Early Versus Delayed Switch in Medication in Patients With Major Depressive Disorder

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00810069
• Collaborator: (none)
• Enrollment: 840
• Locations: 60
• Arms: 2
• Duration (Months): 15.9
• Patients Per Site: 14
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This study investigates two different approaches to the change in antidepressant treatment when an initial treatment is not effective: early intervention or delayed intervention.

Two hypothesis will be tested:

1. that time to confirmed response is shorter in the early intervention strategy vs. delayed intervention strategy

2. that the time to confirmed remission is shorter in the early intervention strategy compared to delayed intervention strategy.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Duloxetine Hydrochloride; Drug: Escitalopram	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 840 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Comparison of Two Different Treatment Strategies in Patients With Major Depressive Disorder Not Exhibiting Improvement on Escitalopram Treatment: Early vs. Delayed Intervention Strategy
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early Intervention Escitalopram 10 milligrams per day for 4 weeks (one 10 milligram [mg]-capsule) followed by Duloxetine flexible dose (60 or 120 mg daily) for 12 weeks.	Drug: Duloxetine Hydrochloride; Flexible dose of 60 or 120 mg daily; Other Names: Cymbalta LY248686 ; Drug: Escitalopram; 10 mg in both Early and Delayed Intervention. Flexible dose of 10 to 20 mg daily in Delayed Intervention.; Other Names: Lexapro Cipralex
Experimental: Delayed Intervention Escitalopram 10 mg per day for 4 weeks (one 10 mg-capsule) followed by Escitalopram 10 to 20 mg per day for 4 weeks (one or two 10 mg capsule[s]). Then, non-responders switched to Duloxetine 60 or 120 mg per day for 8 weeks , and responders continued on Escitalopram 10 to 20 mg per day for 8 weeks.	Drug: Duloxetine Hydrochloride; Flexible dose of 60 or 120 mg daily; Other Names: Cymbalta LY248686 ; Drug: Escitalopram; 10 mg in both Early and Delayed Intervention. Flexible dose of 10 to 20 mg daily in Delayed Intervention.; Other Names: Lexapro Cipralex

Outcome Measures

Primary Outcome Measures

1. Time to Confirmed Response by ≥ 50% Change From Baseline Reduction in the Hamilton Depression Rating Scale-17 Items (HAMD-17) [Week 4 through Week 16]

   Time to confirmed response is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed response defined as ≥ 50% baseline score reduction on the HAMD-17 for 2 consecutive visits. The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale, e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).

2. Estimated Probability of Not Reaching Confirmed Response at 12 Weeks Based on the Survival Function for the Time to Confirmed Response [Week 4 through Week 16]

   Survival function is estimating the probability of participants not achieving confirmed response after 12 weeks. Confirmed response is defined as >=50% change from baseline reduction in the Hamilton Depression Rating Scale-17 Items (HAMD-17). The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).

3. Time to Confirmed Remission by a Hamilton Depression Rating Scale-17 Items (HAMD-17) Score of ≤ 7 That is Maintained for Two Consecutive Visits [Week 4 through Week 16]

   Time to confirmed remission is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed remission defined as a score on the HAMD-17 of ≤ 7 for 2 consecutive visits. The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).

4. Estimated Probability of Not Reaching Confirmed Remission at 12 Weeks Based on the Survival Function for the Time to Confirmed Remission [Week 4 through Week 16]

   Survival function is estimating the probability of participants not achieving confirmed remission. Confirmed remission is defined as a Hamilton Depression Rating Scale-17 Items (HAMD-17) Score of ≤ 7 that is maintained for two consecutive visits. The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).

Secondary Outcome Measures

1. Time to Confirmed Response as Defined by ≥ 50% Reduction From Baseline Reduction in the 16-Item Quick Inventory of Depressive Symptomatology Self Report (QIDS16SR) That is Reported for Two Consecutive Visits [Week 4 through Week 16]

   Time to confirmed response is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed response. QIDS16SR is a 16-item participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27 with higher scores indicative of greater severity.

2. Time to Confirmed Remission as Defined by a 16-Item Quick Inventory of Depressive Symptomatology Self Report (QIDS16SR) Score of ≤ 5 That is Maintained for Two Consecutive Visits. [Week 4 through Week 16]

   Time to confirmed remission is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed remission. A 16-item participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27 with higher scores indicative of greater severity.

