A Study Comparing the Efficacy and Safety of Duloxetine and Placebo for the Treatment of Depression in Elderly Patients

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00406848
• Collaborator: Boehringer Ingelheim (Industry)
• Enrollment: 370
• Locations: 33
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 11.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the efficacy and safety of duloxetine 60 mg once daily to placebo on depression in elderly patients (greater than or equal to 65 years of age). Patients who do not respond in the first 13 weeks will be eligible for rescue using pre-defined criteria. Patients randomized to duloxetine 60 mg/day meeting the rescue criteria will be increased to 120 mg/day. Patients randomized to the placebo arm meeting the rescue criteria will be assigned to duloxetine 60 mg/day.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: duloxetine hydrochloride; Drug: placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 370 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Duloxetine Versus Placebo in the Long-Term Treatment of Patients With Late-Life Major Depression
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Duloxetine	Drug: duloxetine hydrochloride; Placebo for 1 week (double-blind placebo lead-in), then duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.; Other Names: LY248686, Cymbalta
Placebo Comparator: Placebo	Drug: placebo; Placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to 13 Weeks in Hamilton Depression Rating Scale (HAMD-17) Maier Subscale [baseline (Week 1), Week 13]

   The Maier subscale (Items 1,2,7,8,9,10) represents symptoms of depression. Total subscale scores range from 0 (normal) to 24 (severe).

Secondary Outcome Measures

1. Change From Baseline on the 30-item Geriatric Depression Scale (GDS) [baseline (Week 1), Week 13, Week 25]

   The 30-item Geriatric Depression Scale (GDS) is a self-administered test of 30 questions to measure the severity of depression. The yes/no questions result in a range of scores from 0 (normal) to 30 (severe depression).

2. Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items [baseline (Week 1), Week 13, Week 25]

   Total Score assess depression severity (scores 0-52). Core, Maier and Bech subscales assess symptoms of depression (scores:0-20=Core; 0-24=Maier; 0-22=Bech). Anxiety/Somatization subscale assesses severity of anxiety (0-18). Retardation subscale assesses dysfunction in mood and work (0-14). Sleep subscale assesses insomnia (0-6). Individual item scores may range from 0-4 or 0-2. Higher numbers indicate more severe symptoms.

3. Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores [baseline (Week 1), Week 13, Week 25]

   The Brief Pain Inventory (severity and interference scales) (BPI) is a self-reported scale that measures the severity of pain and the interference of pain on function. Severity scores: 0 (no pain) to 10 (severe pain) on each question assessing worst pain, least pain, and average pain in past 24 hours, and pain right now. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life.

4. Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores [baseline (Week 1), Week 13, Week 25]

   Numeric Rating Scales (Semantic Differential Scales) for Pain are 6 self-administered scales that assesses experience of overall pain, back pain, headache, shoulder pain, time in pain while awake, and pain interference with daily activities, during the past week. Each item is scored on a numeric 11-point semantic differential scale (0-10) from 0 = no pain to 10 = pain as severe as you can imagine; or 0 = none of the time to 10 = all of the time; or 0 = no interference to 10 = unable to do any activities at all.

5. Patient's Global Impression of Improvement (PGI-I) at 13 Weeks and 25 Weeks [Week 13, Week 25]

   The PGI-Improvement scale is a patient-rated instrument that measures perceived improvement in symptoms. It is a 7-point scale where a score of 1 indicates that the patient is "very much improved," a score of 4 indicates that the patient has experienced "no change," and a score of 7 indicates that the patient is "very much worse."

6. Change From Baseline in the Clinical Global Impression-Severity (CGI-S) [baseline (Week 1), Week 13, Week 25]

   Measures severity of illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).

7. Change From Baseline in the Mini-Mental State Exam (MMSE) [baseline (Week 1), Week 9, Week 25]

   Mini-Mental State Examination (MMSE)is a widely used rating measure of cognitive ability. Scores range from 0 to 30. The MMSE will be used to categorize patients as with or without dementia. Higher number indicates better cognitive ability. Patients with a MMSE score of 20 to 23 will be categorized as having mild dementia, while those with a score of ≥ 24 will be categorized as having no dementia.

8. Change From Baseline in the Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q-SF) [baseline (Week 1), Week 13, Week 25]

   The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) measures the degree of enjoyment and satisfaction experienced in various areas of daily life. The short version is a self-administered 16 item scale evaluating satisfaction of general activities on a 5-point Likert scale that indicates the degree of enjoyment or satisfaction achieved during the past week (1 = very poor and 5 = very good).

9. Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 [Week 13, Week 25]

   Remission (visitwise binary outcome, yes/no) is defined as HAMD-17 Total Score ≤7 and ≤10. HAMD-17 measures depression severity. The total score can range from 0 (normal) to 52 (severe depression). The visitwise probability of patients meeting criteria for remission (either Total Score ≤7 or ≤10) was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis included the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score.

10. Probability of Response at Endpoint as Measured by ≥50% Improvement in the HAMD-17 Total Score [Week 13, Week 25]

    Response (visitwise binary outcome, yes/no) is defined as ≥ 50% reduction from baseline in the HAMD-17 total score. HAMD-17 measures depression severity. The total score can range from 0 (normal) to 52 (severe depression). The visitwise probability of patients meeting criteria for response was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis included the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score.

11. Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) [Week 13, Week 25]

    Remission defined as HAMD-17 Total Score ≤7 and ≤10. HAMD-17 measures depression severity. Total score ranges: 0 (normal) to 52 (severe depression). Visitwise probability of patients achieving remission was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. CIRS-G evaluates 14 organ-specific categories using a rating strategy of 0=no problems; 1=current mild problem/past significant problem; 2=moderate disability/morbidity; 3=severe/constant significant disability; and 4=extremely severe/immediate treatment required/end organ failure. Total score ranges: 0 to 56.

12. Probability of Efficacy Onset as Measured by at Least 20% Sustained Reduction From Baseline in the HAMD-17 Maier Subscale at Week 3 [Week 3]

    Patients are considered to have met onset (visitwise binary outcome, yes/no) criteria at a particular visit if they had at least 20% reduction from baseline in the HAMD-17 Maier subscale at that visit and at all subsequent visits in the acute phase. Maier subscale measures core symptoms of depression and scores range from 0 (normal) to 24 (severe). The visitwise probability of patients meeting onset criteria was analyzed using a categorical, pseudo-likelihood-based repeated measures approach.

13. Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [baseline (Week 1), Week 13, Week 25]

14. Change From Baseline in Pulse Rate [baseline (Week 1), Week 13, Week 25]

15. Change From Baseline in Weight [baseline (Week 1), Week 13, Week 25]

16. Number of Participants With Abnormal Vital Signs and Weight at Any Time During the Study [Baseline (Week 1) through Week 25]

    A patient has a treatment-emergent elevated supine systolic blood pressure if the value is ≥140 with an increase ≥10 from baseline. A patient has a treatment-emergent elevated supine diastolic blood pressure if the value is ≥90 with an increase ≥10 from baseline. A patient has a treatment-emergent elevated supine pulse if the value is ≥100 with an increase ≥10 from baseline. A patient has abnormal weight change if the gain or loss is ≥7% compared to baseline.

