of 3 milligrams (mg) olanzapine and 25 mg fluoxetine (3/25), 6/25, 12/25, 6/50, or 12/50 mg to be taken orally once daily in the evening for 8 weeks.
DRUGPlacebo
Orally, once daily in the evening for 8 weeks.
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
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Male or female inpatients or outpatients, 10-17 years of age, who have not reached their 18th birthday prior to screening. Patient must weigh at least 20 kilograms (kg) at screening. * Must meet diagnostic criteria for current major depressive episode of Bipolar I Disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Version (DSM-IV-TR) and confirmed by Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime (K-SADS-PL) * Patients entering the study will also be scored by the Children's Depression Rating Scale-Revised (CDRS-R) (entry score of greater than or equal to 40) as well as the adolescent-structured Young Mania Rating Scale (YMRS) (entry score of less than or equal to 15 with YMRS Item 1 \[elevated mood\] score less than equal to 2).
Exclusion criteria
* Patients will be excluded if they are, in the opinion of the investigator, actively suicidal * Have an acute, serious or unstable medical condition * Have clinically significant laboratory abnormalities * Have had one or more seizures of unclear etiology * Have a current or lifetime diagnosis of any of the following according to DSM-IV criteria: Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Psychotic Disorder Not Otherwise Specified, Delirium of any type, Amnestic Disorder, any Substance-Induced Disorder, or any Psychotic Disorder due to a General Medical Condition, unless there is substantive reason to believe patient was misdiagnosed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Children's Depression Rating Scale Revised (CDRS-R) Total Score at Week 8 | Baseline, Week 8 | CDRS-R Total score measures the presence and severity of depression in children. The scale consists of 17 items scored on a 1-to-5- or 1-to-7-point scale. A rating of 1 indicates normal functioning. Total scores range from 17 to 113. In general, scores below 20 indicate an absence of depression, scores of 20 to 30 indicate borderline depression, and scores of 40 to 60 indicate moderate depression. Least Square (LS) mean was adjusted for baseline, country, treatment, visit, and treatment times (\*) visit interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Each Improvement Category Up to Week 8 | Baseline up to Week 8 | CDRS-R scores: No/low improvement is \< 25 percent (%) of maximum reduction from baseline. Mild improvement: maximum reduction from baseline on CDRS-R score ≥ 25% up to \<50% and YMRS elevated mood score ≤ 2. Moderate improvement: maximum reduction from baseline on CDRS-R score ≥50% and \<75% and YMRS elevated mood score ≤ 2. Major improvement: maximum reduction from baseline on CDRS-R score ≥75% and YMRS elevated mood score ≤ 2. CDRS-R measures presence/severity of depression in children. Scale is 17 items scored 1-to-5- or 1-to-7. Rating of 1 indicates normal function. Scores range: 17 to 113. Scores \< 20 absence of depression, scores 20 to 30 borderline depression, scores 40 to 60 indicate moderate depression. YMRS is an 11-item scale that measures severity of manic episodes. Four items rated 0 (symptoms not present) to 8 (symptom extremely severe). Remaining items rated 0 (symptoms not present) to 4 (symptom extremely severe). Score range: 0 to 60. |
| Change From Baseline in the YMRS Total Score at Week 8 | Baseline, Week 8 | The YMRS is an 11-item scale measuring 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 scores ranges: 0 to 60. LS mean was adjusted for baseline, country, treatment, visit, and treatment \* visit interaction. |
| Change From Baseline in the Clinical Global Impression Scale - Bipolar Version (CGI-BP) Score at Week 8 | Baseline, Week 8 | CGI-BP measures severity of illness for bipolar illness. Scores range: 1 (normal, not ill at all) to 7 (among the most extremely ill patients). LS mean was adjusted for baseline, country, treatment, visit, and treatment \* visit interaction. |