3. Clinical Global Impressions of Severity (CGI-S) Scale [Baseline, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, Week 16]

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

4. Visual Analog Scale (VAS) - Overall Pain Severity [Baseline, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, Week 16]

   VAS for pain consists of 6 questions that assess overall pain, headache, back pain, shoulder pain, pain interference with daily activities, and pain while awake. Participant rates pain on a 10 centimeter (cm) line between two anchors (0= no pain and 10=very severe pain).

5. Euro Quality of Life Questionnaire-5 Dimensions (EQ-5D) Scale - Health State Score [Baseline, Week 4, Week 8, Week 12, Week 16]

   The EQ-5D Health State Score is self-rated health on a vertical, visual analogue scale measured in centimeters (cm) and reported as units on a scale. Best imaginable health state = 10 cm and worst imaginable health state = 0 cm.

6. Euro Quality of Life Questionnaire-5 Dimensions (EQ-5D) Scale - United Kingdom (UK) Population Based Index Score [Baseline, Week 4, Week 8, Week 12, Week 16]

   The EQ-5D is a generic, multidimensional, health-related, quality of life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood. A single score between 1 and 3 is generated for each domain. For each participant, the outcome rating on the 5 domains will be mapped to a single index through an algorithm. The index ranges between 0 and 1, with the higher score indicating a better health state perceived by the participant.

7. Sheehan Disability Scale (SDS) Normal Functioning Total Score [Baseline, Week 4, Week 8, Week 12, Week 16]

   The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work/social/family life. Total scores range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life.

8. Resource Utilisation - Number of Hours Worked Per Week [Baseline, Week 4, Week 8, Week 12, Week 16]

9. Resource Utilisation - Number of Work Hours Missed in the Last 4 Weeks [Week 4, Week 8, Week 12, Week 16]

   Only those participants who missed at least 1 hour of work were included.

10. Resource Utilisation - Number of Work Hours Missed Due to Depression in the Last 4 Weeks [Week 4, Week 8, Week 12, Week 16]

    Only those participants who missed at least 1 hour of work due to depression were included.

11. Resource Utilisation - Number of Visits to Primary Healthcare Provider Due to Depression in the Last 4 Weeks [Week 4, Week 8, Week 12, Week 16]

12. Resource Utilisation - Number of Visits to Other Specialists Due to Depression in the Last 4 Weeks [Week 4, Week 8, Week 12, Week 16]

13. Resource Utilisation - Has the Participant Been Hospitalized Due to Depression in the Last 4 Weeks - Number of Participants With a Yes Response [Week 4, Week 8, Week 12, Week 16]

14. Number of Participants With Adverse Events (AEs) [Baseline through Week 16]

    The list of AEs is located in the Reported Adverse Event module.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Male or female participants of at least 18 years of age who meet criteria for Major Depressive Disorder (MDD), single or recurrent episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV®-TR) disease diagnostic criteria.

2. Participants (receiving or not antidepressant treatment) who, based on investigator criteria, initiate treatment with escitalopram or change their current Alzheimer's Disease (AD) treatment to escitalopram for this current MDD episode, at the initial visit.

3. Must have a baseline score of ≥ 19 on the 17-item Hamilton Depression Rating Scale (HAMD-17) at the initial visit.

4. Must have a baseline score of ≥ 4 in the Clinical Global Impression-Severity Scale (CGI-S) at the initial visit.

5. Have a level of understanding sufficient to provide Informed Consent Document (ICD), and to communicate with the investigators and site personnel.

6. Are judged to be reliable and agree to keep all appointments for clinic visits and procedures required by the protocol.

Exclusion Criteria:

1. Have any current primary Axis I disorder other than MDD, including but not limited to dysthymia.

2. Have a diagnosis of dementia, Alzheimer's disease (AD), or organic brain syndrome; or who are cognitively impaired or who have language problems that prevent them from understanding and/or providing valid answers to the rating scale contents.

3. Concomitant participation in other studies with investigational or marketed products.

4. Are not expected to be able to be monitored throughout the entire study period for reasons unrelated to their illness (for instance, change of residence or healthcare center of reference).

5. Are demonstrating a response or demonstrated a response to the AD treatment for the current depression episode previous to baseline visit.

