A Study for Assessing Treatment of Patients Ages 10-17 With Bipolar Depression

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00844857
• Collaborator: (none)
• Enrollment: 291
• Locations: 7
• Arms: 2
• Duration (Months): 34
• Patients Per Site: 41.6
• Patients Per Site Per Month: 1.2

Study Details

Study Description

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)

Condition or Disease	Intervention/Treatment	Phase
Bipolar Depression	Drug: Olanzapine Fluoxetine Combination (OFC); Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 291 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Study to Assess the Efficacy and Safety of Olanzapine and Fluoxetine Combination Versus Placebo in Patients Ages 10-17 in the Treatment of Major Depressive Episodes Associated With Bipolar I Disorder
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Olanzapine/Fluoxetine Combination	Drug: Olanzapine 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.; Other Names: LY900000 Symbyax
Placebo Comparator: Placebo	Drug: Placebo; Orally, once daily in the evening for 8 weeks.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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).

10. 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.

11. 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.

Other Outcome Measures

1. 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).

2. 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.

3. 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.

4. Change From Baseline in Weight Up to Week 8 [Baseline, Week 8]

   Weight LS mean was adjusted for baseline and treatment.

5. 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.

6. 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.

7. Change From Baseline in Prolactin Up to Week 8 [Baseline, Week 8]

   Prolactin LS mean was adjusted for baseline and treatment.

8. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	San Diego	California	United States	92123
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lipetsk		Russian Federation	399313
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Moscow		Russian Federation	123367
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Saratov		Russian Federation	410060
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Stavropol		Russian Federation	355038
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Tver		Russian Federation	170005
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Yaroslavl		Russian Federation	150003

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern Time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00844857
• Other Study ID Numbers: 12116; H6P-MC-HDAX
• First Posted: Feb 16, 2009
• Last Update Posted: Feb 18, 2013
• Last Verified: Jan 1, 2013

• Keywords provided by Eli Lilly and Company: Bipolar I Depression
• Additional relevant MeSH terms: Depression; Depressive Disorder; Bipolar Disorder; Olanzapine; Fluoxetine

Study Results

Participant Flow

Arm/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	Olanzapine/fluoxetine Combination (OFC) 3 milligrams (mg) olanzapine and 25 mg fluoxetine (OFC 3/25) 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.	Matched placebo capsule administered orally once daily for 8 weeks.
Period Title: Overall Study
STARTED	194	97
Population Analyzed	170	85
COMPLETED	116	60
NOT COMPLETED	78	37

