Olanzapine Treatment of Patients With Bipolar I Disorder

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00510146
• Collaborator: (none)
• Enrollment: 514
• Locations: 16
• Arms: 3
• Duration (Months): 35
• Patients Per Site: 32.1
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to assess whether olanzapine is superior to placebo in patients with bipolar depression.

Condition or Disease	Intervention/Treatment	Phase
Depression, Bipolar	Drug: Olanzapine; Drug: Placebo	Phase 3

Detailed Description

1. Dose range and administration mode: Oral Olanzapine 5mg - 20mg/day

2. Duration:

3. Screening phase is 2-28 days.

4. Double-blind treatment phase is 6 weeks

5. Open-label extension phase is 18 weeks

Study Design

• Study Type: Interventional
• Actual Enrollment: 514 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Olanzapine in the Treatment of Patients With Bipolar I Disorder, Depressed: A Randomized, Double-Blind Comparison With Placebo
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Olanzapine During double-blind treatment, participants receive olanzapine at a dose of 5 milligram (mg) which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Drug: Olanzapine; 5-20 mg, oral, once daily, for 24 weeks (participants randomized to olanzapine in double-blind treatment period) or 18 weeks (participants randomized to placebo in double-blind treatment period).; Other Names: LY170053 Zyprexa
Placebo Comparator: Placebo Matching placebo administered once daily, by mouth during double-blind treatment.	Drug: Placebo; placebo tablets, oral, once daily at bedtime, 6 weeks
Experimental: Olanzapine (open-label treatment period) During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and Week 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.	Drug: Olanzapine; 5-20 mg, oral, once daily, for 24 weeks (participants randomized to olanzapine in double-blind treatment period) or 18 weeks (participants randomized to placebo in double-blind treatment period).; Other Names: LY170053 Zyprexa

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (Acute Phase) [Baseline, Endpoint (Week 6)]

   The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).

Secondary Outcome Measures

1. Percentage of Participants With Symptomatic Response at Endpoint (Acute Phase) [Endpoint (Week 6)]

   Response is defined as a reduction (from baseline to endpoint) of 50% or more in the MADRS total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).

2. Percentage of Participants With Symptomatic Remission At Any Time (Acute Phase) [Baseline through Endpoint (Week 6)]

   Percentage of participants with symptomatic remission at any time as defined as a score of less than or equal to 12 in the MADRS total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).

3. Change From Baseline to Endpoint in Clinical Global Improvement- Bipolar (CGI-BP) Severity of Illness Scores-Mania, Depression, Overall Bipolar Illness Scores (Acute Phase) [Baseline, Endpoint (Week 6)]

   CGI-BP is a measure of illness severity especially adapted for bipolar illness. It allows rating of mania, depression, and overall illness. The score ranges from 1 (normal, not ill) to 7 (very seriously ill).

4. Percentage of Participants With Recovery (Acute Phase) [Baseline through Endpoint (Week 6 )]

   Percentage of participants with recovery defined as a value of less than or equal to 12 in the MADRS total score for at least 4 weeks of post-baseline treatment. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).

5. Change From Baseline to Endpoint in Young Mania Rating Scale (YMRS) Total Score (Acute Phase) [Baseline, Endpoint (Week 6)]

   The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.

6. Change From Baseline to Endpoint in Hamilton Depression Rating Scale-17 (HAMD-17) Total Score (Acute Phase) [Baseline, Endpoint (Week 6)]

   The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).

7. Percentage of Participants With Major Depressive Episode at Endpoint on Mini International Neuropsychiatric Interview (MINI), Depressive Episode Module (Acute Phase) [Endpoint (Week 6)]

   In the MINI Major Depressive Episode module, participants are asked a series of Yes/No questions to determine whether or not they are experiencing a major depressive episode or a major depressive episode with melancholic features.

8. Percentage of Participants With Current Hypomanic Episode at Endpoint on MINI Manic Episode Module (Acute Phase) [Endpoint (Week 6)]

   In the MINI Manic Episode module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing hypomanic or manic episodes.

9. Percentage of Participants With Psychotic Disorders and Mood Disorders With Psychotic Features at Endpoint on MINI Psychotic Disorders Module (Acute Phase) [Endpoint (Week 6)]

   In the MINI Psychotic Features Episode module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing mood disorder with psychotic features or current psychotic disorders.

10. Percentage of Participants With Alcohol Dependence and Abuse at Endpoint on MINI Alcohol Dependence/Abuse Module (Acute Phase) [Endpoint (Week 6)]

    In the MINI Alcohol Abuse and Dependence Module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing symptoms indicating current alcohol dependence or abuse.

11. Percentage of Participants With Non-Alcohol Psychoactive Substance Use Disorder at Endpoint on MINI Substance Dependence/Abuse Module (Acute Phase) [Endpoint (Week 6)]

    In the MINI Substance Dependence and Abuse Module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing symptoms indicating current non-alcohol substance use dependence or abuse.

12. Percentage of Participants With Emergence of Mania During the Study (Acute Phase) [Baseline through Endpoint (Week 6)]

    Emergence of mania is defined as first occurrence of score of >=15 in the YMRS total score in the post-baseline period of Acute Phase. The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.

13. Percentage of Participants With Extra-Pyramidal Symptoms (EPS) At Endpoint As Measured by Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) (Acute Phase) [Endpoint (Week 6)]

    EPS symptoms measured by DIEPSS are grouped into 4 categories: parkinsonism, akathisia, dystonia, and dyskinesia. Severity is assessed at 5 levels, from level 0 (none, normal) to level 4 (severe). For Parkinsonism, normal baseline is defined as a score not >=3 on 1 item nor >=2 on 2 items; abnormal endpoint is defined as a score >=3 on 1 item or >=2 on 2 items, or an increase of 3 on Parkinsonism total. Baseline akathisia, dystonia and dyskinesia is defined as a score <2; abnormal endpoint is a score >=2 or an increase >= 2 from that baseline score.