6. Are investigator site personnel directly affiliated with this study and/or their immediate families. "Immediate family" is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

7. Are employed by Lilly or Boehringer Ingelheim (BI) (that is, employees, temporary contract workers, or designees responsible for the conduct of the study). Immediate family of Lilly or BI employees may participate in Lilly or BI-sponsored clinical trials, but are not permitted to participate at a Lilly or BI facility. "Immediate family" is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

8. Women of childbearing potential who are not using a medically accepted means of contraception (for example, intrauterine device, oral contraceptive, contraceptive patch, implant, Depo-Provera [medroxyprogesterone acetate injectable suspension, Pharmacia & Upjohn], or barrier devices) when engaging in sexual intercourse. Women who are pregnant or breast-feeding may not participate in the study.

9. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.

10. Are judged to be at serious suicidal risk in the opinion of the investigator, and/or if the participant's baseline (Visit 1) HAMD-17 scores on item 3 suicide are 3.

11. Have been treated with a monoamine oxidase inhibitor (MAOI) within 14 days prior to Visit 1 or potential need to use an MAOI during the study or within 5 days after discontinuation of study drug.

12. Require initiation or discontinuation of psychotherapy within 6 weeks prior to enrollment (Visit 1) or at any time during the study.

13. Have any contraindication for the use of duloxetine based on Duloxetine Summary of Product Characteristics (SPC) or any contraindication for the use of escitalopram based on Escitalopram SPC.

14. Have a history of lack of response to duloxetine or escitalopram at a clinically appropriate dose for a minimum of 4 weeks, or have previously completed or withdrawn from this study or any other study investigating duloxetine or escitalopram.

15. Have any previous diagnosis of bipolar disorder, schizophrenia, or other psychotic disorders.

16. Have DSM-IV-defined history of substance abuse or dependence within the past year, excluding nicotine and caffeine.

17. Have serious or unstable cardiovascular, hepatic, renal, respiratory or hematological illness; symptomatic peripheral vascular disease; or other medical (including unstable hypertension and not clinically euthyroid) or psychological conditions that, in the opinion of the investigator, would compromise participation or be likely to require hospitalization during the course of the study.

18. Have had Electroconvulsive Therapy (ECT) or Transcranial Magnetic Stimulation within the past year.

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	Copenhagen		Denmark	DK-2100
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	Angouleme		France	16000
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	Arcachon		France	33120
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	Dole		France	39100
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	Gujan Mestras		France	33470
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	Marseille		France	13385
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	Montpellier		France	F-34295
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	Nimes		France	30029
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	Orvault		France	44000
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	Rennes		France	35000
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	Athens		Greece	10675
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	Haidari, Athens		Greece	12462
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	Thessaloniki		Greece	56429
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	Tripoli		Greece	22100
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	Balassagyarmat		Hungary	2660
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	Budapest		Hungary	1134
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	Chieti		Italy	66100
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	Foggia		Italy	71100
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	Milano		Italy	20121
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	Modena		Italy	41100
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	Parma		Italy	43100
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	Pisa		Italy	56100
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	Siena		Italy	53100
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	Teramo		Italy	64100
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	Terracina		Italy	04019
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	Torino		Italy	10126
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	Beek En Donk		Netherlands	5741 CG
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	Brummen		Netherlands	6971 AD
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	Brunssum		Netherlands	6442 AG
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	Deurne		Netherlands	5751 XJ
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	Heerde		Netherlands	8181 TB
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	Bucharest		Romania	020125
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	Constanta		Romania
34	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	Iasi		Romania	700282
35	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	Timisoara		Romania	300182
36	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	Ljubljana		Slovenia	1000
37	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	Alcala De Henares		Spain	28806
38	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	Barcelona		Spain	08025
39	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	Ferrol		Spain	15405
40	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	Foios		Spain	46134
41	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	Madrid		Spain	28029
42	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	Palma De Mallorca		Spain	07013
43	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	Salamanca		Spain	37003
44	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	Sevilla		Spain	41700
45	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 ph	Vigo		Spain	36205
46	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	Zamora		Spain	49021
47	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	Zaragoza		Spain	50002
48	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	Göteborg		Sweden	41345
49	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	Halmstad		Sweden	302 32
50	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	Lulea		Sweden	SE 972 35
51	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	Lund		Sweden	223 61
52	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	Malmo		Sweden	21135
53	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	Stockholm		Sweden	11486
54	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	Sundsvall		Sweden	SE-85231
55	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	Ankara		Turkey	06000
56	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	Antakya		Turkey	31040
57	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	Capa		Turkey	34390
58	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	Diskapi		Turkey	06110
59	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	Izmir		Turkey	35340
60	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	Sisli		Turkey	80220