Baseline Characteristics

Arm/Group Title	Olanzapine/Fluoxetine Combination	Placebo	Total
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.	Total of all reporting groups
Overall Participants	170	85	255
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.59 (2.30)	15.03 (2.13)	14.74 (2.25)
Sex: Female, Male (Count of Participants)
Female	86 50.6%	39 45.9%	125 49%
Male	84 49.4%	46 54.1%	130 51%
Region of Enrollment (participants) [Number]
United States	123 72.4%	65 76.5%	188 73.7%
Russian Federation	31 18.2%	13 15.3%	44 17.3%
Mexico	16 9.4%	7 8.2%	23 9%
Ethnicity (participants) [Number]
Hispanic or Latino	38 22.4%	23 27.1%	61 23.9%
Not Hispanic or Latino	132 77.6%	61 71.8%	193 75.7%
Missing, participant did not reply	0 0%	1 1.2%	1 0.4%
Race (participants) [Number]
American Indian or Alaska Native	9 5.3%	5 5.9%	14 5.5%
Asian	0 0%	0 0%	0 0%
Black or African American	23 13.5%	11 12.9%	34 13.3%
Native Hawaiian or Other Pacific Islander	1 0.6%	0 0%	1 0.4%
White	119 70%	61 71.8%	180 70.6%
Multiple	15 8.8%	7 8.2%	22 8.6%
Missing, participant did not reply	3 1.8%	1 1.2%	4 1.6%
Number of Previous Episodes of Mania During Participants Life (episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes]	3.91 (10.43)	3.75 (5.69)	3.85 (9.12)
Number of Previous Episodes of Depression During Participants Life (episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes]	4.63 (9.13)	4.11 (6.58)	4.45 (8.36)
Number of Previous Mixed Episodes During Participants Life (episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes]	1.79 (7.69)	1.53 (3.96)	1.70 (6.68)
Number of Previous Episodes of Mania in Past 12 Months (episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes]	1.26 (3.91)	1.27 (1.89)	1.27 (3.37)
Number of Previous Episodes of Depression in Past 12 Months (episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes]	1.88 (4.16)	1.71 (2.31)	1.82 (3.64)
Number of Previous Mixed Episodes in Past 12 Months (episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes]	0.68 (3.97)	0.39 (1.05)	0.58 (3.29)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Children's Depression Rating Scale Revised (CDRS-R) Total Score at Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally, once daily for 8 weeks.
Measure Participants	170	84
Least Squares Mean (Standard Error) [units on a scale]	-28.43 (1.13)	-23.40 (1.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	The a priori threshold for statistical significance was 0.05. Mixed Model Repeated Measures Analysis (MMRM) terms included baseline, country, treatment, visit, and treatment * visit interaction.
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Percentage of Participants With Remission Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	156	76
Number [percentage of participants]	59.0 34.7%	43.4 51.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments	The a priori threshold for statistical significance was 0.05.
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Percentage of Participants With Response Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	156	76
Number [percentage of participants]	78.2 46%	59.2 69.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	The a priori threshold for statistical significance was 0.05.
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Percentage of Participants in Each Improvement Category Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine Plus Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	156	76
No or Low Improvement	12.8 7.5%	22.4 26.4%
Mild Improvement	9.0 5.3%	18.4 21.6%
Moderate Improvement	21.8 12.8%	18.4 21.6%
Major Improvement	56.4 33.2%	40.8 48%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	The a priori threshold for statistical significance was 0.05. Ordinal Logistic Regression Model terms include baseline CDRS-R, baseline YMRS, and treatment.
	Method	Ordinal Logistic Regression
	Comments

5. Secondary Outcome

Title	Change From Baseline in the YMRS Total Score at Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	118	60
Least Squares Mean (Standard Error) [units on a scale]	-2.02 (0.47)	-1.57 (0.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.527
	Comments	The a priori threshold for statistical significance was 0.05. MMRM terms included baseline, country, treatment, visit, and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

6. Secondary Outcome

Title	Change From Baseline in the Clinical Global Impression Scale - Bipolar Version (CGI-BP) Score at Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	118	60
Least Squares Mean (Standard Error) [units on a scale]	-2.21 (0.11)	-1.83 (0.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	The a priori threshold for statistical significance was 0.05. MMRM terms included baseline, country, treatment, visit, and treatment*visit interaction
	Method	Mixed Models Analysis
	Comments

7. Secondary Outcome

Title	Change From Baseline in the CDRS-R Total Score Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	170	84
Least Squares Mean (Standard Error) [units on a scale]	-28.57 (1.41)	-23.38 (1.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	The a priori threshold for statistical significance was 0.05. ANCOVA (analysis of covariance) Model terms included baseline, country, and treatment.
	Method	ANCOVA
	Comments

8. Secondary Outcome

Title	Percentage of Participants With at Least One Treatment-Emergent Incident of Akathisia Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	159	79
Number [percentage of participants]	1.3 0.8%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	The a priori threshold for statistical significance was 0.05.
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Percentage of Participants With Treatment Emergent Suicidal Ideation or Behavior Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	170	84
Total Suicidal Ideation (1 - 5)	10.6 6.2%	15.5 18.2%
Total Suicidal Behavior (6 - 10)	1.8 1.1%	2.4 2.8%
Total Suicidal Ideation or Behavior (1 - 10)	10.6 6.2%	15.5 18.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.309
	Comments	P-value for Suicidal Ideation. The a priori threshold for statistical significance was 0.05.
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.667
	Comments	P-value for Suicidal Behavior. The a priori threshold for statistical significance was 0.05.
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.309
	Comments	P-value for Suicidal Ideation or Behavior. The a priori threshold for statistical significance was 0.05.
	Method	Fisher Exact
	Comments