14. Change From Baseline to Endpoint in Blood Pressure (Acute Phase) [Baseline, Endpoint (Week 6)]

15. Change From Baseline to Endpoint in Weight (Acute Phase) [Baseline, Endpoint (Week 6)]

16. Change From Baseline to Endpoint in Glucose and Lipids (Cholesterol, Triglycerides, HDL Cholesterol, LDL Cholesterol) [Baseline, Endpoint (Week 6)]

17. Change From Baseline to Endpoint in Albumin (Acute Phase) [Baseline, Endpoint (Week 6)]

18. Change From Baseline to Endpoint in Alanine Amino Transferase/Serum Glutamate Pyruvate Transaminase (ALT/SGPT), Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase (AST/SGOT), Gamma Glutamyl Transferase (GGT) [Baseline, Endpoint (Week 6)]

19. Change From Baseline to Endpoint in Direct Bilirubin, Total Bilirubin, Uric Acid (Acute Phase) [Baseline, Endpoint (Week 6)]

20. Change From Baseline to Endpoint in Erythrocyte Count (Acute Phase) [Baseline, Endpoint (Week 6)]

21. Change From Baseline to Endpoint in Hematocrit (Acute Phase) [Baseline, Endpoint (Week 6)]

22. Change From Baseline to Endpoint in Hemoglobin A1c (Acute Phase) [Baseline, Endpoint (Week 6)]

23. Change From Baseline to Endpoint in Hemoglobin (Acute Phase) [Baseline, Endpoint (Week 6)]

24. Change From Baseline to Endpoint in Prolactin (Acute Phase) [Baseline, Endpoint (Week 6)]

25. Change From Baseline to Endpoint in Urinalysis (UA)- Specific Gravity (Acute Phase) [Baseline, Endpoint (Week 6)]

26. Change in Electrocardiogram (ECG) From Baseline to Endpoint (Acute Phase) [Baseline, Endpoint (Week 6)]

    Time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole, fixed correction factor (QTcF interval); Bazett-Corrected QT Interval (QTcB interval).

27. Change From Baseline to Endpoint in Heart Rate (Acute Phase) [Baseline, Endpoint (Week 6)]

28. Change From Baseline to Endpoint in MINI Suicidality Total Scores (Acute Phase) [Baseline, Endpoint (Week 6)]

    The MINI module C (MINI-C) is a rating scale for severity of suicidal thoughts and behaviors. The MINI-C is composed of 12 Yes/No questions with variable scores assigned to each question. The scale ranges from 0 to 52 with higher scores indicating a greater presence of suicidal thoughts and/or behaviors.

29. Number of Participants With Adverse Events (Acute Phase) [Baseline through Week 6 (Acute Phase)]

    Please refer to the Adverse Event overview for details regarding adverse events and serious adverse events.

30. Percentage of Participants With Symptomatic Response in Montgomery-Asberg Depression Rating (MADRS) Depression Rating (Open-Label Phase) [Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)]

    The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Response is defined as a reduction (from baseline to endpoint) of 50% or more in the MADRS total score.

31. Percentage of Participants With Symptomatic Remission in the MADRS Total Score (Open-Label Phase) [Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)]

    Percentage of participants with symptomatic remission at any time as defined as a score of less than or equal to 12 in the MADRS total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).

32. Percentage of Participants With Recovery (Open-Label Phase) [Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)]

    Percentage of participants with recovery defined as a value of less than or equal to 12 in the MADRS total score for at least 4 weeks of post-baseline treatment. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).

33. Change From Baseline to Endpoint in Young Mania Rating Scale (YMRS) Total Score (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

    The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.

34. Percentage of Participants With Emergence of Mania During the Study (Open-Label Phase) [Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)]

    Emergence of mania is defined as first occurrence of score of >=15 in the YMRS total score in the Open-Label Extension. The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.

35. Percentage of Participants With Extra-Pyramidal Symptoms (EPS) at Endpoint As Measured by Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) (Open-Label Phase) [Endpoint (Week 24)]

    EPS symptoms measured by DIEPSS are grouped into 4 categories: parkinsonism, akathisia, dystonia, and dyskinesia. Severity is assessed at 5 levels, from level 0 (none, normal) to level 4 (severe). For Parkinsonism, normal baseline is defined as a score not >=3 on 1 item nor >=2 on 2 items; abnormal endpoint is defined as a score >=3 on 1 item or >=2 on 2 items, or an increase of 3 on Parkinsonism total. Baseline akathisia, dystonia and dyskinesia is defined as a score <2; abnormal endpoint is a score >=2 or an increase >= 2 from that baseline score.

36. Change From Baseline to Endpoint in Blood Pressure (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

37. Change From Baseline to Endpoint in Weight (Open-Label Phase) [Baseline (End of Acute Phase/ Week 6), Endpoint (Week 24)]

38. Change From Baseline to Endpoint in Albumin and Total Protein (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

39. Change From Baseline to Endpoint in Alkaline Phosphatase, Creatinine Phosphokinase (CPK), GGT (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

40. Change From Baseline to Endpoint in Chloride (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

41. Change From Baseline to Endpoint in Creatinine (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

42. Change From Baseline to Endpoint in Erythrocyte Count (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

43. Change From Baseline to Endpoint in Hemoglobin (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

44. Change From Baseline to Endpoint in Platelet Count (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

45. Change From Baseline to Endpoint in Prolactin (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

46. Change From Baseline to Endpoint in Uric Acid (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

47. Change From Baseline to Endpoint in Glucose and Lipids (Cholesterol, Triglycerides, HDL Cholesterol, LDL Cholesterol) (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

48. Change From Baseline to Endpoint in ECG (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

    Time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole, fixed correction factor (QTcF interval); Bazett-Corrected QT Interval (QTcB interval).

49. Change From Baseline to Endpoint in Heart Rate (Open-Label Phase) [Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)]

50. Percentage of Participants With High Suicidality at Endpoint (Open-Label Phase) [Endpoint (Week 24)]

    The MINI module C (MINI-C) is a rating scale for severity of suicidal thoughts and behaviors. The MINI-C is composed of 12 Yes/No questions with variable scores assigned to each question. The scale ranges from 0 to 52 with higher scores indicating a greater presence of suicidal thoughts and/or behaviors. Based upon scores, suicidality is defined as Low (1-8), Medium (9-16), and High (>=17).