17. Number of Participants Experiencing Sustained Hypertension (SH) or Orthostatic Hypotension (OH) [baseline (Week 1) through Week 25]

    Sustained Hypertension is defined as supine systolic BP >= 140 (or diastolic BP >= 90) mm Hg and increase from baseline (highest value in baseline visit interval) >= 10 mm Hg for 3 or more consecutive visits in postbaseline visit interval. Orthostatic Hypotension is defined as standing diastolic BP at least 10 mm Hg less than the supine diastolic BP or the standing systolic BP at least 20 mm Hg less than the supine systolic BP at any time in postbaseline visit interval and a patient does not meet this criterion at any visit in baseline interval.

18. Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation [baseline (Week 1) through Week 25]

    Adverse Events and Serious Adverse Events leading to study discontinuation.

19. Change From Baseline in Laboratory Values - Platelet Count [baseline (Week 1), Week 13, Week 25]

    Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.

20. Change From Baseline in Laboratory Values - Uric Acid [baseline (Week 1), Week 13, Week 25]

    Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.

21. Change From Baseline in Laboratory Values - Erythrocyte Count [baseline (Week 1), Week 25]

    Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.

22. Change From Baseline in Laboratory Values - Hemoglobin, Mean Cell Hemoglobin Concentration (MCHC) [baseline (Week 1), Week 25]

    Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.

23. Change From Baseline in Laboratory Values - Chloride and Fasting Glucose [baseline (Week 1), Week 25]

    Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.

24. Number of Participants With Abnormal Laboratory Values - Low Leukocyte Count [baseline (Week 1) through Week 13]

    The number of participants with abnormal laboratory values at any time during the study period. Results are reported for laboratory analytes that exhibited statistically significantly different proportions of participants who had abnormal values between treatment groups. Statistical significance was considered at the 0.05 level. The lower limit of normal for leukocyte count is 3.8 Billion/Liter. Participants who had a value below that number were considered to have abnormally low leukocyte count.

25. Change From Baseline in Electrocardiograms [baseline (Week 1), Week 25]

    The Electrocardiogram measures include the following time intervals: QT interval, QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF), QT Interval Corrected for Heart Rate Using Bazett's Formula (QTcB), PR interval and QRS interval.

26. Number of Participants With Successful Treatment Outcome [Baseline (Week 1) through Week 25]

    Successful treatment outcome defined as: Participant completed the study and being in remission (HAMD-17 Total score ≤7 and ≤10) at least for the last two visits (4 weeks)of the study. The HAMD-17 is used to assess the severity of depression. The total score ranges from 0 (not at all depressed) to 52 (severely depressed).

27. Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores [baseline (Week 1), Week 9, Week 25]

    The cognitive assessment battery is composed of four tests: Verbal Learning (score 0-15)and Delayed Recall(score 0-15) test, SDST(Score 0-133),2DCT(score 0-40),Trail Making(Part B)(score 0-180).They are designed to challenge the patient's abilities in the following areas: verbal learning and memory; attention to visually presented material; and working memory and executive function. Composite Cognitive score(0-51)is derived from normalized individual test scores. For Trail Making Test,lower number indicates better cognition. For all other test scores,higher number indicates better cognition.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Are male or female outpatients at least 65 years of age who meet the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR) diagnostic criteria for Major Depressive Disorder (MDD)

• Have a Mini Mental Score Exam (MMSE) score of at least 20 at Visit 1

• Have a degree of understanding such that the patient can communicate intelligibly with the investigator and study coordinator

Exclusion Criteria:

• Patients judged clinically to be at serious suicidal risk in the opinion of the investigator

• Have any prior history of bipolar disorder, panic disorder, psychosis, schizophrenia, or obsessive-compulsive disorder

• Have any current (within the past 12 months) DSM-IV-TR primary Axis I diagnosis other than MDD

• Have moderate to severe dementia

• Have a serious medical illness, including any cardiovascular (CV), hepatic, renal, respiratory, hematologic, endocrinologic, or neurologic disease, or clinically significant laboratory abnormality that is not stabilized or is anticipated to require hospitalization within 6 months, in the opinion of the investigator

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.	Pasadena	California	United States	91107
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.	Sherman Oaks	California	United States	91403
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.	Hamden	Connecticut	United States	06518
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.	Coral Springs	Florida	United States	33065
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.	West Palm Beach	Florida	United States	33407
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.	Atlanta	Georgia	United States	30328
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.	Hoffman Estates	Illinois	United States	60194
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.	Lake Charles	Louisiana	United States	70601
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.	Gaithersburg	Maryland	United States	20877
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.	Glen Burnie	Maryland	United States	21061
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.	Fall River	Massachusetts	United States	02721
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.	Nashua	New Hampshire	United States	03060
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.	Toms River	New Jersey	United States	08755
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.	Olean	New York	United States	14760
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.	Staten Island	New York	United States	10312
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.	Oklahoma City	Oklahoma	United States	73109
17	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.	Philadelphia	Pennsylvania	United States	19139
18	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.	Lincoln	Rhode Island	United States	02865
19	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.	Bartlett	Tennessee	United States	38134
20	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.	Memphis	Tennessee	United States	38105
21	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.	Wichita Falls	Texas	United States	76309
22	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.	Charleston	West Virginia	United States	25301
23	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.	Brown Deer	Wisconsin	United States	53223
24	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.	Arcachon		France	33120
25	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.	Douai		France	59500
26	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.	Limoges		France	87025
27	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.	Metz		France	57020
28	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.	Nice		France	06002
29	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.	Strasbourg		France	67000
30	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.	Valence		France	26000
31	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.	Mexico City		Mexico	14050
32	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.	Monterrey		Mexico	64710
33	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.	Ponce		Puerto Rico	00731-7779

Sponsors and Collaborators

• Eli Lilly and Company
• Boehringer Ingelheim

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lilly Clinical Trial Registry

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00406848
• Other Study ID Numbers: 10815; F1J-US-HMFA
• First Posted: Dec 4, 2006
• Last Update Posted: Sep 29, 2010
• Last Verified: Sep 1, 2010

• Additional relevant MeSH terms: Depressive Disorder; Depressive Disorder, Major; Duloxetine Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	This study had a double-blind one-week placebo lead-in period before randomization, so baseline is defined as Week 1. 370 total patients were randomized and make up the safety analysis population. 299 of these patients were randomized under protocol amendments c, d and e, and make up the efficacy analysis population.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Period Title: Overall Study
STARTED	249	121
COMPLETED	156	67
NOT COMPLETED	93	54