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00810069
• Other Study ID Numbers: 12329; F1J-EW-HMGD
• First Posted: Dec 17, 2008
• Last Update Posted: Jun 21, 2011
• Last Verified: May 1, 2011

• Keywords provided by , ,: Major Depressive Disorder; MDD; Depression
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Duloxetine Hydrochloride; Citalopram

Study Results

Participant Flow

Recruitment Details	Participants showing improvement (≥30% baseline score reduction on the HAMD-17) during Period I did not continue to Period II of the study. Qualified participants for Period II were randomized to either Early Intervention Strategy Arm or Delayed Intervention Strategy Arm.
Pre-assignment Detail	Baseline demographics and primary and secondary outcomes are reported only for Period II (Double Blind Treatment Strategy). Adverse events (AEs) are reported for Period I (Acute Escitalopram Treatment) and Period II.

Arm/Group Title	Escitalopram (Acute Treatment)	Early Intervention	Delayed Intervention
Arm/Group Description	Escitalopram 10 milligrams (mg) per day for 4 weeks	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Period Title: Lead-in Period I
STARTED	840	0	0
COMPLETED	566	0	0
NOT COMPLETED	274	0	0
Period Title: Lead-in Period I
STARTED	0	282	284
COMPLETED	0	226	212
NOT COMPLETED	0	56	72

Baseline Characteristics

Arm/Group Title	Early Intervention	Delayed Intervention	Total
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.	Total of all reporting groups
Overall Participants	282	284	566
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.3 (13.48)	47.4 (12.72)	47.9 (13.10)
Sex: Female, Male (Count of Participants)
Female	196 69.5%	197 69.4%	393 69.4%
Male	86 30.5%	87 30.6%	173 30.6%
Region of Enrollment (participants) [Number]
France	54 19.1%	54 19%	108 19.1%
Hungary	6 2.1%	6 2.1%	12 2.1%
Slovenia	6 2.1%	4 1.4%	10 1.8%
Greece	10 3.5%	10 3.5%	20 3.5%
Spain	71 25.2%	73 25.7%	144 25.4%
Turkey	10 3.5%	10 3.5%	20 3.5%
Romania	18 6.4%	18 6.3%	36 6.4%
Denmark	12 4.3%	14 4.9%	26 4.6%
Netherlands	5 1.8%	4 1.4%	9 1.6%
Italy	19 6.7%	20 7%	39 6.9%
Sweden	71 25.2%	71 25%	142 25.1%
Race (participants) [Number]
Black or African American	2 0.7%	2 0.7%	4 0.7%
White	280 99.3%	282 99.3%	562 99.3%
Clinical Global Impression-Major Depressive Disorder-Severity (CGI-MDD-S) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.6 (0.59)	4.6 (0.64)	4.6 (0.62)
Quick Inventory of Depressive Symptomatology-Self Reported (QIDS16SR) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	16.4 (3.82)	16.7 (3.43)	16.5 (3.63)
17-item Hamilton Depression Rating Scale (HAMD-17) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	24.0 (3.57)	24.4 (3.83)	24.2 (3.70)
Visual Analog Scale (VAS) Overall Pain Severity (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.6 (2.76)	3.8 (2.81)	3.7 (2.78)
Sheehan Disability Scale (SDS) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	19.9 (5.12)	19.9 (5.52)	19.9 (5.32)
Euro Quality of Life-5 Dimensions Questionnaire (EQ-5D) Score (units on a scale) [Mean (Standard Deviation) ]
EQ-5D UK Population-based Index Score	0.40 (0.291)	0.34 (0.312)	0.37 (0.303)
Health State Score	4.23 (1.873)	3.86 (1.704)	4.05 (1.798)
Number of work hours worked per week (hours) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [hours]	38.0 (8.30)	37.2 (9.53)	37.6 (8.94)
Number of work hours missed in the last 4 weeks (hours) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [hours]	86.9 (63.09)	87.5 (66.32)	87.2 (64.67)
Number of work hours missed due to depression in the last 4 weeks (hours) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [hours]	88.8 (64.14)	88.5 (67.05)	88.6 (65.56)
Number of visits to primary healthcare provider due to depression in the last 4 weeks (visits) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [visits]	1.6 (0.95)	1.8 (1.10)	1.7 (1.03)
Number of visits to emergency room or equivalent facility due to depression in the last 4 weeks (visits) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [visits]	1.1 (0.27)	1.1 (0.48)	1.1 (0.40)
Number of visits to other specialists due to depression in the last 4 weeks (visits) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [visits]	2.0 (1.44)	1.6 (0.98)	1.8 (1.26)
Has the participant been hospitalized due to depression in the last 4 weeks (participants) [Number]
Yes	4 1.4%	5 1.8%	9 1.6%
No	277 98.2%	278 97.9%	555 98.1%
Unknown	1 0.4%	0 0%	1 0.2%
Missing	0 0%	1 0.4%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Time to Confirmed Response by ≥ 50% Change From Baseline Reduction in the Hamilton Depression Rating Scale-17 Items (HAMD-17)
Description	Time to confirmed response is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed response defined as ≥ 50% baseline score reduction on the HAMD-17 for 2 consecutive visits. The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale, e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).
Time Frame	Week 4 through Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Median (95% Confidence Interval) [weeks]	6.4	8.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Kaplan-Meier Estimates (weeks): analysis of early intervention versus delayed intervention strategies
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.213
	Comments	P-value is for early intervention strategy versus delayed intervention strategy.
	Method	Kaplan-Meier Analysis
	Comments	Kaplan-Meier analysis with Wilcoxon test to compare strategies.