| Change From Baseline in the CDRS-R Total Score Up to Week 8 | Baseline, Week 8 | CDRS-R Total score measure the presence and severity of depression in children and consists of 17 items scored on a 1-to-5- or 1-to-7-point scale. Rating of 1 indicates normal function. Total scores range from 17 to 113. In general, scores \< 20 indicate an absence of depression, scores of 20 to 30 indicate borderline depression, and scores of 40 to 60 indicate moderate depression. LS mean was adjusted for baseline, country, and treatment. |
| Percentage of Participants With at Least One Treatment-Emergent Incident of Akathisia Up to Week 8 | Baseline up to Week 8 | Akathisia was measured using the Barnes Akathisia Rating Scale where the global scores range from 0 (absent) to 5 (severe) and a score ≥ 2 is considered abnormal. |
| Percentage of Participants With Treatment Emergent Suicidal Ideation or Behavior Up to Week 8 | Baseline up to Week 8 | Columbia-Suicide Severity Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Percentage of participants with suicidal ideation, behavior, and acts are provided. Suicidal ideation: a yes answer to any 1 of 5 suicidal ideation questions, which includes wish to be dead, and 4 different categories of active suicidal ideation. Suicidal behavior: a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal act: a yes answer to actual attempt or completed suicide. |
| Percentage of Participants With at Least One Incident of Worsening of Mania Up to Week 8 | Baseline up to Week 8 | Worsening of mania was defined as YMRS score of ≥20 and a CGI severity of mania score of ≥ 5 at the same visit. The YMRS is an 11-item scale measuring severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe) with 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. CGI measures severity of the participant's overall severity of bipolar symptoms and scores range from 1 (normal) to 7 (among the most extremely ill participants). |
| Change From Baseline in Symptoms of Attention-Deficit/Hyperactivity Disorder Up to Week 8 | Baseline up to Week 8 | Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version (ADHDRS-IV-PI): Investigator Administered and Scored measures the 18 symptoms contained in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often). Scores range: 0 to 54. The LS mean was adjusted for baseline and treatment. |
| Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Parent Scale Up to Week 8 | Baseline, Week 8 | The KINDL consists of 24 Likert-scale items. Total scores were standardized to a 0 (lowest quality of life) to 100 (highest quality of life). LS mean was adjusted for baseline, country, and treatment. |
| Percentage of Participants With Remission Up to Week 8 | Baseline up to Week 8 | Remission is defined as a CDRS-R total score less than or equal to (≤)28, and Young Mania Rating Scale (YMRS) total score ≤ 8 and Clinical Global Impressions-Bipolar Version (CGI-BP) total score ≤3. CDRS-R is a 17-item scale measuring presence/severity of depression in children and is scored on a 1-to-5- or 1-to-7-point scale. Rating of 1 indicates normal function. Scores range: 17 to 113. Scores \<20 indicate an absence of depression, scores 20 to 30 indicate borderline depression, scores 40 to 60 indicate moderate depression. The YMRS is an 11-item scale measuring severity of manic episodes; 4 items are rated on a scale from 0 (symptoms not present) to 8 (symptom extremely severe) with remaining items rated on a scale from 0 (symptoms not present) to 4 (symptom extremely severe). YMRS score ranges from 0 to 60. CGI-BP measures participant's overall severity of bipolar symptoms. Scores range: 1 (normal, not at all ill ) to 7 (among the most extremely ill participants). |