Baseline Characteristics

Arm/Group Title	Duloxetine	Placebo	Total
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Total of all reporting groups
Overall Participants	249	121	370
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.89 (6.10)	73.02 (5.64)	72.93 (5.95)
Sex: Female, Male (Count of Participants)
Female	163 65.5%	71 58.7%	234 63.2%
Male	86 34.5%	50 41.3%	136 36.8%
Race/Ethnicity, Customized (Number) [Number]
African	5 2%	6 5%	11 3%
Caucasian	198 79.5%	92 76%	290 78.4%
Hispanic	46 18.5%	22 18.2%	68 18.4%
Native American	0 0%	1 0.8%	1 0.3%
Region of Enrollment (participants) [Number]
France	13 5.2%	8 6.6%	21 5.7%
United States	195 78.3%	94 77.7%	289 78.1%
Mexico	17 6.8%	8 6.6%	25 6.8%
Puerto Rico	24 9.6%	11 9.1%	35 9.5%
17 item Hamilton Depression Rating Scale Total Score(HAMD-17) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	19.42 (5.56)	19.32 (5.78)	19.39 (5.62)
17 item Hamilton Depression Rating Scale (HAMD-17) - Maier subscale (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	9.96 (3.11)	10.08 (3.36)	10.00 (3.19)
Geriatric Depression Scale (GDS) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	18.54 (6.91)	17.64 (6.66)	18.26 (6.83)
Numerical Rating Scale (NRS) Overall Pain Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.79 (2.96)	3.59 (2.67)	3.73 (2.87)
Brief Pain Inventory (BPI) 24-hour Average Pain Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.48 (2.70)	3.48 (2.57)	3.48 (2.66)
Mini Mental State Exam (MMSE) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	28.55 (1.83)	28.42 (1.72)	28.51 (1.79)
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	29.25 (5.57)	28.46 (5.40)	29.00 (5.52)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to 13 Weeks in Hamilton Depression Rating Scale (HAMD-17) Maier Subscale
Description	The Maier subscale (Items 1,2,7,8,9,10) represents symptoms of depression. Total subscale scores range from 0 (normal) to 24 (severe).
Time Frame	baseline (Week 1), Week 13

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	201	95
Least Squares Mean (Standard Error) [units on a scale]	-4.34 (0.29)	-3.90 (0.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments	Tested was the null hypothesis that there would be no difference in changes from baseline (Week 1) to Week 13 on the HAMD-17 Maier subscale between duloxetine and placebo treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.397
	Comments	The a priori threshold for statistical significance was 0.05.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

2. Secondary Outcome

Title	Change From Baseline on the 30-item Geriatric Depression Scale (GDS)
Description	The 30-item Geriatric Depression Scale (GDS) is a self-administered test of 30 questions to measure the severity of depression. The yes/no questions result in a range of scores from 0 (normal) to 30 (severe depression).
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	200	90
Week 13 change	-6.01 (0.53)	-4.53 (0.79)
Week 25 change	-7.02 (0.58)	-3.66 (1.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.115
	Comments	p-value is for difference between duloxetine and placebo on change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is for difference between duloxetine and placebo on change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

3. Secondary Outcome

Title	Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items
Description	Total Score assess depression severity (scores 0-52). Core, Maier and Bech subscales assess symptoms of depression (scores:0-20=Core; 0-24=Maier; 0-22=Bech). Anxiety/Somatization subscale assesses severity of anxiety (0-18). Retardation subscale assesses dysfunction in mood and work (0-14). Sleep subscale assesses insomnia (0-6). Individual item scores may range from 0-4 or 0-2. Higher numbers indicate more severe symptoms.
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

Randomized patients with non-missing data at baseline and post-baseline visit.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	201	95
Total - Week 13 Change	-7.42 (0.52)	-7.15 (0.77)
Total - Week 25 Change	-8.98 (0.57)	-7.00 (1.01)
Maier subscale Week 25 Change	-5.31 (0.29)	-4.17 (0.54)
Bech subscale Week 13 Change	-4.35 (0.30)	-3.98 (0.46)
Bech subscale Week 25 Change	-5.36 (0.31)	-4.07 (0.58)
Core Mood subscale Week 13 Change	-3.29 (0.24)	-3.02 (0.36)
Core Mood subscale Week 25 Change	-4.08 (0.23)	-3.00 (0.43)
Anxiety/Somatization subscale Week 13	-2.38 (0.20)	-2.26 (0.30)
Anxiety/Somatization subscale Week 25	-2.90 (0.22)	-2.44 (0.38)
Sleep subscale Week 13 Change	-1.14 (0.12)	-1.14 (0.18)
Sleep subscale Week 25 Change	-1.37 (0.13)	-1.35 (0.24)
Retardation subscale Week 13 Change	-2.70 (0.21)	-2.73 (0.31)
Retardation subscale Week 25 Change	-3.42 (0.20)	-2.77 (0.38)
Item 1: Depressed Mood - Week 13 Change	-1.13 (0.09)	-1.02 (0.13)
Item 1: Depressed Mood Week 25 Change	-1.36 (0.09)	-1.02 (0.16)
Item 2: Feelings of Guilt Week 13 Change	-0.70 (0.06)	-0.60 (0.09)
Item 2: Feelings of Guilt Week 25 Change	-0.91 (0.06)	-0.65 (0.12)
Item 3: Suicide Week 13 Change	-0.16 (0.04)	-0.18 (0.05)
Item 3: Suicide Week 25 Change	-0.19 (0.04)	-0.11 (0.07)
Item 4: Insomnia Early Week 13 Change	-0.37 (0.06)	-0.29 (0.09)
Item 4: Insomnia Early Week 25 Change	-0.42 (0.06)	-0.41 (0.12)
Item 5: Insomnia Middle Week 13 Change	-0.40 (0.06)	-0.47 (0.09)
Item 5: Insomnia Middle Week 25 Change	-0.49 (0.06)	-0.46 (0.11)
Item 6: Insomnia Late Week 13 Change	-0.36 (0.06)	-0.41 (0.08)
Item 6: Insomnia Late Week 25 Change	-0.45 (0.05)	-0.53 (0.10)
Item 7: Work and Activities Week 13 Change	-0.82 (0.08)	-0.81 (0.12)
Item 7: Work and Activities Week 25 Change	-1.12 (0.09)	-0.87 (0.16)
Item 8: Retardation Week 13 Change	-0.48 (0.05)	-0.51 (0.08)
Item 8: Retardation Week 25 Change	-0.57 (0.05)	-0.54 (0.09)
Item 9: Agitation Week 13 Change	-0.39 (0.06)	-0.32 (0.08)
Item 9: Agitation Week 25 Change	-0.45 (0.06)	-0.53 (0.11)
Item 10: Anxiety/Psychic Week 13 Change	-0.81 (0.07)	-0.75 (0.11)
Item 10: Anxiety/Psychic Week 25 Change	-0.98 (0.08)	-0.85 (0.14)
Item 11: Anxiety (Somatic) Week 13 Change	-0.49 (0.06)	-0.55 (0.09)
Item 11: Anxiety (Somatic) Week 25 Change	-0.70 (0.06)	-0.60 (0.11)
Item 12: Somatic Symptom/Gastrointestinal Week 13	-0.16 (0.04)	-0.20 (0.06)
Item 12: Somatic Symptom/Gastrointestinal Week 25	-0.23 (0.04)	-0.26 (0.07)
Item 13: Somatic Symptoms/General Week 13 Change	-0.41 (0.06)	-0.40 (0.09)
Item 13: Somatic Symptoms/General Week 25 Change	-0.52 (0.07)	-0.59 (0.13)
Item 14: Genital Symptoms Week 13 Change	-0.29 (0.06)	-0.46 (0.08)
Item 14: Genital Symptoms Week 25 Change	-0.41 (0.06)	-0.47 (0.12)
Item 15: Hypochondriasis Week 13 Change	-0.47 (0.06)	-0.32 (0.08)
Item 15: Hypochondriasis Week 25 Change	-0.49 (0.06)	-0.39 (0.11)
Item 16: Loss of Weight Week 13 Change	-0.02 (0.03)	-0.09 (0.04)
Item 16: Loss of Weight Week 25 Change	-0.13 (0.02)	-0.01 (0.04)
Item 17: Insight Week 13 Change	-0.09 (0.02)	-0.10 (0.03)
Item 17: Insight Week 25 Change	-0.07 (0.03)	-0.11 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.773
	Comments	p-value is for HAMD-17 total score change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.084
	Comments	p-value is for HAMD-17 total score change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments	p-value is for Maier subscale change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.488
	Comments	p-value is for Bech subscale change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments	p-value is for HAMD-17 Bech subscale change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.529
	Comments	p-value is for Core Mood subscale change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments	p-value is for Core Mood subscale change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.749
	Comments	p-value is for Anxiety/Somatization subscale change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.296
	Comments	p-value is for Anxiety/Somatization subscale change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.984
	Comments	p-value is for Sleep subscale change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.930
	Comments	p-value is for Sleep subscale change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.934
	Comments	p-value is for Retardation subscale change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.123
	Comments	p-value is for Retardation subscale change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