51. Number of Participants With Adverse Events (Open-Label Phase) [Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)]

    Please refer to the Adverse Event overview for details regarding adverse events and serious adverse events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Each patient must be reliable, have a level of understanding sufficient to perform all tests and examinations required by the protocol, and must understand the nature of the study and have provided informed consent

• All female patients must test negative for pregnancy and females of breast-feeding potential must agree not to breastfeed an infant during the study and for 1 month following the last dose of study drug

• Patients must fulfill the criteria for a major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR) as well as criteria for bipolar I disorder, depressed, as defined in the DSM-IV-TR, based on clinical assessment and confirmed by the structured diagnostic interview, the Mini International Neuropsychiatric Interview (MINI), at study entry

• Patients must have a current 17-item Hamilton Depression Rating Scale (HAMD-17) score greater than or equal to 18 at Visit 1 and Visit 2

• Patients must have a current Young Mania Rating Scale (YMRS) total score less than or equal to 8 at Visit 2.

Exclusion Criteria:

• Has received treatment within the past 30 days with a drug (not including study drug) that has not received regulatory approval for any indication at the time of study entry

• Has participated in a clinical trial of another investigational drug, including olanzapine, within 1 month (30 days) before study entry

• Was previously treated with olanzapine and had bipolar depression considered to be treatment-resistant to olanzapine or to olanzapine in combination with an available selective serotonin reuptake inhibitor (SSRI)

• Is experiencing (at the time of study entry) a current episode of bipolar depression that is greater than 90 days in duration

• Has been treatment-resistant to any therapy prescribed for bipolar depression when olanzapine alone or with an SSRI prescribed at an appropriate dose and duration

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.	Beijing		China	100088
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.	Changsha		China	410008
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.	Chengdu		China	610041
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.	Guang Zhou		China	510370
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.	Hangzhou		China	310003
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.	Harbin		China	150001
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.	Kunming		China	650032
8	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.	Nanjing		China	210029
9	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.	Shanghai		China	200030
10	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.	Wu Han		China	430060
11	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.	Xi'An		China	710032
12	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.	Hiroshima		Japan	731-0501
13	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.	Shiga		Japan	525-0037
14	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.	Tokyo		Japan	170-0002
15	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.	Seongnam-Si		Korea, Republic of	463-707
16	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.	Seoul		Korea, Republic of	110-744

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 - 5hrs, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00510146
• Other Study ID Numbers: 11218; F1D-MC-HGMP
• First Posted: Aug 1, 2007
• Last Update Posted: May 26, 2011
• Last Verified: Apr 1, 2011

• Additional relevant MeSH terms: Bipolar Disorder; Olanzapine

Study Results

Participant Flow

Pre-assignment Detail	Study Period I (2-28 days) included screening and lead-in period for discontinuation of excluded medications at least 25 hours before day of randomization. Study Period II was 6-week, double-blind (Acute Phase) of treatment. Study Period III was 18-week, open-label extension for those who completed Study Period II.

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Period Title: Double-Blind Treatment
STARTED	343	171
COMPLETED	267	122
NOT COMPLETED	76	49
Period Title: Double-Blind Treatment
STARTED	267	122
COMPLETED	196	96
NOT COMPLETED	71	26

Baseline Characteristics

Arm/Group Title	Olanzapine	Placebo	Total
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.	Total of all reporting groups
Overall Participants	343	171	514
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.93 (11.13)	34.96 (11.02)	35.61 (11.09)
Sex: Female, Male (Count of Participants)
Female	205 59.8%	95 55.6%	300 58.4%
Male	138 40.2%	76 44.4%	214 41.6%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	36 10.5%	22 12.9%	58 11.3%
African	18 5.2%	4 2.3%	22 4.3%
Hispanic	6 1.7%	3 1.8%	9 1.8%
East Asian	282 82.2%	141 82.5%	423 82.3%
Native American	1 0.3%	1 0.6%	2 0.4%
Region of Enrollment (participants) [Number]
China	140 40.8%	70 40.9%	210 40.9%
Japan	104 30.3%	52 30.4%	156 30.4%
Korea, Republic of	20 5.8%	10 5.8%	30 5.8%
Taiwan	19 5.5%	9 5.3%	28 5.4%
United States	60 17.5%	30 17.5%	90 17.5%
Age at onset, Bipolar I Disorder (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.57 (10.98)	26.12 (9.90)	27.09 (10.64)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (Acute Phase)
Description	The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population (ITT) with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF)

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	339	169
Baseline	29.36 (5.71)	28.69 (6.33)
Change	-14.26 (9.73)	-11.71 (11.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in MADRS total score from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.15
	Confidence Interval	(2-Sided) 95%; -3.93 to -0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With Symptomatic Response at Endpoint (Acute Phase)
Description	Response is defined as a reduction (from baseline to endpoint) of 50% or more in the MADRS total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time Frame	Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population; all randomized participants.

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	343	171
Number [percentage of participants]	52.5 15.3%	43.3 25.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.050
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with symptomatic response at endpoint from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Percentage of Participants With Symptomatic Remission At Any Time (Acute Phase)
Description	Percentage of participants with symptomatic remission at any time as defined as a score of less than or equal to 12 in the MADRS total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time Frame	Baseline through Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population; all randomized participants.

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	343	171
Number [percentage of participants]	53.9 15.7%	49.7 29.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.367
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with symptomatic remission at any time from a Cochran-Mantel-Haenszel test using region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Change From Baseline to Endpoint in Clinical Global Improvement- Bipolar (CGI-BP) Severity of Illness Scores-Mania, Depression, Overall Bipolar Illness Scores (Acute Phase)
Description	CGI-BP is a measure of illness severity especially adapted for bipolar illness. It allows rating of mania, depression, and overall illness. The score ranges from 1 (normal, not ill) to 7 (very seriously ill).
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population (ITT) with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF)

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	339	169
Baseline-Mania	1.07 (0.29)	1.11 (0.35)
Change-Mania	0.00 (0.43)	0.09 (0.59)
Baseline-Depression	4.54 (0.73)	4.53 (0.73)
Change-Depression	-1.45 (1.26)	-1.20 (1.36)
Baseline- Overall	4.45 (0.79)	4.44 (0.79)
Change- Overall	-1.40 (1.28)	-1.08 (1.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in CGI-BP Mania score from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.20 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.037
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in CGI-BP Depression score from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.47 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in CGI-BP Overall score from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.53 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants With Recovery (Acute Phase)
Description	Percentage of participants with recovery defined as a value of less than or equal to 12 in the MADRS total score for at least 4 weeks of post-baseline treatment. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time Frame	Baseline through Endpoint (Week 6 )

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population; all randomized participants.