| Percentage of Participants With Response Up to Week 8 | Baseline up to Week 8 | Response is defined as a CDRS-R total score greater than or equal to (≥)50% reduction from baseline and YMRS elevated mood score ≤2. CDRS-R Total score measure the presence and severity of depression in children. The scale consists of 17 items scored on a 1-to-5- or 1-to-7-point scale. Rating of 1 indicates normal function. Scores range: 17 to 113. In general, \<20 indicate an absence of depression, scores 20 to 30 indicate borderline depression, and scores of 40 to 60 indicate moderate depression. YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptoms not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptoms not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Kid and Kiddo Combined Scale Up to Week 8 | Baseline, Week 8 | The KINDL consists of 24 Likert-scale items. Kid-KINDL was administered to ages 8-11 and Kiddo-KINDL to ages 12-16. Total scores were standardized to a 0 (lowest quality of life) to 100 (highest quality of life). LS mean was adjusted for baseline, country, and treatment. |
| Change From Baseline in Weight Up to Week 8 | Baseline, Week 8 | Weight LS mean was adjusted for baseline and treatment. |
| Change From Baseline in Fasting Metabolic Parameters Up to Week 8 | Baseline, Week 8 | Fasting glucose, fasting cholesterol and fasting triglycerides. LS means were adjusted for baseline and treatment. |
| Change From Baseline in Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase (ALT/SGPT) Up to Week 8 | Baseline, Week 8 | ALT/SGPT LS mean was adjusted for baseline and treatment. |
| Change From Baseline in Prolactin Up to Week 8 | Baseline, Week 8 | Prolactin LS mean was adjusted for baseline and treatment. |
| Change From Baseline in Electrocardiogram (ECG) QTcF Interval Up to Week 8 | Baseline, Week 8 | QTcF is defined as ECG QT interval corrected for heart rate using the Fridericia correction factor. |
| Percentage of Participants With at Least One Treatment-Emergent Incident of Parkinsonism Up to Week 8 | Baseline, Week 8 | Parkinsonism was measured using the Simpson-Angus Scale with a total scores range from 0 to 40. A score \> 3 was considered abnormal. Simpson-Angus Scale consists of 10 items, each rated on a 5-point scale, 0 (complete absence of the condition) to 4 (presence of the condition in extreme form). |
| Percentage of Participants With at Least One Treatment-Emergent Incident of Dyskinesia Up to Week 8 | Baseline, Week 8 | Dyskinesia was measured using the Abnormal Involuntary Movement Scale (AIMS) a 12-item scale designed to record the occurrence of dyskinetic movements. Items 1 through 10 are rated on a 5-point scale: 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 11 and 12 are yes/no questions regarding the dental condition of a patient. Total score (0-40) is obtained by adding the scores of the first 10 items. An abnormal result is defined as having a score ≥3 for at least 1 of the first 7 items or a score ≥2 for at least two of the first 7 items. |
Countries
Russia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Olanzapine/Fluoxetine Combination OFC 3/25 mg administered orally as an initial dose beginning at randomization, 6/25 mg at Visit 3 (Day 3), 6/50 mg at Visit 4 (Week 1), and 12/50 mg at Visit 5 (Week 2). If no tolerability or safety issues occurred after Visit 5 the participant continued on the maximum tolerated dose, not to exceed 12/50 mg and not less than 6/25 mg, for a total of 8 weeks. | 170 |
| Placebo Matched placebo capsule administered orally once daily for 8 weeks. | 85 |
| Total | 255 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 24 | 5 |
| Overall Study | Clinical Relapse | 0 | 1 |
| Overall Study | Did Not Take Study Drug | 3 | 1 |
| Overall Study | Entry Criteria Not Met | 0 | 1 |
| Overall Study | Good Clinical Practice Violations | 21 | 11 |
| Overall Study | Lack of Efficacy | 5 | 5 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Parent/Caregiver Decision | 6 | 2 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Protocol Violation | 6 | 0 |
| Overall Study | Sponsor Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 7 |
Baseline characteristics
| Characteristic | Olanzapine/Fluoxetine Combination | Total | Placebo |
|---|---|---|---|
| Age Continuous | 14.59 years STANDARD_DEVIATION 2.3 | 14.74 years STANDARD_DEVIATION 2.25 | 15.03 years STANDARD_DEVIATION 2.13 |
| Ethnicity Hispanic or Latino | 38 participants | 61 participants | 23 participants |
| Ethnicity Missing, participant did not reply | 0 participants | 1 participants | 1 participants |
| Ethnicity Not Hispanic or Latino | 132 participants | 193 participants | 61 participants |