4. Secondary Outcome

Title	Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores
Description	The Brief Pain Inventory (severity and interference scales) (BPI) is a self-reported scale that measures the severity of pain and the interference of pain on function. Severity scores: 0 (no pain) to 10 (severe pain) on each question assessing worst pain, least pain, and average pain in past 24 hours, and pain right now. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life.
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	191	87
Worst Pain - Week 13	-0.66 (0.14)	-0.18 (0.19)
Worst Pain - Week 25	-0.74 (0.14)	-0.36 (0.20)
Least Pain - Week 13	-0.47 (0.11)	-0.00 (0.15)
Least Pain - Week 25	-0.54 (0.11)	-0.26 (0.16)
Average Pain - Week 13	-0.83 (0.13)	-0.14 (0.18)
Average Pain - Week 25	-0.87 (0.12)	-0.37 (0.18)
Pain Right Now - Week 13	-0.78 (0.13)	-0.26 (0.18)
Pain Right Now - Week 25	-0.86 (0.13)	-0.46 (0.18)
Interference with General Activity - Week13	-0.58 (0.13)	-0.03 (0.19)
Interference with General Activity - Week 25	-0.65 (0.13)	-0.23 (0.19)
Interference with Mood - Week 13	-0.82 (0.14)	-0.03 (0.19)
Interference with Mood - Week 25	-0.95 (0.13)	-0.25 (0.19)
Interference with Walking Ability - Week 13	-0.74 (0.14)	-0.19 (0.20)
Interference with Walking Ability - Week 25	-0.75 (0.15)	-0.24 (0.21)
Interference with Normal Work - Week 13	-0.72 (0.15)	-0.01 (0.21)
Interference with Normal Work - Week 25	-0.79 (0.15)	-0.19 (0.21)
Int. with Relations with other people- Week 13	-0.60 (0.13)	-0.03 (0.19)
Int. with Relations with other people-Week 25	-0.73 (0.13)	-0.18 (0.19)
Interference with Sleep - Week 13	-0.77 (0.15)	-0.17 (0.21)
Interference with Sleep - Week 25	-0.94 (0.14)	-0.26 (0.21)
Interference with Enjoyment of Life- Week 13	-0.93 (0.15)	0.03 (0.21)
Interference with Enjoyment of Life- Week 25	-1.04 (0.15)	-0.08 (0.21)
Average Interference Score - Week 13	-0.76 (0.12)	-0.07 (0.17)
Average Interference Score - Week 25	-0.86 (0.12)	-0.19 (0.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments	p-value is for Severity of Worst Pain Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.100
	Comments	p-value is for Severity of Worst Pain - Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is for Severity of Least Pain Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.126
	Comments	p-value is for Severity of Least Pain Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is for Severity of Average Pain Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	p-value is for Severity of Average Pain Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	p-value is for Severity of Pain Right Now Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	p-value is for Severity of Pain Right Now Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is for Interference with General Activity Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments	p-value is for Interference with General Activity Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is for Interference with Mood Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is for Interference with Mood Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	p-value is for Interference with Walking Ability Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.040
	Comments	p-value is for Interference with Walking Ability Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is for Interference with Normal Work Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	p-value is for Interference with Normal Work Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	p-value is for Interference with Relations with Other People Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	p-value is for Interference with Relations with Other People Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	p-value is for Interference with Sleep Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value is for Interference with Sleep Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is for Interference with Enjoyment of Life Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is for Interference with Enjoyment of Life Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is for Average Interference Score Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is for Average Interference Score Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

5. Secondary Outcome

Title	Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores
Description	Numeric Rating Scales (Semantic Differential Scales) for Pain are 6 self-administered scales that assesses experience of overall pain, back pain, headache, shoulder pain, time in pain while awake, and pain interference with daily activities, during the past week. Each item is scored on a numeric 11-point semantic differential scale (0-10) from 0 = no pain to 10 = pain as severe as you can imagine; or 0 = none of the time to 10 = all of the time; or 0 = no interference to 10 = unable to do any activities at all.
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	191	87
Overall Pain - Week 13	-0.65 (0.13)	-0.05 (0.18)
Overall Pain - Week 25	-0.67 (0.13)	-0.40 (0.19)
Headaches - Week 13	-0.32 (0.12)	0.01 (0.16)
Headaches - Week 25	-0.28 (0.12)	0.01 (0.18)
Back Pain - Week 13	-0.63 (0.14)	0.00 (0.20)
Back Pain - Week 25	-0.75 (0.14)	-0.15 (0.21)
Shoulder Pain - Week 13	-0.54 (0.12)	-0.22 (0.17)
Shoulder Pain - Week 25	-0.55 (0.13)	-0.30 (0.18)
Pain Interference with Daily Activities - Week 13	-0.84 (0.14)	-0.20 (0.20)
Pain Interference with Daily Activities - Week 25	-0.91 (0.15)	-0.34 (0.21)
Time in Pain While Awake - Week 13	-0.75 (0.14)	-0.04 (0.19)
Time in Pain While Awake - Week 25	-0.80 (0.13)	-0.33 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.005
	Comments	p-value is for Overall Pain Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.204
	Comments	p-value is for Overall Pain Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.078
	Comments	p-value is for Headaches Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.147
	Comments	p-value is for Headaches Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is for Back Pain Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	p-value is for Back Pain Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.124
	Comments	p-value is for Shoulder Pain Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.231
	Comments	p-value is for Shoulder Pain Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is for Interference with Daily Activities Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	p-value is for Interference with Daily Activities Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is for Time in Pain While Awake Week 13 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments	p-value is for Time in Pain While Awake Week 25 main effect of treatment.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