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	343	171
Number [percentage of participants]	13.7 4%	9.4 5.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.156
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with recovery from a Cochran-Mantel-Haenszel test using region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

6. Secondary Outcome

Title	Change From Baseline to Endpoint in Young Mania Rating Scale (YMRS) Total Score (Acute Phase)
Description	The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population (ITT) with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF)

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	339	169
Baseline	2.14 (2.10)	1.95 (2.18)
Change	-0.78 (2.56)	0.31 (4.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.99
	Confidence Interval	(2-Sided) 95%; -1.56 to -0.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to Endpoint in Hamilton Depression Rating Scale-17 (HAMD-17) Total Score (Acute Phase)
Description	The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population (ITT) with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF)

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	318	155
Baseline	22.62 (3.47)	22.35 (3.53)
Change	-11.44 (7.02)	-9.12 (7.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.21
	Confidence Interval	(2-Sided) 95%; -3.61 to -0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants With Major Depressive Episode at Endpoint on Mini International Neuropsychiatric Interview (MINI), Depressive Episode Module (Acute Phase)
Description	In the MINI Major Depressive Episode module, participants are asked a series of Yes/No questions to determine whether or not they are experiencing a major depressive episode or a major depressive episode with melancholic features.
Time Frame	Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	339	169
Major Depressive Episode	55.5 16.2%	60.4 35.3%
Major Depressive Episode with Melancholic Features	77.8 22.7%	74.1 43.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.297
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with major depressive episode from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.264
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with major depressive episode with melancholic features from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

9. Secondary Outcome

Title	Percentage of Participants With Current Hypomanic Episode at Endpoint on MINI Manic Episode Module (Acute Phase)
Description	In the MINI Manic Episode module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing hypomanic or manic episodes.
Time Frame	Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	332	169
Number [percentage of participants]	2.1 0.6%	0.6 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.195
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with current hypomanic episode from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

10. Secondary Outcome

Title	Percentage of Participants With Psychotic Disorders and Mood Disorders With Psychotic Features at Endpoint on MINI Psychotic Disorders Module (Acute Phase)
Description	In the MINI Psychotic Features Episode module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing mood disorder with psychotic features or current psychotic disorders.
Time Frame	Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	339	169
Mood Disorder with Psychotic Features	3.6 1%	2.4 1.4%
Psychotic Disorders	0.0 0%	0.6 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.163
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with current psychotic disorders from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.442
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with current mood disorders with psychotic features from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

11. Secondary Outcome

Title	Percentage of Participants With Alcohol Dependence and Abuse at Endpoint on MINI Alcohol Dependence/Abuse Module (Acute Phase)
Description	In the MINI Alcohol Abuse and Dependence Module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing symptoms indicating current alcohol dependence or abuse.
Time Frame	Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	335	169
Dependence	0.6 0.2%	0.6 0.4%
Abuse	0.6 0.2%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with current alcohol dependence from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.324
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with current alcohol abuse from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

12. Secondary Outcome

Title	Percentage of Participants With Non-Alcohol Psychoactive Substance Use Disorder at Endpoint on MINI Substance Dependence/Abuse Module (Acute Phase)
Description	In the MINI Substance Dependence and Abuse Module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing symptoms indicating current non-alcohol substance use dependence or abuse.
Time Frame	Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	335	169
Dependence	0.0 0%	0.0 0%
Abuse	0.0 0%	0.0 0%

13. Secondary Outcome

Title	Percentage of Participants With Emergence of Mania During the Study (Acute Phase)
Description	Emergence of mania is defined as first occurrence of score of >=15 in the YMRS total score in the post-baseline period of Acute Phase. The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.
Time Frame	Baseline through Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	343	171
Number [percentage of participants]	0.6 0.2%	2.9 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with emergence of mania at endpoint from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

14. Secondary Outcome

Title	Percentage of Participants With Extra-Pyramidal Symptoms (EPS) At Endpoint As Measured by Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) (Acute Phase)
Description	EPS symptoms measured by DIEPSS are grouped into 4 categories: parkinsonism, akathisia, dystonia, and dyskinesia. Severity is assessed at 5 levels, from level 0 (none, normal) to level 4 (severe). For Parkinsonism, normal baseline is defined as a score not >=3 on 1 item nor >=2 on 2 items; abnormal endpoint is defined as a score >=3 on 1 item or >=2 on 2 items, or an increase of 3 on Parkinsonism total. Baseline akathisia, dystonia and dyskinesia is defined as a score <2; abnormal endpoint is a score >=2 or an increase >= 2 from that baseline score.
Time Frame	Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Participants with a normal baseline and an endpoint result.

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	337	169
Akathisia (N=335, 169)	2.7 0.8%	1.2 0.7%
Dyskinesia (N=337, 169)	0.0 0%	0.0 0%
Dystonia (N=337, 169)	0.0 0%	0.0 0%
Parkinsonism (N=337, 169)	0.9 0.3%	0.6 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.269
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with EPS symptoms (akathisia) at endpoint from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.736
	Comments	p-value represents a comparison of the olanzapine and placebo groups in percentage of participants with EPS symptoms (parkinsonism) at endpoint from a Cochran-Mantel-Haenszel test using geographic region as strata.
	Method	Cochran-Mantel-Haenszel
	Comments