| Number of Previous Episodes of Depression During Participants Life | 4.63 episodes STANDARD_DEVIATION 9.13 | 4.45 episodes STANDARD_DEVIATION 8.36 | 4.11 episodes STANDARD_DEVIATION 6.58 |
| Number of Previous Episodes of Depression in Past 12 Months | 1.88 episodes STANDARD_DEVIATION 4.16 | 1.82 episodes STANDARD_DEVIATION 3.64 | 1.71 episodes STANDARD_DEVIATION 2.31 |
| Number of Previous Episodes of Mania During Participants Life | 3.91 episodes STANDARD_DEVIATION 10.43 | 3.85 episodes STANDARD_DEVIATION 9.12 | 3.75 episodes STANDARD_DEVIATION 5.69 |
| Number of Previous Episodes of Mania in Past 12 Months | 1.26 episodes STANDARD_DEVIATION 3.91 | 1.27 episodes STANDARD_DEVIATION 3.37 | 1.27 episodes STANDARD_DEVIATION 1.89 |
| Number of Previous Mixed Episodes During Participants Life | 1.79 episodes STANDARD_DEVIATION 7.69 | 1.70 episodes STANDARD_DEVIATION 6.68 | 1.53 episodes STANDARD_DEVIATION 3.96 |
| Number of Previous Mixed Episodes in Past 12 Months | 0.68 episodes STANDARD_DEVIATION 3.97 | 0.58 episodes STANDARD_DEVIATION 3.29 | 0.39 episodes STANDARD_DEVIATION 1.05 |
| Race American Indian or Alaska Native | 9 participants | 14 participants | 5 participants |
| Race Asian | 0 participants | 0 participants | 0 participants |
| Race Black or African American | 23 participants | 34 participants | 11 participants |
| Race Missing, participant did not reply | 3 participants | 4 participants | 1 participants |
| Race Multiple | 15 participants | 22 participants | 7 participants |
| Race Native Hawaiian or Other Pacific Islander | 1 participants | 1 participants | 0 participants |
| Race White | 119 participants | 180 participants | 61 participants |
| Region of Enrollment Mexico | 16 participants | 23 participants | 7 participants |
| Region of Enrollment Russian Federation | 31 participants | 44 participants | 13 participants |
| Region of Enrollment United States | 123 participants | 188 participants | 65 participants |
| Sex: Female, Male Female | 86 Participants | 125 Participants | 39 Participants |
| Sex: Female, Male Male | 84 Participants | 130 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 125 / 170 | 49 / 85 |
| serious Total, serious adverse events | 9 / 170 | 6 / 85 |
Outcome results
Primary
Change From Baseline in the Children's Depression Rating Scale Revised (CDRS-R) Total Score at Week 8
CDRS-R Total score measures the presence and severity of depression in children. The scale consists of 17 items scored on a 1-to-5- or 1-to-7-point scale. A rating of 1 indicates normal functioning. Total scores range from 17 to 113. In general, scores below 20 indicate an absence of depression, scores of 20 to 30 indicate borderline depression, and scores of 40 to 60 indicate moderate depression. Least Square (LS) mean was adjusted for baseline, country, treatment, visit, and treatment times (\*) visit interaction.
Time frame: Baseline, Week 8
Population: Population analyzed was the Modified Intention-to-Treat (M-ITT) Population: defined as all randomized participants who took at least 1 dose of study drug and excluding participants from 2 Good Clinical Practice (GCP) noncompliant sites and who had a baseline and at least 1 post-baseline CDRS-R measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in the Children's Depression Rating Scale Revised (CDRS-R) Total Score at Week 8 | -28.43 units on a scale | Standard Error 1.13 |
| Placebo | Change From Baseline in the Children's Depression Rating Scale Revised (CDRS-R) Total Score at Week 8 | -23.40 units on a scale | Standard Error 1.49 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to Week 8 between OFC and placebo.~A conservative estimate of effect size of 0.4 was used in the sample size estimation for this study. A randomized ratio of 2:1 provided a 90% power with an effect size of 0.4.p-value: 0.003Mixed Models Analysis
Secondary
Change From Baseline in Symptoms of Attention-Deficit/Hyperactivity Disorder Up to Week 8
Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version (ADHDRS-IV-PI): Investigator Administered and Scored measures the 18 symptoms contained in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often). Scores range: 0 to 54. The LS mean was adjusted for baseline and treatment.