2. Primary Outcome

Title	Estimated Probability of Not Reaching Confirmed Response at 12 Weeks Based on the Survival Function for the Time to Confirmed Response
Description	Survival function is estimating the probability of participants not achieving confirmed response after 12 weeks. Confirmed response is defined as >=50% change from baseline reduction in the Hamilton Depression Rating Scale-17 Items (HAMD-17). The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).
Time Frame	Week 4 through Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Mean (95% Confidence Interval) [estimated probability (percent)]	28	26

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Survival function estimated over a 12 week period (Week 4 through Week 16): analysis of early intervention versus delayed intervention strategies
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.653
	Comments	P-value is for comparison of early intervention versus delayed intervention as a function of survival rate over a 12 week period (Week 4 through Week 16).
	Method	Kaplan Meier analysis
	Comments	P-value for comparison of rates is based on normal approximation using Greenwood's estimation for standard error.
Method of Estimation	Estimation Parameter	survival rate difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time to Confirmed Response as Defined by ≥ 50% Reduction From Baseline Reduction in the 16-Item Quick Inventory of Depressive Symptomatology Self Report (QIDS16SR) That is Reported for Two Consecutive Visits
Description	Time to confirmed response is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed response. QIDS16SR is a 16-item participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27 with higher scores indicative of greater severity.
Time Frame	Week 4 through Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Median (95% Confidence Interval) [weeks]	6.0	6.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Analysis of early intervention strategy versus delayed intervention strategy
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.947
	Comments	P-value is for early intervention strategy versus delayed intervention strategy.
	Method	Kaplan Meier analysis
	Comments	Kaplan-Meier analysis with Wilcoxon test to compare strategies.

4. Secondary Outcome

Title	Time to Confirmed Remission as Defined by a 16-Item Quick Inventory of Depressive Symptomatology Self Report (QIDS16SR) Score of ≤ 5 That is Maintained for Two Consecutive Visits.
Description	Time to confirmed remission is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed remission. A 16-item participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27 with higher scores indicative of greater severity.
Time Frame	Week 4 through Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	280	284
Median (95% Confidence Interval) [weeks]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Analysis of early intervention strategy versus delayed intervention strategy
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.597
	Comments	P-value is for early intervention versus delayed intervention strategies.
	Method	Kaplan-Meier analysis
	Comments	Kaplan-Meier analysis with Wilcoxon test to compare strategies