15. Secondary Outcome

Title	Change From Baseline to Endpoint in Blood Pressure (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	320	159
Baseline- Standing Systolic (N=320, 159)	112.39 (13.25)	115.65 (14.39)
Change- Standing Systolic (N=320, 159)	-0.99 (10.83)	-0.67 (11.18)
Baseline- Sitting Systolic (N=340, 169)	112.35 (13.42)	114.39 (13.67)
Change- Sitting Systolic (N=340, 169)	-0.36 (11.10)	0.04 (12.16)
Baseline- Standing Diastolic (N=320, 159)	74.77 (10.20)	76.87 (10.26)
Change- Standing Diastolic (N=320, 159)	-0.48 (8.71)	-0.14 (8.44)
Baseline- Sitting Diastolic (N=340, 169)	73.07 (9.93)	73.92 (9.86)
Change- Sitting Diastolic (N=340, 169)	-0.11 (9.37)	0.39 (9.08)
Baseline- Orthostatic Change-Systolic (N=320, 159)	0.54 (6.51)	1.21 (7.67)
Change- Orthostatic Change-Systolic (N=320, 159)	-0.65 (8.20)	-0.45 (11.45)
Baseline- Orthostatic Change-Diastolic (N=320, 159	1.92 (5.93)	2.96 (5.57)
Change- Orthostatic Change-Diastolic (N=320, 159)	-0.52 (6.79)	-0.47 (6.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.146
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-standing systolic blood pressure from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.249
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-sitting systolic blood pressure from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.146
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-standing diastolic blood pressure from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-sitting diastolic blood pressure from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.284
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-orthostatic change in systolic blood pressure from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-orthostatic change in diastolic blood pressure from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

16. Secondary Outcome

Title	Change From Baseline to Endpoint in Weight (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	340	169
Baseline	66.11 (18.11)	68.30 (18.73)
Endpoint	2.45 (2.82)	-0.13 (2.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-in weight from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

17. Secondary Outcome

Title	Change From Baseline to Endpoint in Glucose and Lipids (Cholesterol, Triglycerides, HDL Cholesterol, LDL Cholesterol)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	329	160
Baseline- Fasting Glucose (N=320, 155)	5.11 (0.58)	5.12 (0.57)
Change- Fasting Glucose (N=320, 155)	0.10 (0.61)	0.02 (0.54)
Baseline- Cholesterol (N=329, 160)	4.83 (1.01)	4.81 (1.00)
Change- Cholesterol (N=329, 160)	0.24 (0.76)	-0.07 (0.49)
Baseline-Triglycerides (N=329, 160)	1.39 (0.85)	1.34 (0.80)
Change- Triglycerides (N=329, 160)	0.26 (0.97)	0.03 (0.71)
Baseline- LDL Cholesterol (N=328, 159)	2.77 (0.87)	2.83 (0.84)
Change- LDL Cholesterol (N=328, 159)	0.17 (0.66)	-0.09 (0.48)
Baseline- HDL Cholesterol (N=329, 160)	1.43 (0.41)	1.36 (0.35)
Change- HDL Cholesterol (N=329, 160)	-0.03 (0.25)	0.02 (0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.179
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-in fasting glucose from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-in cholesterol from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-in triglycerides from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-in LDL cholesterol from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.095
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint-in HDL cholesterol from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

18. Secondary Outcome

Title	Change From Baseline to Endpoint in Albumin (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	329	160
Baseline	43.07 (3.85)	43.47 (3.69)
Change	-0.81 (2.89)	0.03 (3.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in albumin from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

19. Secondary Outcome

Title	Change From Baseline to Endpoint in Alanine Amino Transferase/Serum Glutamate Pyruvate Transaminase (ALT/SGPT), Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase (AST/SGOT), Gamma Glutamyl Transferase (GGT)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	329	160
Baseline (ALT/SGPT)	21.68 (16.53)	21.18 (13.17)
Change (ALT/SGPT)	8.34 (26.90)	0.00 (13.63)
Baseline (AST/SGOT)	21.61 (8.34)	20.25 (6.70)
Change (AST/SGOT)	4.31 (15.66)	1.26 (11.06)
Baseline (GGT)	24.87 (36.59)	23.63 (23.17)
Change (GGT)	5.36 (22.70)	-1.21 (11.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in ALT/SGPT from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in AST/SGOT from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in GGT from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

20. Secondary Outcome

Title	Change From Baseline to Endpoint in Direct Bilirubin, Total Bilirubin, Uric Acid (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	329	160
Baseline- Direct Bilirubin	2.45 (1.23)	2.40 (1.08)
Change- Direct Bilirubin	-0.21 (1.03)	0.12 (1.02)
Baseline- Total Bilirubin	9.74 (5.18)	9.42 (4.58)
Change- Total Bilirubin	-0.68 (4.57)	0.47 (4.27)
Baseline- Uric Acid	307.19 (92.03)	314.38 (86.69)
Change- Uric Acid	19.55 (51.10)	-1.86 (50.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in direct bilirubin from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in total bilirubin from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in uric acid from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

21. Secondary Outcome

Title	Change From Baseline to Endpoint in Erythrocyte Count (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	328	158
Baseline	4.65 (0.51)	4.71 (0.52)
Change	-0.05 (0.27)	0.02 (0.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in erythrocyte count from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

22. Secondary Outcome

Title	Change From Baseline to Endpoint in Hematocrit (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	328	158
Baseline	0.42 (0.04)	0.43 (0.05)
Change	-0.01 (0.03)	0.00 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in hematocrit from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

23. Secondary Outcome

Title	Change From Baseline to Endpoint in Hemoglobin A1c (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	312	146
Baseline	5.34 (0.37)	5.37 (0.37)
Change	0.04 (0.26)	-0.03 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in hemoglobin A1c from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

24. Secondary Outcome

Title	Change From Baseline to Endpoint in Hemoglobin (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	328	158
Baseline	8.65 (0.99)	8.73 (0.97)
Change	-0.11 (0.50)	0.05 (0.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in hemoglobin from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

25. Secondary Outcome

Title	Change From Baseline to Endpoint in Prolactin (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	318	147
Baseline	15.40 (16.89)	15.86 (21.54)
Change	12.07 (24.00)	-1.18 (26.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in prolactin from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

26. Secondary Outcome

Title	Change From Baseline to Endpoint in Urinalysis (UA)- Specific Gravity (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	314	148
Baseline	1.02 (0.01)	1.02 (0.01)
Change	-0.00 (0.01)	0.00 (0.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in urinalysis-specific gravity from Wilcoxon's rank-sum test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

27. Secondary Outcome

Title	Change in Electrocardiogram (ECG) From Baseline to Endpoint (Acute Phase)
Description	Time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole, fixed correction factor (QTcF interval); Bazett-Corrected QT Interval (QTcB interval).
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	295	145
Baseline- QTcF	406.85 (19.53)	408.10 (18.72)
Change- QTcF	2.82 (14.21)	0.50 (12.27)
Baseline- QTcB	415.79 (20.55)	418.42 (19.95)
Change- QTcB	6.58 (18.01)	1.21 (16.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.104
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in QTcF interval from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in QTcB interval from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