6. Secondary Outcome

Title	Patient's Global Impression of Improvement (PGI-I) at 13 Weeks and 25 Weeks
Description	The PGI-Improvement scale is a patient-rated instrument that measures perceived improvement in symptoms. It is a 7-point scale where a score of 1 indicates that the patient is "very much improved," a score of 4 indicates that the patient has experienced "no change," and a score of 7 indicates that the patient is "very much worse."
Time Frame	Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	178	84
Week 13	2.74 (0.13)	3.02 (0.19)
Week 25	2.38 (0.12)	2.85 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.214
	Comments	p-value is for PGI-I at Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: PGI-I = Treatment + Pooled Investigator + Visit + Treatment* Visit

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.063
	Comments	p-value is for PGI-I at Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: PGI-I = Treatment + Pooled Investigator + Visit + Treatment* Visit

7. Secondary Outcome

Title	Change From Baseline in the Clinical Global Impression-Severity (CGI-S)
Description	Measures severity of illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	203	94
Week 13 Change	-1.25 (0.09)	-1.04 (0.13)
Week 25 Change	-1.65 (0.09)	-1.17 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.162
	Comments	p-value is for change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.009
	Comments	p-value is for change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change =Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

8. Secondary Outcome

Title	Change From Baseline in the Mini-Mental State Exam (MMSE)
Description	Mini-Mental State Examination (MMSE)is a widely used rating measure of cognitive ability. Scores range from 0 to 30. The MMSE will be used to categorize patients as with or without dementia. Higher number indicates better cognitive ability. Patients with a MMSE score of 20 to 23 will be categorized as having mild dementia, while those with a score of ≥ 24 will be categorized as having no dementia.
Time Frame	baseline (Week 1), Week 9, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	159	69
Week 9 Change (n=159, n=69)	0.12 (0.13)	0.24 (0.18)
Week 25 Change (n=161, n=71)	0.29 (0.13)	0.35 (0.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.555
	Comments	p-value is for change from baseline (Week 1) to Week 9.
	Method	ANCOVA
	Comments	Model: Change = Treatment + Pooled Investigator + Baseline

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.785
	Comments	p-value is for change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change = Treatment + Pooled Investigator + Baseline

9. Secondary Outcome

Title	Change From Baseline in the Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q-SF)
Description	The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) measures the degree of enjoyment and satisfaction experienced in various areas of daily life. The short version is a self-administered 16 item scale evaluating satisfaction of general activities on a 5-point Likert scale that indicates the degree of enjoyment or satisfaction achieved during the past week (1 = very poor and 5 = very good).
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	167	82
Week 13 Change	6.58 (0.71)	5.27 (0.98)
Week 25 Change (n=168, n=82)	7.44 (0.78)	4.79 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.255
	Comments	p-value is for change from baseline (Week 1) to Week 13.
	Method	ANCOVA
	Comments	Model: Change = Treatment + Pooled Investigator + Baseline

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments	p-value is for change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change = Treatment + Pooled Investigator + Baseline

10. Secondary Outcome

Title	Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10
Description	Remission (visitwise binary outcome, yes/no) is defined as HAMD-17 Total Score ≤7 and ≤10. HAMD-17 measures depression severity. The total score can range from 0 (normal) to 52 (severe depression). The visitwise probability of patients meeting criteria for remission (either Total Score ≤7 or ≤10) was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis included the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score.
Time Frame	Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	201	95
Remission (HAMD17 ≤ 7) - Week 13	0.37 (0.26)	0.33 (0.42)
Remission (HAMD17 ≤ 7) - Week 25	0.54 (0.22)	0.49 (0.46)
Remission (HAMD17 ≤ 10) - Week 13	0.54 (0.19)	0.53 (0.31)
Remission (HAMD17 ≤ 10) - Week 25	0.70 (0.21)	0.72 (0.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.706
	Comments	p-values for Week 13 remission (HAMD17 ≤ 7).
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Remission = Treatment + Pooled Investigator + Visit + Baseline + Treatment*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.694
	Comments	p-values for Week 25 Remission HAMD17 ≤ 7
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM)analysis model:Remission = Treatment + Pooled Investigator + Visit + Baseline + Treatment*Visit.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.864
	Comments	p-values for Week 13 Remission - HAMD17 ≤ 10
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM)analysis model:Remission = Treatment + Pooled Investigator + Visit + Baseline + Treatment*Visit.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.817
	Comments	p-values for Week 25 Remission - HAMD17 ≤ 10
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM)analysis model:Remission = Treatment + Pooled Investigator + Visit + Baseline + Treatment*Visit.

11. Secondary Outcome

Title	Probability of Response at Endpoint as Measured by ≥50% Improvement in the HAMD-17 Total Score
Description	Response (visitwise binary outcome, yes/no) is defined as ≥ 50% reduction from baseline in the HAMD-17 total score. HAMD-17 measures depression severity. The total score can range from 0 (normal) to 52 (severe depression). The visitwise probability of patients meeting criteria for response was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis included the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score.
Time Frame	Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	201	95
Week 13	0.44 (0.19)	0.48 (0.29)
Week 25	0.61 (0.20)	0.72 (0.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.664
	Comments	p-value is for probability of response at Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM)analysis model:Response = Treatment + Pooled Investigator + Visit + Baseline + Treatment*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.310
	Comments	p-value is for probability of response at Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM)analysis model:Response = Treatment + Pooled Investigator + Visit + Baseline + Treatment*Visit.