10. Secondary Outcome

Title	Percentage of Participants With at Least One Incident of Worsening of Mania Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	170	84
Number [percentage of participants]	1.2 0.7%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	The a priori threshold for statistical significance was 0.05.
	Method	Fisher Exact
	Comments

11. Secondary Outcome

Title	Change From Baseline in Symptoms of Attention-Deficit/Hyperactivity Disorder Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	152	74
Least Squares Mean (Standard Error) [units on a scale]	-4.31 (0.70)	-3.57 (1.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.545
	Comments	P-value for ADHDRS-IV-PI Total Score. The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline, country and treatment.
	Method	ANCOVA
	Comments

12. Secondary Outcome

Title	Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Parent Scale Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	83	39
Least Squares Mean (Standard Error) [units on a scale]	15.98 (1.94)	10.88 (2.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.066
	Comments	The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline, country and treatment.
	Method	ANCOVA
	Comments

13. Other Pre-specified Outcome

Title	Percentage of Participants With at Least One Treatment-Emergent Incident of Parkinsonism Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	158	80
Number [percentage of participants]	0.6 0.4%	1.3 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	The a priori threshold for statistical significance was 0.05.
	Method	Fisher Exact
	Comments

14. Other Pre-specified Outcome

Title	Percentage of Participants With at Least One Treatment-Emergent Incident of Dyskinesia Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	160	80
Number [percentage of participants]	0.6 0.4%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in proportions between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	The a priori threshold for statistical significance was 0.05.
	Method	Fisher Exact
	Comments

15. Other Pre-specified Outcome

Title	Change From Baseline in the Quality of Life Questionnaire for Children and Adolescents (KINDL) Kid and Kiddo Combined Scale Up to Week 8
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	107	40
Least Squares Mean (Standard Error) [units on a scale]	12.83 (1.65)	7.91 (2.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.050
	Comments	The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline, country and treatment.
	Method	ANCOVA
	Comments

16. Other Pre-specified Outcome

Title	Change From Baseline in Weight Up to Week 8
Description	Weight LS mean was adjusted for baseline and treatment.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	170	84
Least Squares Mean (Standard Error) [kilogram (kg)]	4.37 (0.23)	0.50 (0.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline and treatment.
	Method	ANCOVA
	Comments

17. Other Pre-specified Outcome

Title	Change From Baseline in Fasting Metabolic Parameters Up to Week 8
Description	Fasting glucose, fasting cholesterol and fasting triglycerides. LS means were adjusted for baseline and treatment.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	158	81
Fasting Glucose (157, 79)	0.03 (0.04)	0.03 (0.06)
Fasting Cholesterol (158, 81)	0.42 (0.05)	-0.11 (0.07)
Fasting Triglycerides (158, 81)	0.40 (0.06)	-0.04 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.980
	Comments	P-value for Fasting Glucose. The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline and treatment.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value for Fasting Cholesterol. The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline and treatment
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value for Fasting Triglycerides. The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline and treatment.
	Method	ANCOVA
	Comments

18. Other Pre-specified Outcome

Title	Change From Baseline in Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase (ALT/SGPT) Up to Week 8
Description	ALT/SGPT LS mean was adjusted for baseline and treatment.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	170	84
Least Squares Mean (Standard Deviation) [units/Liter (U/L)]	7.63 (1.46)	0.46 (2.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline and treatment.
	Method	ANCOVA
	Comments

19. Other Pre-specified Outcome

Title	Change From Baseline in Prolactin Up to Week 8
Description	Prolactin LS mean was adjusted for baseline and treatment.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	170	84
Least Squares Mean (Standard Error) [microgram/Liter (μg/L)]	8.66 (0.77)	0.70 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline and treatment.
	Method	ANCOVA
	Comments