28. Secondary Outcome

Title	Change From Baseline to Endpoint in Heart Rate (Acute Phase)
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	309	148
Baseline	69.63 (12.65)	70.51 (11.94)
Change	3.49 (11.18)	0.87 (11.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint in heart rate from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments

29. Secondary Outcome

Title	Change From Baseline to Endpoint in MINI Suicidality Total Scores (Acute Phase)
Description	The MINI module C (MINI-C) is a rating scale for severity of suicidal thoughts and behaviors. The MINI-C is composed of 12 Yes/No questions with variable scores assigned to each question. The scale ranges from 0 to 52 with higher scores indicating a greater presence of suicidal thoughts and/or behaviors.
Time Frame	Baseline, Endpoint (Week 6)

Outcome Measure Data

Analysis Population Description

Safety population; participants with non-missing baseline value and at least one non-missing post baseline value, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	337	169
Baseline	2.09 (3.44)	2.40 (3.49)
Change	-0.42 (3.71)	-0.59 (3.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.943
	Comments	p-value represents a comparison of the olanzapine and placebo groups in change from baseline to endpoint for MINI Suicidality Total Score from the following ANCOVA model: Change=Treatment+Baseline+Geographic Region.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.59 to 0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

30. Secondary Outcome

Title	Number of Participants With Adverse Events (Acute Phase)
Description	Please refer to the Adverse Event overview for details regarding adverse events and serious adverse events.
Time Frame	Baseline through Week 6 (Acute Phase)

Outcome Measure Data

Analysis Population Description

All enrolled participants in Acute Phase

Arm/Group Title	Olanzapine	Placebo
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation.	Matching placebo administered once daily, by mouth during double-blind treatment.
Measure Participants	343	171
Serious	6 1.7%	7 4.1%
Non-Serious	238 69.4%	88 51.5%

31. Secondary Outcome

Title	Percentage of Participants With Symptomatic Response in Montgomery-Asberg Depression Rating (MADRS) Depression Rating (Open-Label Phase)
Description	The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Response is defined as a reduction (from baseline to endpoint) of 50% or more in the MADRS total score.
Time Frame	Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Total participants in the open-label extension phase.

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	389
Number [percentage of participants]	43.7 12.7%

32. Secondary Outcome

Title	Percentage of Participants With Symptomatic Remission in the MADRS Total Score (Open-Label Phase)
Description	Percentage of participants with symptomatic remission at any time as defined as a score of less than or equal to 12 in the MADRS total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time Frame	Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Total participants in open-label extension phase.

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	389
Number [percentage of participants]	85.1 24.8%

33. Secondary Outcome

Title	Percentage of Participants With Recovery (Open-Label Phase)
Description	Percentage of participants with recovery defined as a value of less than or equal to 12 in the MADRS total score for at least 4 weeks of post-baseline treatment. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time Frame	Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Total participants in open-label extension phase.

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	389
Number [percentage of participants]	69.9 20.4%

34. Secondary Outcome

Title	Change From Baseline to Endpoint in Young Mania Rating Scale (YMRS) Total Score (Open-Label Phase)
Description	The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	385
Baseline	1.11 (2.87)
Change	-0.03 (2.55)

35. Secondary Outcome

Title	Percentage of Participants With Emergence of Mania During the Study (Open-Label Phase)
Description	Emergence of mania is defined as first occurrence of score of >=15 in the YMRS total score in the Open-Label Extension. The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60.
Time Frame	Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Total participants in the open-label extension phase.

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	389
Number [percentage of participants]	0.8 0.2%

36. Secondary Outcome

Title	Percentage of Participants With Extra-Pyramidal Symptoms (EPS) at Endpoint As Measured by Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) (Open-Label Phase)
Description	EPS symptoms measured by DIEPSS are grouped into 4 categories: parkinsonism, akathisia, dystonia, and dyskinesia. Severity is assessed at 5 levels, from level 0 (none, normal) to level 4 (severe). For Parkinsonism, normal baseline is defined as a score not >=3 on 1 item nor >=2 on 2 items; abnormal endpoint is defined as a score >=3 on 1 item or >=2 on 2 items, or an increase of 3 on Parkinsonism total. Baseline akathisia, dystonia and dyskinesia is defined as a score <2; abnormal endpoint is a score >=2 or an increase >= 2 from that baseline score.
Time Frame	Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with a normal baseline and at least one post-baseline result.

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	385
Akathisia (N=378)	0.8 0.2%
Dyskinesia (N=385)	0.3 0.1%
Dystonia (N=385)	0.0 0%
Parkinsonism (N=385)	1.0 0.3%

37. Secondary Outcome

Title	Change From Baseline to Endpoint in Blood Pressure (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	383
Baseline-Standing Diastolic (N=361)	74.98 (10.77)
Change- Standing Diastolic (N=361)	0.15 (8.28)
Baseline- Sitting Diastolic (N=383)	73.32 (10.73)
Change- Sitting Diastolic (N=383)	-0.03 (8.68)
Baseline- Standing Systolic (N=361)	112.06 (14.58)
Change- Standing Systolic (N=361)	0.96 (10.37)
Baseline- Sitting Systolic (N=383)	112.26 (14.45)
Change- Sitting Systolic (N=383)	0.27 (10.28)
Baseline- Orthostatic Change-Diastolic (N=358)	1.75 (5.25)
Change- Orthostatic Change- Diastolic (N=358)	0.16 (6.56)
Baseline- Orthostatic Change- Systolic (N=358)	0.19 (6.19)
Change- Orthostatic Change- Systolic (N=358)	0.65 (7.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.736
	Comments	p-value represents change from baseline to endpoint-standing diastolic blood pressure from t-tests on change.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.944
	Comments	p-value represents change from baseline to endpoint-sitting diastolic blood pressure from t-tests on change.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.080
	Comments	p-value represents change from baseline to endpoint-standing systolic blood pressure from t-tests on change.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.612
	Comments	p-value represents change from baseline to endpoint-sitting systolic blood pressure from t-tests on change.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.640
	Comments	p-value represents change from baseline to endpoint-orthostatic change in diastolic blood pressure from t-tests on change.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.122
	Comments	p-value represents change from baseline to endpoint-orthostatic change in systolic blood pressure from t-tests on change.
	Method	t-test, 2 sided
	Comments