12. Secondary Outcome

Title	Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G)
Description	Remission defined as HAMD-17 Total Score ≤7 and ≤10. HAMD-17 measures depression severity. Total score ranges: 0 (normal) to 52 (severe depression). Visitwise probability of patients achieving remission was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. CIRS-G evaluates 14 organ-specific categories using a rating strategy of 0=no problems; 1=current mild problem/past significant problem; 2=moderate disability/morbidity; 3=severe/constant significant disability; and 4=extremely severe/immediate treatment required/end organ failure. Total score ranges: 0 to 56.
Time Frame	Week 13, Week 25

Outcome Measure Data

Analysis Population Description

Randomized patients with non-missing data at baseline and post-baseline visit.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	201	95
Remission HAMD-17 ≤ 7 Week 13 (CIRS-G ≥ 6)	0.44 (0.07)	0.44 (0.10)
Remission HAMD-17 ≤ 7 Week 13 (CIRS-G < 6)	0.33 (0.07)	0.20 (0.10)
Remission HAMD-17 ≤ 10 Week 13 (CIRS-G ≥ 6)	0.53 (0.07)	0.52 (0.10)
Remission HAMD-17 ≤ 10 Week 13 (CIRS-G <6)	0.53 (0.07)	0.57 (0.14)
Remission HAMD-17 ≤ 7 Week 25 (CIRS-G ≥ 6)	0.52 (0.08)	0.42 (0.13)
Remission HAMD-17 ≤ 7 Week 25 (CIRS-G <6)	0.53 (0.08)	0.45 (0.25)
Remission HAMD-17 ≤ 10 Week 25 (CIRS-G ≥ 6)	0.71 (0.06)	0.65 (0.12)
Remission HAMD-17 ≤ 10 Week 25 (CIRS-G <6)	0.63 (0.08)	0.72 (0.25)

13. Secondary Outcome

Title	Probability of Efficacy Onset as Measured by at Least 20% Sustained Reduction From Baseline in the HAMD-17 Maier Subscale at Week 3
Description	Patients are considered to have met onset (visitwise binary outcome, yes/no) criteria at a particular visit if they had at least 20% reduction from baseline in the HAMD-17 Maier subscale at that visit and at all subsequent visits in the acute phase. Maier subscale measures core symptoms of depression and scores range from 0 (normal) to 24 (severe). The visitwise probability of patients meeting onset criteria was analyzed using a categorical, pseudo-likelihood-based repeated measures approach.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	201	95
Least Squares Mean (Standard Error) [Probability of onset]	0.43 (0.04)	0.30 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM)analysis model: Onset = Treatment + Visit + Baseline + Treatment*Visit.

14. Secondary Outcome

Title	Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline and at least one non-missing post-baseline value.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	246	118
Systolic BP Week 13 Change	0.19 (0.94)	-0.58 (1.39)
Diastolic BP Week 13 Change	1.89 (0.62)	-1.58 (0.92)
Systolic BP Week 25 Change	2.22 (1.09)	0.54 (1.99)
Diastolic BP Week 25 Change	2.44 (0.68)	0.65 (1.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.637
	Comments	p-value is for Systolic BP change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is for Diastolic BP change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.452
	Comments	p-value is for Systolic BP change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.193
	Comments	p-value is for Diastolic BP change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

15. Secondary Outcome

Title	Change From Baseline in Pulse Rate
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline and at least one non-missing post-baseline value.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	246	118
Week 13 Change	0.03 (0.60)	-1.56 (0.88)
Week 25 Change	2.10 (0.69)	-0.87 (1.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.121
	Comments	p-value is for change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments	p-value is for change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

16. Secondary Outcome

Title	Change From Baseline in Weight
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline and at least one non-missing post-baseline value.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	248	121
Week 13 Change	-0.86 (0.17)	0.06 (0.26)
Week 25 Change	-0.69 (0.22)	-0.03 (0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is for Weight change from baseline (Week 1) to Week 13.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.127
	Comments	p-value is for Weight change from baseline (Week 1) to Week 25.
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) analysis model: Change = Treatment + Pooled Investigator + Visit + Treatment* Visit + Baseline + Baseline*Visit.

17. Secondary Outcome

Title	Number of Participants With Abnormal Vital Signs and Weight at Any Time During the Study
Description	A patient has a treatment-emergent elevated supine systolic blood pressure if the value is ≥140 with an increase ≥10 from baseline. A patient has a treatment-emergent elevated supine diastolic blood pressure if the value is ≥90 with an increase ≥10 from baseline. A patient has a treatment-emergent elevated supine pulse if the value is ≥100 with an increase ≥10 from baseline. A patient has abnormal weight change if the gain or loss is ≥7% compared to baseline.
Time Frame	Baseline (Week 1) through Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a normal baseline and at least one post-baseline value in each treatment group.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	248	121
Diastolic Blood Pressure - High (n=210, n=98)	22 8.8%	5 4.1%
Pulse - High (n=243, n=115)	10 4%	4 3.3%
Systolic Blood Pressure - High (n=119, n=58)	28 11.2%	7 5.8%
Weight Change (gain)	11 4.4%	2 1.7%
Weight Change (loss)	15 6%	6 5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.135
	Comments	p-value is for Diastolic Blood Pressure.
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments	Pulse
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	p-value is for Pulse.
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.107
	Comments	p-value is for Systolic Blood Pressure
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.235
	Comments	p-value is for Weight Change (gain)
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.813
	Comments	p-value is for Weight Change (loss)
	Method	Fisher Exact
	Comments

18. Secondary Outcome

Title	Number of Participants Experiencing Sustained Hypertension (SH) or Orthostatic Hypotension (OH)
Description	Sustained Hypertension is defined as supine systolic BP >= 140 (or diastolic BP >= 90) mm Hg and increase from baseline (highest value in baseline visit interval) >= 10 mm Hg for 3 or more consecutive visits in postbaseline visit interval. Orthostatic Hypotension is defined as standing diastolic BP at least 10 mm Hg less than the supine diastolic BP or the standing systolic BP at least 20 mm Hg less than the supine systolic BP at any time in postbaseline visit interval and a patient does not meet this criterion at any visit in baseline interval.
Time Frame	baseline (Week 1) through Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a normal baseline and at least one post-baseline value in each treatment group.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	246	118
Sustained Hypertension	5 2%	1 0.8%
Orthostatic Hypotension (n=183, n=90)	57 22.9%	21 17.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.668
	Comments	p-value is for Sustained Hypertension
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.201
	Comments	p-value is for Orthostatic Hypotension
	Method	Fisher Exact
	Comments

19. Secondary Outcome

Title	Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation
Description	Adverse Events and Serious Adverse Events leading to study discontinuation.
Time Frame	baseline (Week 1) through Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients.

Arm/Group Title	Duloxetine	Placebo Non-rescue	Placebo Rescue
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants who were randomized to placebo at baseline and for whom treatment rescue was not required during continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they continued to receive placebo until completing or discontinuing from the study.	Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Measure Participants	249	86	35
Total Discontinued due to Adverse Events	38 15.3%	7 5.8%	0 0%
Diarrhoea	3 1.2%	0 0%	0 0%
Fatigue	3 1.2%	0 0%	0 0%
Headache	1 0.4%	2 1.7%	0 0%
Nausea	3 1.2%	0 0%	0 0%
Constipation	2 0.8%	0 0%	0 0%
Dizziness	2 0.8%	0 0%	0 0%
Hypertension	1 0.4%	1 0.8%	0 0%
Memory impairment	2 0.8%	0 0%	0 0%
Urinary Tract Infection	2 0.8%	0 0%	0 0%
Vomiting	1 0.4%	1 0.8%	0 0%
Alopecia	1 0.4%	0 0%	0 0%
Anxiety	1 0.4%	0 0%	0 0%
Blood pressure increased	0 0%	1 0.8%	0 0%
Chills	1 0.4%	0 0%	0 0%
Depression	1 0.4%	0 0%	0 0%
Erectile dysfunction	1 0.4%	0 0%	0 0%
Faecal incontinence	1 0.4%	0 0%	0 0%
Gastrooesophageal reflux disease	1 0.4%	0 0%	0 0%
Hip fracture	1 0.4%	0 0%	0 0%
Insomnia	1 0.4%	0 0%	0 0%
Intracranial aneurysm	1 0.4%	0 0%	0 0%
Lethargy	1 0.4%	0 0%	0 0%
Oesophageal adenocarcinoma metastatic	1 0.4%	0 0%	0 0%
Palpitations	1 0.4%	0 0%	0 0%
Paranasal sinus hypersecretion	1 0.4%	0 0%	0 0%
Pneumoperitoneum	1 0.4%	0 0%	0 0%
Presyncope	0 0%	1 0.8%	0 0%
Rash pruritic	0 0%	1 0.8%	0 0%
Renal failure acute	1 0.4%	0 0%	0 0%
Suicidal ideation	1 0.4%	0 0%	0 0%
Tremor	1 0.4%	0 0%	0 0%