Time frame: Baseline up to Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and ADHDRS-IV-PI results at baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in Symptoms of Attention-Deficit/Hyperactivity Disorder Up to Week 8 | -4.31 units on a scale | Standard Error 0.7 |
| Placebo | Change From Baseline in Symptoms of Attention-Deficit/Hyperactivity Disorder Up to Week 8 | -3.57 units on a scale | Standard Error 1 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: 0.545ANCOVA
Secondary
Change From Baseline in the CDRS-R Total Score Up to Week 8
CDRS-R Total score measure the presence and severity of depression in children and consists of 17 items scored on a 1-to-5- or 1-to-7-point scale. Rating of 1 indicates normal function. Total scores range from 17 to 113. In general, scores \< 20 indicate an absence of depression, scores of 20 to 30 indicate borderline depression, and scores of 40 to 60 indicate moderate depression. LS mean was adjusted for baseline, country, and treatment.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites who had CDRS-R total scores at baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in the CDRS-R Total Score Up to Week 8 | -28.57 units on a scale | Standard Error 1.41 |
| Placebo | Change From Baseline in the CDRS-R Total Score Up to Week 8 | -23.38 units on a scale | Standard Error 1.75 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: 0.002ANCOVA
Secondary
Change From Baseline in the Clinical Global Impression Scale - Bipolar Version (CGI-BP) Score at Week 8
CGI-BP measures severity of illness for bipolar illness. Scores range: 1 (normal, not ill at all) to 7 (among the most extremely ill patients). LS mean was adjusted for baseline, country, treatment, visit, and treatment \* visit interaction.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and who had CGI-BP total scores at baseline and at least 1 post-baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in the Clinical Global Impression Scale - Bipolar Version (CGI-BP) Score at Week 8 | -2.21 units on a scale | Standard Error 0.11 |
| Placebo | Change From Baseline in the Clinical Global Impression Scale - Bipolar Version (CGI-BP) Score at Week 8 | -1.83 units on a scale | Standard Error 0.15 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to Week 8 between OFC and placebo.p-value: 0.03Mixed Models Analysis
Secondary
Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Parent Scale Up to Week 8
The KINDL consists of 24 Likert-scale items. Total scores were standardized to a 0 (lowest quality of life) to 100 (highest quality of life). LS mean was adjusted for baseline, country, and treatment.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and KINDL Parent Scale at baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Parent Scale Up to Week 8 | 15.98 units on a scale | Standard Error 1.94 |
| Placebo | Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Parent Scale Up to Week 8 | 10.88 units on a scale | Standard Error 2.56 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: 0.066ANCOVA
Secondary
Change From Baseline in the YMRS Total Score at Week 8
The YMRS is an 11-item scale measuring 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 scores ranges: 0 to 60. LS mean was adjusted for baseline, country, treatment, visit, and treatment \* visit interaction.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites who had YMRS total scores with a baseline and at least 1 post-baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in the YMRS Total Score at Week 8 | -2.02 units on a scale | Standard Error 0.47 |
| Placebo | Change From Baseline in the YMRS Total Score at Week 8 | -1.57 units on a scale | Standard Error 0.63 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to Week 8 between OFC and placebo.p-value: 0.527Mixed Models Analysis
Secondary
Percentage of Participants in Each Improvement Category Up to Week 8
CDRS-R scores: No/low improvement is \< 25 percent (%) of maximum reduction from baseline. Mild improvement: maximum reduction from baseline on CDRS-R score ≥ 25% up to \<50% and YMRS elevated mood score ≤ 2. Moderate improvement: maximum reduction from baseline on CDRS-R score ≥50% and \<75% and YMRS elevated mood score ≤ 2. Major improvement: maximum reduction from baseline on CDRS-R score ≥75% and YMRS elevated mood score ≤ 2. CDRS-R measures presence/severity of depression in children. Scale is 17 items scored 1-to-5- or 1-to-7. Rating of 1 indicates normal function. Scores range: 17 to 113. Scores \< 20 absence of depression, scores 20 to 30 borderline depression, scores 40 to 60 indicate moderate depression. YMRS is an 11-item scale that measures severity of manic episodes. Four items rated 0 (symptoms not present) to 8 (symptom extremely severe). Remaining items rated 0 (symptoms not present) to 4 (symptom extremely severe). Score range: 0 to 60.
Time frame: Baseline up to Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and who had both CDRS-R and YMRS total scores with a baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Percentage of Participants in Each Improvement Category Up to Week 8 | No or Low Improvement | 12.8 percentage of participants |
| Olanzapine/Fluoxetine Combination | Percentage of Participants in Each Improvement Category Up to Week 8 | Mild Improvement | 9.0 percentage of participants |
| Olanzapine/Fluoxetine Combination | Percentage of Participants in Each Improvement Category Up to Week 8 | Moderate Improvement | 21.8 percentage of participants |
| Olanzapine/Fluoxetine Combination | Percentage of Participants in Each Improvement Category Up to Week 8 | Major Improvement | 56.4 percentage of participants |
| Placebo | Percentage of Participants in Each Improvement Category Up to Week 8 | Major Improvement | 40.8 percentage of participants |
| Placebo | Percentage of Participants in Each Improvement Category Up to Week 8 | No or Low Improvement | 22.4 percentage of participants |
| Placebo | Percentage of Participants in Each Improvement Category Up to Week 8 | Moderate Improvement | 18.4 percentage of participants |
| Placebo | Percentage of Participants in Each Improvement Category Up to Week 8 | Mild Improvement | 18.4 percentage of participants |
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 0.007Ordinal Logistic Regression
Secondary
Percentage of Participants With at Least One Incident of Worsening of Mania Up to Week 8
Worsening of mania was defined as YMRS score of ≥20 and a CGI severity of mania score of ≥ 5 at the same visit. The YMRS is an 11-item scale measuring severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe) with 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. CGI measures severity of the participant's overall severity of bipolar symptoms and scores range from 1 (normal) to 7 (among the most extremely ill participants).