38. Secondary Outcome

Title	Change From Baseline to Endpoint in Weight (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/ Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	384
Baseline	68.31 (18.54)
Change	2.27 (4.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents change from baseline to endpoint for weight from t-tests on change.
	Method	t-test, 2 sided
	Comments

39. Secondary Outcome

Title	Change From Baseline to Endpoint in Albumin and Total Protein (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	381
Baseline- Albumin	42.64 (3.58)
Change- Albumin	0.53 (2.86)
Baseline- Total Protein	73.24 (4.39)
Change- Total Protein	0.56 (3.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents change from baseline to endpoint for albumin from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value represents change from baseline to endpoint for total protein from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

40. Secondary Outcome

Title	Change From Baseline to Endpoint in Alkaline Phosphatase, Creatinine Phosphokinase (CPK), GGT (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	381
Baseline- Alkaline Phosphatase	68.58 (19.33)
Change- Alkaline Phosphatase	2.37 (12.85)
Baseline- CPK	107.36 (133.21)
Change- CPK	-1.73 (124.56)
Baseline- GGT	28.90 (32.08)
Change- GGT	0.78 (25.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value represents change from baseline to endpoint for alkaline phosphatase from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	p-value represents change from baseline to endpoint for CPK from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.354
	Comments	p-value represents change from baseline to endpoint for GGT from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

41. Secondary Outcome

Title	Change From Baseline to Endpoint in Chloride (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	381
Baseline	103.62 (2.16)
Change	0.33 (2.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	p-value represents change from baseline to endpoint for chlorine from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

42. Secondary Outcome

Title	Change From Baseline to Endpoint in Creatinine (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	381
Baseline	67.48 (14.98)
Change	2.05 (7.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents change from baseline to endpoint for creatinine from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

43. Secondary Outcome

Title	Change From Baseline to Endpoint in Erythrocyte Count (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	380
Baseline	4.64 (0.53)
Change	0.03 (0.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments	p-value represents change from baseline to endpoint for erythrocyte count from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

44. Secondary Outcome

Title	Change From Baseline to Endpoint in Hemoglobin (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	380
Baseline	8.61 (1.01)
Change	0.04 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments	p-value represents change from baseline to endpoint for hemoglobin from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

45. Secondary Outcome

Title	Change From Baseline to Endpoint in Platelet Count (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	380
Baseline	257.96 (64.25)
Change	-4.56 (49.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments	p-value represents change from baseline to endpoint for platelet count from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

46. Secondary Outcome

Title	Change From Baseline to Endpoint in Prolactin (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	346
Baseline	21.64 (18.48)
Change	-3.41 (17.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents change from baseline to endpoint for prolactin from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

47. Secondary Outcome

Title	Change From Baseline to Endpoint in Uric Acid (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	381
Baseline	324.74 (89.39)
Change	14.73 (56.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents change from baseline to endpoint for uric acid from Wilcoxon's signed-rank test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

48. Secondary Outcome

Title	Change From Baseline to Endpoint in Glucose and Lipids (Cholesterol, Triglycerides, HDL Cholesterol, LDL Cholesterol) (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	380
Baseline- Fasting Glucose (N=375)	5.20 (0.57)
Change- Fasting Glucose (N=375)	0.06 (0.63)
Baseline- Cholesterol (N=380)	4.96 (1.08)
Change- Cholesterol (N=380)	0.05 (0.70)
Baseline- Triglycerides (N=380)	1.55 (1.06)
Change- Triglycerides (N=380)	0.10 (0.97)
Baseline- LDL Cholesterol (N=378)	2.88 (0.91)
Change- LDL Cholesterol (N=378)	0.06 (0.63)
Baseline- HDL Cholesterol (N=380)	1.39 (0.40)
Change- HDL Cholesterol (N=380)	-0.05 (0.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments	p-value represents change from baseline to endpoint for fasting glucose from t-tests on change.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.130
	Comments	p-value represents change from baseline to endpoint for cholesterol from t-tests on change.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.055
	Comments	p-value represents change from baseline to endpoint for triglycerides from t-tests on change.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments	p-value represents change from baseline to endpoint for LDL cholesterol from t-tests on change.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value represents change from baseline to endpoint for HDL cholesterol from t-tests on change.
	Method	t-test, 2 sided
	Comments

49. Secondary Outcome

Title	Change From Baseline to Endpoint in ECG (Open-Label Phase)
Description	Time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole, fixed correction factor (QTcF interval); Bazett-Corrected QT Interval (QTcB interval).
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	366
Baseline- QTcF	410.09 (19.44)
Change- QTcF	1.80 (15.07)
Baseline- QTcB	421.72 (19.61)
Change- QTcB	1.76 (16.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments	p-value represents change from baseline to endpoint for QTcF from t-test.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments	p-value represents change from baseline to endpoint for QTcB from t-test.
	Method	t-test, 2 sided
	Comments

50. Secondary Outcome

Title	Change From Baseline to Endpoint in Heart Rate (Open-Label Phase)
Time Frame	Baseline (End of Acute Phase/Week 6), Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Participants who entered Open-Label Phase with non-missing baseline (end of Acute Phase) and post-baseline visit, last observation carried forward (LOCF).

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	370
Baseline	71.85 (11.64)
Change	0.06 (10.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.919
	Comments	p-value represents change from baseline to endpoint for heart rate from t-test.
	Method	t-test, 2 sided
	Comments

51. Secondary Outcome

Title	Percentage of Participants With High Suicidality at Endpoint (Open-Label Phase)
Description	The MINI module C (MINI-C) is a rating scale for severity of suicidal thoughts and behaviors. The MINI-C is composed of 12 Yes/No questions with variable scores assigned to each question. The scale ranges from 0 to 52 with higher scores indicating a greater presence of suicidal thoughts and/or behaviors. Based upon scores, suicidality is defined as Low (1-8), Medium (9-16), and High (>=17).
Time Frame	Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Total participants in the open-label extension phase.