20. Secondary Outcome

Title	Change From Baseline in Laboratory Values - Platelet Count
Description	Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	227	108
Platelet Count Week 13 Change	7.92 (45.75)	-4.66 (42.95)
Platelet Count Week 25 Change	10.58 (51.66)	-6.11 (39.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is for Platelet Count change from baseline (Week 1) to Week 13.
	Method	ANOVA
	Comments	Model: Change=Treatment+Pooled Investigator

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is for Platelet Count change from baseline (Week 1) to Week 25.
	Method	ANOVA
	Comments	Model: Change=Treatment+Pooled Investigator

21. Secondary Outcome

Title	Change From Baseline in Laboratory Values - Uric Acid
Description	Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.
Time Frame	baseline (Week 1), Week 13, Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	230	112
Week 13 Change	-11.63 (63.05)	9.30 (47.39)
Week 25 Change	-9.93 (59.64)	10.26 (48.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is for Uric Acid change from baseline (Week 1) to Week 13.
	Method	ANOVA
	Comments	Model: Change = Treatment + Pooled Investigator

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is for Uric Acid change from baseline (Week 1) to Week 25.
	Method	ANOVA
	Comments	Model: Change = Treatment + Pooled Investigator

22. Secondary Outcome

Title	Change From Baseline in Laboratory Values - Erythrocyte Count
Description	Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.
Time Frame	baseline (Week 1), Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	228	109
Erythrocyte Count	-0.04 (0.29)	0.01 (0.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	p-value is for Erythrocyte Count change from baseline (Week 1) to Week 25.
	Method	ANOVA
	Comments	Model: Change=Treatment+Pooled Investigator

23. Secondary Outcome

Title	Change From Baseline in Laboratory Values - Hemoglobin, Mean Cell Hemoglobin Concentration (MCHC)
Description	Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.
Time Frame	baseline (Week 1), Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	228	109
Hemoglobin Week 25 Change	-0.11 (0.56)	0.01 (0.46)
Mean Cell Hemoglobin Concentration Week 25 Change	-0.20 (0.81)	-0.02 (0.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	p-value is for Hemoglobin change from baseline (Week 1) to Week 25.
	Method	ANOVA
	Comments	Model: Change = Treatment + Pooled Investigator

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments	p-value is for Mean Cell Hemoglobin Concentration change from baseline (Week 1) to Week 25.
	Method	ANOVA
	Comments	Model: Change=Treatment+Pooled Investigator

24. Secondary Outcome

Title	Change From Baseline in Laboratory Values - Chloride and Fasting Glucose
Description	Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.
Time Frame	baseline (Week 1), Week 25

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	230	112
Chloride Week 25 Change	-0.63 (2.83)	0.01 (2.77)
Fasting Glucose Week 25 Change (n=155, n=67)	0.37 (1.88)	-0.11 (1.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.040
	Comments	p-value is for Chloride change from baseline (Week 1) to Week 25.
	Method	ANOVA
	Comments	Model: Change = Treatment + Pooled Investigator

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments	p-value is for Fasting Glucose change from baseline (Week 1) to Week 25.
	Method	ANOVA
	Comments	Model: Change=Treatment+Pooled Investigator

25. Secondary Outcome

Title	Number of Participants With Abnormal Laboratory Values - Low Leukocyte Count
Description	The number of participants with abnormal laboratory values at any time during the study period. Results are reported for laboratory analytes that exhibited statistically significantly different proportions of participants who had abnormal values between treatment groups. Statistical significance was considered at the 0.05 level. The lower limit of normal for leukocyte count is 3.8 Billion/Liter. Participants who had a value below that number were considered to have abnormally low leukocyte count.
Time Frame	baseline (Week 1) through Week 13

Outcome Measure Data

Analysis Population Description

All randomized patients with a normal baseline and at least one post-baseline value in each treatment group.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	225	109
Leukocyte Count (Low)	11 4.4%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments
	Method	Fisher Exact
	Comments

26. Secondary Outcome

Title	Change From Baseline in Electrocardiograms
Description	The Electrocardiogram measures include the following time intervals: QT interval, QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF), QT Interval Corrected for Heart Rate Using Bazett's Formula (QTcB), PR interval and QRS interval.
Time Frame	baseline (Week 1), Week 25

Outcome Measure Data

Analysis Population Description

Participants with a baseline and at least one non-missing post baseline value.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	194	68
QT Interval Week 25 Change	-11.80 (2.19)	-10.95 (3.43)
QTcF Interval Week 25 Change	-5.02 (1.48)	-5.91 (2.33)
QTcB Interval Week 25 Change	-1.38 (1.61)	-3.78 (2.55)
PR Interval Week 25 Change	-5.91 (1.45)	-1.34 (2.32)
QRS Interval Week 25 Change	-1.11 (0.80)	-3.25 (1.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.815
	Comments	p-value is for QT Interval change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.721
	Comments	p-value is for QTcF Interval change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.376
	Comments	p-value is for QTcB Interval change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.065
	Comments	p-value is for PR Interval change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.110
	Comments	p-value is for QRS Interval change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

27. Secondary Outcome

Title	Number of Participants With Successful Treatment Outcome
Description	Successful treatment outcome defined as: Participant completed the study and being in remission (HAMD-17 Total score ≤7 and ≤10) at least for the last two visits (4 weeks)of the study. The HAMD-17 is used to assess the severity of depression. The total score ranges from 0 (not at all depressed) to 52 (severely depressed).
Time Frame	Baseline (Week 1) through Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and that have non-missing successful treatment values.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	204	95
Successful Treatment Outcome (with HAMD17 ≤ 7)	55 22.1%	17 14%
Successful Treatment Outcome (with HAMD17 ≤ 10)	74 29.7%	21 17.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.110
	Comments	p-value is for Successful Treatment Outcome defined with HAMD-17 ≤7 criteria.
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	p-value is for Successful Treatment Outcome defined with HAMD-17 ≤10 criteria.
	Method	Fisher Exact
	Comments