Time frame: Baseline up to Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites with YMRS and CGI total scores at baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine/Fluoxetine Combination | Percentage of Participants With at Least One Incident of Worsening of Mania Up to Week 8 | 1.2 percentage of participants |
| Placebo | Percentage of Participants With at Least One Incident of Worsening of Mania Up to Week 8 | 0.0 percentage of participants |
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 1Fisher Exact
Secondary
Percentage of Participants With at Least One Treatment-Emergent Incident of Akathisia Up to Week 8
Akathisia was measured using the Barnes Akathisia Rating Scale where the global scores range from 0 (absent) to 5 (severe) and a score ≥ 2 is considered abnormal.
Time frame: Baseline up to Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug excluding participants from 2 GCP noncompliant sites; LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine/Fluoxetine Combination | Percentage of Participants With at Least One Treatment-Emergent Incident of Akathisia Up to Week 8 | 1.3 percentage of participants |
| Placebo | Percentage of Participants With at Least One Treatment-Emergent Incident of Akathisia Up to Week 8 | 0.0 percentage of participants |
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 1Fisher Exact
Secondary
Percentage of Participants With Remission Up to Week 8
Remission is defined as a CDRS-R total score less than or equal to (≤)28, and Young Mania Rating Scale (YMRS) total score ≤ 8 and Clinical Global Impressions-Bipolar Version (CGI-BP) total score ≤3. CDRS-R is a 17-item scale measuring presence/severity of depression in children and is scored on a 1-to-5- or 1-to-7-point scale. Rating of 1 indicates normal function. Scores range: 17 to 113. Scores \<20 indicate an absence of depression, scores 20 to 30 indicate borderline depression, scores 40 to 60 indicate moderate depression. The YMRS is an 11-item scale measuring severity of manic episodes; 4 items are rated on a scale from 0 (symptoms not present) to 8 (symptom extremely severe) with remaining items rated on a scale from 0 (symptoms not present) to 4 (symptom extremely severe). YMRS score ranges from 0 to 60. CGI-BP measures participant's overall severity of bipolar symptoms. Scores range: 1 (normal, not at all ill ) to 7 (among the most extremely ill participants).
Time frame: Baseline up to Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and who had both the CDRS-R, YMRS and CGI-BP total scores at baseline and at least 1 post-baseline measurement; Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine/Fluoxetine Combination | Percentage of Participants With Remission Up to Week 8 | 59.0 percentage of participants |
| Placebo | Percentage of Participants With Remission Up to Week 8 | 43.4 percentage of participants |
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 0.035Fisher Exact
Secondary
Percentage of Participants With Response Up to Week 8
Response is defined as a CDRS-R total score greater than or equal to (≥)50% reduction from baseline and YMRS elevated mood score ≤2. CDRS-R Total score measure the presence and severity of depression in children. The scale consists of 17 items scored on a 1-to-5- or 1-to-7-point scale. Rating of 1 indicates normal function. Scores range: 17 to 113. In general, \<20 indicate an absence of depression, scores 20 to 30 indicate borderline depression, and scores of 40 to 60 indicate moderate depression. YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptoms not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptoms not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.