5. Secondary Outcome

Title	Clinical Global Impressions of Severity (CGI-S) Scale
Description	Measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants).
Time Frame	Baseline, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Baseline (n=282, 284)	4.6 (0.59)	4.6 (0.64)
Week 4 (n=281, 284)	4.3 (0.61)	4.3 (0.66)
Week 6 (n=271, 277)	3.6 (0.88)	3.7 (0.97)
Week 8 (n=254, 254)	3.2 (1.11)	3.3 (1.15)
Week 10 (n=231, 236)	2.8 (1.17)	2.9 (1.22)
Week 12 (n=203, 214)	2.6 (1.21)	2.7 (1.20)
Week 14 (n=184, 194)	2.4 (1.13)	2.5 (1.17)
Week 16 (n=178, 182)	2.2 (1.09)	2.2 (1.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 6
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.624
	Comments	P-value for Week 6: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.208
	Comments	P-value for Week 8: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed Models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments	P-value for Week 10: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.37 to -0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments	P-value for Week 12: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interactions, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.35 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.181
	Comments	P-value for Week 14: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 16
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.994
	Comments	P-value for Week 16: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.20 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

6. Secondary Outcome

Title	Visual Analog Scale (VAS) - Overall Pain Severity
Description	VAS for pain consists of 6 questions that assess overall pain, headache, back pain, shoulder pain, pain interference with daily activities, and pain while awake. Participant rates pain on a 10 centimeter (cm) line between two anchors (0= no pain and 10=very severe pain).
Time Frame	Baseline, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Baseline (n=282, 284)	3.6 (2.76)	3.8 (2.81)
Week 4 (n=281, 283)	3.0 (2.54)	3.5 (2.77)
Week 6 (n=270, 271)	2.6 (2.41)	3.3 (2.85)
Week 8 (n=245, 241)	2.4 (2.53)	3.0 (2.70)
Week 10 (n=207, 204)	2.4 (2.48)	2.7 (2.60)
Week 12 (n=170, 181)	2.1 (2.42)	2.6 (2.66)
Week 14 (n=151, 152)	2.0 (2.35)	2.5 (2.54)
Week 16 (n=143, 152)	2.0 (2.32)	2.3 (2.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 6
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	P-value for Week 6: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -0.98 to -0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	P-value for Week 8: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -0.87 to -0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.445
	Comments	P-value for Week 10: analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.55 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.169
	Comments	P-value for Week 12: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.71 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.21
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.393
	Comments	P-value for Week 14: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.23
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 16
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.510
	Comments	P-value for Week 16: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline scores and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.61 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.23
	Estimation Comments

7. Secondary Outcome

Title	Euro Quality of Life Questionnaire-5 Dimensions (EQ-5D) Scale - Health State Score
Description	The EQ-5D Health State Score is self-rated health on a vertical, visual analogue scale measured in centimeters (cm) and reported as units on a scale. Best imaginable health state = 10 cm and worst imaginable health state = 0 cm.
Time Frame	Baseline, Week 4, Week 8, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	283
Baseline (n=281, 283)	4.2 (1.87)	3.9 (1.70)
Week 4 (n=282, 280)	4.9 (1.76)	4.5 (1.62)
Week 8 (n=244, 237)	5.7 (1.88)	5.4 (1.94)
Week 12 (n=169, 177)	5.9 (1.96)	5.8 (1.98)
Week 16 (n=142, 153)	6.5 (1.90)	6.5 (1.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.401
	Comments	P-value for Week 8: Analysis of early intervention versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.618
	Comments	P-value for Week 12: Analysis of early intervention versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.27 to 0.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 16
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.856
	Comments	P-value for Week 16: Analysis of early intervention versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments

8. Secondary Outcome

Title	Euro Quality of Life Questionnaire-5 Dimensions (EQ-5D) Scale - United Kingdom (UK) Population Based Index Score
Description	The EQ-5D is a generic, multidimensional, health-related, quality of life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood. A single score between 1 and 3 is generated for each domain. For each participant, the outcome rating on the 5 domains will be mapped to a single index through an algorithm. The index ranges between 0 and 1, with the higher score indicating a better health state perceived by the participant.
Time Frame	Baseline, Week 4, Week 8, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	279	282
Baseline (n=279, 282)	0.4 (0.29)	0.3 (0.31)
Week 4 (n=279, 282)	0.5 (0.30)	0.5 (0.32)
Week 8 (n=244, 238)	0.7 (0.25)	0.6 (0.30)
Week 12 (n=168, 178)	0.7 (0.22)	0.6 (0.28)
Week 16 (n=143, 153)	0.7 (0.24)	0.7 (0.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments	P-value for Week 8: Analysis of early versus delayed intervention LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.10 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.02
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.071
	Comments	P-value for Week 12: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.02
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 16
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.792
	Comments	P-value for Week 16: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.03
	Estimation Comments