28. Secondary Outcome

Title	Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores
Description	The cognitive assessment battery is composed of four tests: Verbal Learning (score 0-15)and Delayed Recall(score 0-15) test, SDST(Score 0-133),2DCT(score 0-40),Trail Making(Part B)(score 0-180).They are designed to challenge the patient's abilities in the following areas: verbal learning and memory; attention to visually presented material; and working memory and executive function. Composite Cognitive score(0-51)is derived from normalized individual test scores. For Trail Making Test,lower number indicates better cognition. For all other test scores,higher number indicates better cognition.
Time Frame	baseline (Week 1), Week 9, Week 25

Outcome Measure Data

Analysis Population Description

All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Measure Participants	183	90
Composite Cognitive Score Week 9	-0.38 (0.38)	0.01 (0.51)
Composite Cognitive Score Week 25	0.96 (0.40)	0.31 (0.54)
Learning Trials Score Week 9	-0.06 (0.12)	-0.04 (0.17)
Learning Trials Score Week 25	0.34 (0.13)	0.06 (0.18)
Delayed Recall Score Week 9	-0.65 (0.21)	-0.59 (0.28)
Delayed Recall Score Week 25	0.12 (0.22)	-0.36 (0.29)
SDST Score Week 9	1.98 (0.76)	3.99 (1.04)
SDST Score Week 25	5.60 (0.84)	3.61 (1.15)
2DCT Score Week 9	0.30 (0.46)	0.94 (0.63)
2DCT Score Week 25	0.87 (0.51)	1.01 (0.70)
Trail Making Test (Part B) Week 9	-5.60 (2.90)	-3.09 (4.00)
Trail Making Test (Part B) Week 25	-1.59 (2.82)	-6.86 (3.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.511
	Comments	p-value is for Composite Cognitive Score change from baseline (Week 1) to Week 9.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.300
	Comments	p-value is for Composite Cognitive Score change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.922
	Comments	p-value is for Learning Trials Score change from baseline (Week 1) to Week 9.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.190
	Comments	p-value is for Learning Trials Score change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.850
	Comments	p-value is for Delayed Recall Score change from baseline (Week 1) to Week 9.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.158
	Comments	p-value is for Delayed Recall Score change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.099
	Comments	p-value is for SDST Score change from baseline (Week 1) to Week 9.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.141
	Comments	p-value is for SDST Score change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.379
	Comments	p-value is for 2DCT Score change from baseline (Week 1) to Week 9.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.858
	Comments	p-value is for 2DCT Score change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.591
	Comments	p-value is for Trail Making Test Score change from baseline (Week 1) to Week 9.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.242
	Comments	p-value is for Trail Making Test Score change from baseline (Week 1) to Week 25.
	Method	ANCOVA
	Comments	Model: Change=Treatment+Pooled Investigator+Baseline

Adverse Events

Time Frame	Baseline (Week 1) through Week 25.
Adverse Event Reporting Description	The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Arm/Group Title	Duloxetine		Placebo		Rescued Placebo
Arm/Group Description	Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.		Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity. Results are for the randomized placebo patients who reported events while they were on placebo.		Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally for the remainder of the study. Results are for the randomized placebo patients who were rescued to duloxetine and reported events while they were on duloxetine.
All Cause Mortality
	Duloxetine		Placebo		Rescued Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Duloxetine		Placebo		Rescued Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/249 (5.2%)		4/121 (3.3%)		1/35 (2.9%)
Cardiac disorders
Arrhythmia	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Atrial flutter	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Coronary artery occlusion	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Gastrointestinal disorders
Pneumoperitoneum	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
General disorders
Chest pain	2/249 (0.8%)	2	0/121 (0%)	0	0/35 (0%)	0
Infections and infestations
Abscess intestinal	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Influenza	0/249 (0%)	0	1/121 (0.8%)	1	0/35 (0%)	0
Injury, poisoning and procedural complications
Ankle fracture	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Head injury	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Hip fracture	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Musculoskeletal and connective tissue disorders
Spinal osteoarthritis	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oesophageal adenocarcinoma metastatic	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Nervous system disorders
Intracranial aneurysm	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Presyncope	0/249 (0%)	0	1/121 (0.8%)	1	0/35 (0%)	0
Renal and urinary disorders
Renal failure acute	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Reproductive system and breast disorders
Prostatitis	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/249 (0%)	0	1/121 (0.8%)	1	0/35 (0%)	0
Dyspnoea	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Interstitial lung disease	1/249 (0.4%)	1	0/121 (0%)	0	0/35 (0%)	0
Pulmonary embolism	0/249 (0%)	0	0/121 (0%)	0	1/35 (2.9%)	1
Surgical and medical procedures
Toe amputation	0/249 (0%)	0	1/121 (0.8%)	1	0/35 (0%)	0
Vascular disorders
Orthostatic hypotension	1/249 (0.4%)	2	0/121 (0%)	0	0/35 (0%)	0
Other (Not Including Serious) Adverse Events
	Duloxetine		Placebo		Rescued Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	199/249 (79.9%)		77/121 (63.6%)		17/35 (48.6%)
Gastrointestinal disorders
Constipation	37/249 (14.9%)	37	5/121 (4.1%)	6	3/35 (8.6%)	3
Diarrhoea	31/249 (12.4%)	33	3/121 (2.5%)	3	0/35 (0%)	0
Dry mouth	34/249 (13.7%)	35	7/121 (5.8%)	7	1/35 (2.9%)	1
Nausea	28/249 (11.2%)	29	7/121 (5.8%)	7	0/35 (0%)	0
General disorders
Fatigue	14/249 (5.6%)	17	3/121 (2.5%)	3	1/35 (2.9%)	1
Infections and infestations
Upper respiratory tract infection	13/249 (5.2%)	14	0/121 (0%)	0	0/35 (0%)	0
Injury, poisoning and procedural complications
Contusion	12/249 (4.8%)	16	4/121 (3.3%)	4	2/35 (5.7%)	2
Fall	59/249 (23.7%)	80	17/121 (14%)	21	6/35 (17.1%)	11
Musculoskeletal and connective tissue disorders
Back pain	13/249 (5.2%)	14	8/121 (6.6%)	9	0/35 (0%)	0
Pain in extremity	10/249 (4%)	11	2/121 (1.7%)	3	2/35 (5.7%)	2
Nervous system disorders
Dizziness	26/249 (10.4%)	30	6/121 (5%)	7	2/35 (5.7%)	2
Headache	32/249 (12.9%)	37	13/121 (10.7%)	13	0/35 (0%)	0
Skin and subcutaneous tissue disorders
Hyperhidrosis	15/249 (6%)	15	2/121 (1.7%)	2	0/35 (0%)	0
Vascular disorders
Orthostatic hypotension	5/249 (2%)	5	2/121 (1.7%)	2	2/35 (5.7%)	2

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.