Time frame: Baseline up to Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and who had all of CDRS-R and YMRS total scores at baseline and at least 1 post-baseline measurement; LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine/Fluoxetine Combination | Percentage of Participants With Response Up to Week 8 | 78.2 percentage of participants |
| Placebo | Percentage of Participants With Response Up to Week 8 | 59.2 percentage of participants |
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 0.003Fisher Exact
Secondary
Percentage of Participants With Treatment Emergent Suicidal Ideation or Behavior Up to Week 8
Columbia-Suicide Severity Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Percentage of participants with suicidal ideation, behavior, and acts are provided. Suicidal ideation: a yes answer to any 1 of 5 suicidal ideation questions, which includes wish to be dead, and 4 different categories of active suicidal ideation. Suicidal behavior: a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal act: a yes answer to actual attempt or completed suicide.
Time frame: Baseline up to Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites; LOCF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Percentage of Participants With Treatment Emergent Suicidal Ideation or Behavior Up to Week 8 | Total Suicidal Ideation (1 - 5) | 10.6 percentage of participants |
| Olanzapine/Fluoxetine Combination | Percentage of Participants With Treatment Emergent Suicidal Ideation or Behavior Up to Week 8 | Total Suicidal Behavior (6 - 10) | 1.8 percentage of participants |
| Olanzapine/Fluoxetine Combination | Percentage of Participants With Treatment Emergent Suicidal Ideation or Behavior Up to Week 8 | Total Suicidal Ideation or Behavior (1 - 10) | 10.6 percentage of participants |
| Placebo | Percentage of Participants With Treatment Emergent Suicidal Ideation or Behavior Up to Week 8 | Total Suicidal Ideation (1 - 5) | 15.5 percentage of participants |
| Placebo | Percentage of Participants With Treatment Emergent Suicidal Ideation or Behavior Up to Week 8 | Total Suicidal Behavior (6 - 10) | 2.4 percentage of participants |
| Placebo | Percentage of Participants With Treatment Emergent Suicidal Ideation or Behavior Up to Week 8 | Total Suicidal Ideation or Behavior (1 - 10) | 15.5 percentage of participants |
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 0.309Fisher Exact
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 0.667Fisher Exact
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 0.309Fisher Exact
Other Pre-specified
Change From Baseline in Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase (ALT/SGPT) Up to Week 8
ALT/SGPT LS mean was adjusted for baseline and treatment.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and ALT/SGPT at baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase (ALT/SGPT) Up to Week 8 | 7.63 units/Liter (U/L) | Standard Deviation 1.46 |
| Placebo | Change From Baseline in Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase (ALT/SGPT) Up to Week 8 | 0.46 units/Liter (U/L) | Standard Deviation 2.08 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: 0.005ANCOVA
Other Pre-specified
Change From Baseline in Electrocardiogram (ECG) QTcF Interval Up to Week 8
QTcF is defined as ECG QT interval corrected for heart rate using the Fridericia correction factor.
Time frame: Baseline, Week 8
Population: Population analyzed M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and QTcF at baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in Electrocardiogram (ECG) QTcF Interval Up to Week 8 | 8.19 millisecond (msec) | Standard Error 1.01 |
| Placebo | Change From Baseline in Electrocardiogram (ECG) QTcF Interval Up to Week 8 | -1.07 millisecond (msec) | Standard Error 1.44 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: <0.001ANCOVA
Other Pre-specified
Change From Baseline in Fasting Metabolic Parameters Up to Week 8
Fasting glucose, fasting cholesterol and fasting triglycerides. LS means were adjusted for baseline and treatment.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug excluding participants from 2 GCP noncompliant sites and fasting glucose, cholesterol and triglycerides at baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in Fasting Metabolic Parameters Up to Week 8 | Fasting Glucose (157, 79) | 0.03 millimoles/liter (mmol/L) | Standard Error 0.04 |
| Olanzapine/Fluoxetine Combination | Change From Baseline in Fasting Metabolic Parameters Up to Week 8 | Fasting Cholesterol (158, 81) | 0.42 millimoles/liter (mmol/L) | Standard Error 0.05 |
| Olanzapine/Fluoxetine Combination | Change From Baseline in Fasting Metabolic Parameters Up to Week 8 | Fasting Triglycerides (158, 81) | 0.40 millimoles/liter (mmol/L) | Standard Error 0.06 |
| Placebo | Change From Baseline in Fasting Metabolic Parameters Up to Week 8 | Fasting Glucose (157, 79) | 0.03 millimoles/liter (mmol/L) | Standard Error 0.06 |