9. Secondary Outcome

Title	Sheehan Disability Scale (SDS) Normal Functioning Total Score
Description	The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work/social/family life. Total scores range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life.
Time Frame	Baseline, Week 4, Week 8, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	216	217
Baseline (n=216, 217)	19.9 (5.12)	19.9 (5.52)
Week 4 (n=215, 215)	16.9 (6.36)	17.5 (6.11)
Week 8 (n=186, 188)	13.5 (6.50)	14.0 (6.79)
Week 12 (n=140, 144)	12.1 (6.84)	13.2 (7.51)
Week 16 (n=113, 121)	10.3 (7.27)	10.2 (6.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.597
	Comments	P-value for Week 8: Analysis of early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -1.74 to 1.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.70
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.360
	Comments	P-value for Week 12: Analysis for early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.68
	Confidence Interval	(2-Sided) 95%; -2.13 to 0.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.74
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Repeated Measurements Analysis: Early Intervention versus Delayed Intervention Strategy at Week 16
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.937
	Comments	P-value for Week 16: Analysis for early versus delayed intervention strategies LS Mean/Estimate
	Method	Mixed Models Analysis
	Comments	Mixed models repeated measures with fixed effects for strategy, country, visit, strategy-by-visit interaction, baseline score and baseline-by-visit
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -1.52 to 1.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.81
	Estimation Comments

10. Primary Outcome

Title	Time to Confirmed Remission by a Hamilton Depression Rating Scale-17 Items (HAMD-17) Score of ≤ 7 That is Maintained for Two Consecutive Visits
Description	Time to confirmed remission is defined as the time from the day of study randomization (Visit 2) to the date of first observation of confirmed remission defined as a score on the HAMD-17 of ≤ 7 for 2 consecutive visits. The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).
Time Frame	Week 4 through Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Median (95% Confidence Interval) [weeks]	12.9	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Kaplan-Meier estimates (weeks): analysis of early intervention versus delayed intervention strategies
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.075
	Comments	P-value is for early intervention strategy versus delayed intervention strategy.
	Method	Kaplan-Meier analysis
	Comments	Kaplan-Meier analysis with Wilcoxon test to compare strategies

11. Primary Outcome

Title	Estimated Probability of Not Reaching Confirmed Remission at 12 Weeks Based on the Survival Function for the Time to Confirmed Remission
Description	Survival function is estimating the probability of participants not achieving confirmed remission. Confirmed remission is defined as a Hamilton Depression Rating Scale-17 Items (HAMD-17) Score of ≤ 7 that is maintained for two consecutive visits. The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe).
Time Frame	Week 4 through Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Mean (95% Confidence Interval) [estimated probability (percent)]	52	59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Intervention, Delayed Intervention
	Comments	Survival function estimated over a 12 week period (Week 4 through Week 16): analysis of early intervention versus delayed intervention strategies
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.116
	Comments	P-value is for comparison of early intervention versus delayed intervention as a function of survival rate over a 12 week period (Week 4 through Week 16).
	Method	Kaplan-Meier analysis
	Comments	P-value for comparison of rates is based on normal approximation using Greenwood's estimation for standard error.
Method of Estimation	Estimation Parameter	Survival rate difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Resource Utilisation - Number of Hours Worked Per Week
Time Frame	Baseline, Week 4, Week 8, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population, which included all randomized participants with at least 1 post-randomization assessment available after Week 4. For efficacy analyses, participants were included in the analysis if they had a baseline and a post-baseline (after Week 4) value of the variable in question.