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	389
Number [percentage of participants]	1.3 0.4%

52. Secondary Outcome

Title	Number of Participants With Adverse Events (Open-Label Phase)
Description	Please refer to the Adverse Event overview for details regarding adverse events and serious adverse events.
Time Frame	Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24)

Outcome Measure Data

Analysis Population Description

Total participants in the open-label extension phase.

Arm/Group Title	Olanzapine (Open-label Treatment Period)
Arm/Group Description	During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion.
Measure Participants	389
Serious	14 4.1%
Non-Serious	209 60.9%

Adverse Events

Arm/Group Title	Olanzapine		Placebo		Olanzapine (Open Label Treatment Period
Arm/Group Description	During double-blind treatment, participants receive olanzapine at a dose of 5 mg. which is increased to 10 mg. per day no later than 3-7 days after Visit 2. Subsequent dose increases above 10 mg. (up to a maximum of 20 mg per day) are permitted in 5 mg. per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg. requires study discontinuation.		Matching placebo administered once daily, by mouth during double-blind treatment.		During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Visit 9. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Visit 10. Those on higher doses will be reduced between Visit 9 and 10 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at visit 10; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at visit 10). Dose increases beyond visit 10 are permitted and at the investigator's discretion.
All Cause Mortality
	Olanzapine		Placebo		Olanzapine (Open Label Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Olanzapine		Placebo		Olanzapine (Open Label Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/343 (1.7%)		7/171 (4.1%)		14/389 (3.6%)
Gastrointestinal disorders
Pancreatitis	1/343 (0.3%)	1	0/171 (0%)	0	1/389 (0.3%)	1
Hepatobiliary disorders
Biliary tract disorder	0/343 (0%)	0	0/171 (0%)	0	1/389 (0.3%)	1
Cholecystitis	1/343 (0.3%)	1	0/171 (0%)	0	0/389 (0%)	0
Infections and infestations
Appendicitis	0/343 (0%)	0	0/171 (0%)	0	1/389 (0.3%)	1
Injury, poisoning and procedural complications
Drug exposure during pregnancy	0/343 (0%)	0	1/171 (0.6%)	1	0/389 (0%)	0
Nervous system disorders
Cerebral infarction	0/343 (0%)	0	0/171 (0%)	0	1/389 (0.3%)	1
Paralysis	1/343 (0.3%)	1	0/171 (0%)	0	1/389 (0.3%)	1
Psychiatric disorders
Adjustment disorder	0/343 (0%)	0	0/171 (0%)	0	1/389 (0.3%)	1
Anxiety	0/343 (0%)	0	1/171 (0.6%)	1	0/389 (0%)	0
Bipolar I disorder	1/343 (0.3%)	1	2/171 (1.2%)	2	1/389 (0.3%)	1
Completed suicide	0/343 (0%)	0	0/171 (0%)	0	2/389 (0.5%)	2
Depression	0/343 (0%)	0	1/171 (0.6%)	1	1/389 (0.3%)	1
Depressive symptom	0/343 (0%)	0	1/171 (0.6%)	1	0/389 (0%)	0
Hallucination, auditory	0/343 (0%)	0	0/171 (0%)	0	1/389 (0.3%)	1
Insomnia	0/343 (0%)	0	1/171 (0.6%)	1	0/389 (0%)	0
Mania	0/343 (0%)	0	0/171 (0%)	0	1/389 (0.3%)	1
Suicidal ideation	1/343 (0.3%)	1	2/171 (1.2%)	2	1/389 (0.3%)	1
Suicide attempt	0/343 (0%)	0	0/171 (0%)	0	2/389 (0.5%)	2
Vascular disorders
Hypertension	1/343 (0.3%)	1	0/171 (0%)	0	1/389 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Olanzapine		Placebo		Olanzapine (Open Label Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	238/343 (69.4%)		88/171 (51.5%)		209/389 (53.7%)
Gastrointestinal disorders
Constipation	19/343 (5.5%)	21	5/171 (2.9%)	5	6/389 (1.5%)	6
Diarrhoea	7/343 (2%)	8	6/171 (3.5%)	6	5/389 (1.3%)	5
Dry mouth	18/343 (5.2%)	18	6/171 (3.5%)	6	4/389 (1%)	4
Nausea	7/343 (2%)	7	8/171 (4.7%)	9	4/389 (1%)	4
General disorders
Fatigue	10/343 (2.9%)	10	6/171 (3.5%)	8	3/389 (0.8%)	3
Thirst	11/343 (3.2%)	11	1/171 (0.6%)	1	1/389 (0.3%)	1
Hepatobiliary disorders
Hepatic function abnormal	11/343 (3.2%)	11	1/171 (0.6%)	1	6/389 (1.5%)	6
Infections and infestations
Nasopharyngitis	24/343 (7%)	25	6/171 (3.5%)	6	20/389 (5.1%)	25
Upper respiratory tract infection	6/343 (1.7%)	7	6/171 (3.5%)	7	3/389 (0.8%)	3
Investigations
Alanine aminotransferase increased	11/343 (3.2%)	11	0/171 (0%)	0	12/389 (3.1%)	13
Weight increased	59/343 (17.2%)	59	6/171 (3.5%)	6	67/389 (17.2%)	67
Metabolism and nutrition disorders
Increased appetite	46/343 (13.4%)	46	4/171 (2.3%)	5	15/389 (3.9%)	15
Nervous system disorders
Akathisia	14/343 (4.1%)	14	2/171 (1.2%)	2	9/389 (2.3%)	9
Dizziness	13/343 (3.8%)	13	6/171 (3.5%)	6	6/389 (1.5%)	6
Headache	15/343 (4.4%)	17	8/171 (4.7%)	9	10/389 (2.6%)	12
Hypersomnia	15/343 (4.4%)	15	2/171 (1.2%)	2	14/389 (3.6%)	14
Sedation	29/343 (8.5%)	33	4/171 (2.3%)	4	3/389 (0.8%)	3
Somnolence	59/343 (17.2%)	60	11/171 (6.4%)	11	17/389 (4.4%)	20
Tremor	14/343 (4.1%)	15	5/171 (2.9%)	5	7/389 (1.8%)	7
Psychiatric disorders
Anxiety	11/343 (3.2%)	13	5/171 (2.9%)	5	10/389 (2.6%)	10
Insomnia	11/343 (3.2%)	11	8/171 (4.7%)	8	8/389 (2.1%)	9

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.