| Placebo | Change From Baseline in Fasting Metabolic Parameters Up to Week 8 | Fasting Cholesterol (158, 81) | -0.11 millimoles/liter (mmol/L) | Standard Error 0.07 |
| Placebo | Change From Baseline in Fasting Metabolic Parameters Up to Week 8 | Fasting Triglycerides (158, 81) | -0.04 millimoles/liter (mmol/L) | Standard Error 0.08 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: 0.98ANCOVA
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: <0.001ANCOVA
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: <0.001ANCOVA
Other Pre-specified
Change From Baseline in Prolactin Up to Week 8
Prolactin LS mean was adjusted for baseline and treatment.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and prolactin at baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in Prolactin Up to Week 8 | 8.66 microgram/Liter (μg/L) | Standard Error 0.77 |
| Placebo | Change From Baseline in Prolactin Up to Week 8 | 0.70 microgram/Liter (μg/L) | Standard Error 1.1 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: <0.001ANCOVA
Other Pre-specified
Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Kid and Kiddo Combined Scale Up to Week 8
The KINDL consists of 24 Likert-scale items. Kid-KINDL was administered to ages 8-11 and Kiddo-KINDL to ages 12-16. Total scores were standardized to a 0 (lowest quality of life) to 100 (highest quality of life). LS mean was adjusted for baseline, country, and treatment.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug excluding participants from 2 GCP noncompliant sites and had KINDL Kid and Kiddo results at baseline and at least 1 post-baseline measurement. Due to small number of 10- and 11-year olds results from the 2 versions were pooled; LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Kid and Kiddo Combined Scale Up to Week 8 | 12.83 units on a scale | Standard Error 1.65 |
| Placebo | Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Kid and Kiddo Combined Scale Up to Week 8 | 7.91 units on a scale | Standard Error 2.4 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: 0.05ANCOVA
Other Pre-specified
Change From Baseline in Weight Up to Week 8
Weight LS mean was adjusted for baseline and treatment.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites and weight at baseline and at least 1 post-baseline measurement; LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Fluoxetine Combination | Change From Baseline in Weight Up to Week 8 | 4.37 kilogram (kg) | Standard Error 0.23 |
| Placebo | Change From Baseline in Weight Up to Week 8 | 0.50 kilogram (kg) | Standard Error 0.33 |
Comparison: Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.p-value: <0.001ANCOVA
Other Pre-specified
Percentage of Participants With at Least One Treatment-Emergent Incident of Dyskinesia Up to Week 8
Dyskinesia was measured using the Abnormal Involuntary Movement Scale (AIMS) a 12-item scale designed to record the occurrence of dyskinetic movements. Items 1 through 10 are rated on a 5-point scale: 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 11 and 12 are yes/no questions regarding the dental condition of a patient. Total score (0-40) is obtained by adding the scores of the first 10 items. An abnormal result is defined as having a score ≥3 for at least 1 of the first 7 items or a score ≥2 for at least two of the first 7 items.
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites; LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine/Fluoxetine Combination | Percentage of Participants With at Least One Treatment-Emergent Incident of Dyskinesia Up to Week 8 | 0.6 percentage of participants |
| Placebo | Percentage of Participants With at Least One Treatment-Emergent Incident of Dyskinesia Up to Week 8 | 0.0 percentage of participants |
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 1Fisher Exact
Other Pre-specified
Percentage of Participants With at Least One Treatment-Emergent Incident of Parkinsonism Up to Week 8
Parkinsonism was measured using the Simpson-Angus Scale with a total scores range from 0 to 40. A score \> 3 was considered abnormal. Simpson-Angus Scale consists of 10 items, each rated on a 5-point scale, 0 (complete absence of the condition) to 4 (presence of the condition in extreme form).
Time frame: Baseline, Week 8
Population: Population analyzed was the M-ITT Population: all randomized participants who took at least 1 dose of study drug and excluding participants from 2 GCP noncompliant sites; LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine/Fluoxetine Combination | Percentage of Participants With at Least One Treatment-Emergent Incident of Parkinsonism Up to Week 8 | 0.6 percentage of participants |
| Placebo | Percentage of Participants With at Least One Treatment-Emergent Incident of Parkinsonism Up to Week 8 | 1.3 percentage of participants |
Comparison: Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.p-value: 1Fisher Exact