20. Other Pre-specified Outcome

Title	Change From Baseline in Electrocardiogram (ECG) QTcF Interval Up to Week 8
Description	QTcF is defined as ECG QT interval corrected for heart rate using the Fridericia correction factor.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

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/Group Title	Olanzapine/Fluoxetine Combination	Placebo
Arm/Group Description	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.	Matched placebo capsule administered orally once daily for 8 weeks.
Measure Participants	158	78
Least Squares Mean (Standard Error) [millisecond (msec)]	8.19 (1.01)	-1.07 (1.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine/Fluoxetine Combination, Placebo
	Comments	Tested was the null hypothesis that there was no difference in mean changes from baseline to up to Week 8 between OFC and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The a priori threshold for statistical significance was 0.05. ANCOVA Model terms included baseline and treatment.
	Method	ANCOVA
	Comments

Adverse Events

Adverse Event Reporting Description	Adverse events were reported for all randomized participants who took at least 1 dose of study drug, excluding 2 GCP noncompliant sites.
Arm/Group Title	Olanzapine/Fluoxetine Combination		Placebo
Arm/Group Description	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.		Matched placebo capsule administered orally once daily for 8 weeks.
All Cause Mortality
	Olanzapine/Fluoxetine Combination		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Olanzapine/Fluoxetine Combination		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/170 (5.3%)		6/85 (7.1%)
Immune system disorders
Anaphylaxis	0/170 (0%)	0	1/85 (1.2%)	1
Infections and infestations
Pyoderma	0/170 (0%)	0	1/85 (1.2%)	1
Psychiatric disorders
Aggression aggravated	2/170 (1.2%)	3	1/85 (1.2%)	1
Agitation	1/170 (0.6%)	1	0/85 (0%)	0
Bipolar affective disorder aggravated	1/170 (0.6%)	1	0/85 (0%)	0
Depression worsened	0/170 (0%)	0	1/85 (1.2%)	1
Homicidal ideation	1/170 (0.6%)	1	0/85 (0%)	0
Psychosis aggravated	0/170 (0%)	0	1/85 (1.2%)	1
Self injurious behavior	1/170 (0.6%)	1	0/85 (0%)	0
Suicidal ideation	2/170 (1.2%)	2	1/85 (1.2%)	1
Suicide attempt	1/170 (0.6%)	2	0/85 (0%)	0
Reproductive system and breast disorders
Ovulation disorder	1/86 (1.2%)	1	0/39 (0%)	0
Other (Not Including Serious) Adverse Events
	Olanzapine/Fluoxetine Combination		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	125/170 (73.5%)		49/85 (57.6%)
Gastrointestinal disorders
Nausea	8/170 (4.7%)	8	11/85 (12.9%)	13
Vomiting	8/170 (4.7%)	8	5/85 (5.9%)	5
Investigations
Triglyceride increased	9/170 (5.3%)	10	1/85 (1.2%)	1
Weight gain	32/170 (18.8%)	32	1/85 (1.2%)	1
Metabolism and nutrition disorders
Decreased appetite	0/170 (0%)	0	5/85 (5.9%)	6
Increased appetite	28/170 (16.5%)	28	1/85 (1.2%)	1
Nervous system disorders
Drowsiness	9/170 (5.3%)	9	0/85 (0%)	0
Headache	24/170 (14.1%)	33	12/85 (14.1%)	16
Sedation	11/170 (6.5%)	12	0/85 (0%)	0
Psychiatric disorders
Insomnia	4/170 (2.4%)	4	5/85 (5.9%)	5
Respiratory, thoracic and mediastinal disorders
Nasal congestion	2/170 (1.2%)	3	5/85 (5.9%)	5
Skin and subcutaneous tissue disorders
Rash	1/170 (0.6%)	1	5/85 (5.9%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.