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Week 4 (n=153, 159)	37.7 (11.61)	38.6 (13.33)
Week 8 (n=136, 141)	37.9 (9.08)	37.7 (8.42)
Week 12 (n=119, 115)	37.7 (7.40)	38.1 (13.72)
Week 16 (n=96, 96)	37.2 (7.80)	38.0 (14.74)

13. Secondary Outcome

Title	Resource Utilisation - Number of Work Hours Missed in the Last 4 Weeks
Description	Only those participants who missed at least 1 hour of work were included.
Time Frame	Week 4, Week 8, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population, which included all randomized participants with at least 1 post-randomization assessment available after Week 4. For efficacy analyses, participants were included in the analysis if they had a baseline and a post-baseline (after Week 4) value of the variable in question.

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Week 4 (n=73, 89)	88.6 (64.30)	95.0 (67.40)
Week 8 (n=54, 67)	92.5 (66.12)	102.3 (69.38)
Week 12 (n=38, 56)	85.0 (65.73)	104.5 (68.72)
Week 16 (n=25, 39)	91.5 (63.49)	126.4 (63.64)

14. Secondary Outcome

Title	Resource Utilisation - Number of Work Hours Missed Due to Depression in the Last 4 Weeks
Description	Only those participants who missed at least 1 hour of work due to depression were included.
Time Frame	Week 4, Week 8, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population, which included all randomized participants with at least 1 post-randomization assessment available after Week 4. For efficacy analyses, participants were included in the analysis if they had a baseline and a post-baseline (after Week 4) value of the variable in question.

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Week 4 (n=70, 86)	90.6 (64.98)	95.1 (67.90)
Week 8 (n=47, 61)	98.5 (65.34)	109.7 (68.08)
Week 12 (n=31, 52)	98.7 (64.32)	111.4 (66.42)
Week 16 (n=24, 38)	91.9 (64.99)	126.0 (63.40)

15. Secondary Outcome

Title	Resource Utilisation - Number of Visits to Primary Healthcare Provider Due to Depression in the Last 4 Weeks
Time Frame	Week 4, Week 8, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population, which included all randomized participants with at least 1 post-randomization assessment available after Week 4. For efficacy analyses, participants were included in the analysis if they had a baseline and a post-baseline (after Week 4) value of the variable in question.

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Week 4 (n=36, 55)	1.5 (1.00)	1.6 (1.04)
Week 8 (n=14, 22)	1.1 (0.27)	1.7 (1.13)
Week 12 (n=8, 12)	1.3 (0.46)	1.6 (1.00)
Week 16 (n=4, 7)	2.0 (2.00)	1.6 (1.13)

16. Secondary Outcome

Title	Resource Utilisation - Number of Visits to Other Specialists Due to Depression in the Last 4 Weeks
Time Frame	Week 4, Week 8, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population, which included all randomized participants with at least 1 post-randomization assessment available after Week 4. For efficacy analyses, participants were included in the analysis if they had a baseline and a post-baseline (after Week 4) value of the variable in question.

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Week 4 (n=25, 16)	2.2 (2.05)	1.7 (0.87)
Week 8 (n=8, 8)	1.6 (0.74)	1.9 (1.13)
Week 12 (n=3, 2)	1.7 (1.15)	1.0 (0.00)
Week 16 (n=2, 1)	2.0 (0.00)	3.0 (NA)

17. Secondary Outcome

Title	Resource Utilisation - Has the Participant Been Hospitalized Due to Depression in the Last 4 Weeks - Number of Participants With a Yes Response
Time Frame	Week 4, Week 8, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Week 4	1 0.4%	0 0%
Week 8	0 0%	0 0%
Week 12	0 0%	0 0%
Week 16	0 0%	0 0%

18. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	The list of AEs is located in the Reported Adverse Event module.
Time Frame	Baseline through Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Population

Arm/Group Title	Early Intervention	Delayed Intervention
Arm/Group Description	Duloxetine flexible dose (60 or 120 milligrams [mg] daily) for 12 weeks	Escitalopram flexible dose (10 to 20 milligrams [mg] daily) for 4 weeks. Then in participants with no-response, switch treatment to duloxetine flexible dose (60 or 120 mg daily) for 8 weeks. In participants with a response continue treatment with escitalopram (10 to 20 milligrams [mg] daily) for 8 weeks.
Measure Participants	282	284
Number of participants with adverse events	112 39.7%	101 35.6%
Number of participants with serious adverse events	8 2.8%	4 1.4%

Adverse Events

Adverse Event Reporting Description	Adverse events section reports events for participants in Period I (840) and Period II (282 early intervention, 284 delayed intervention). During Period II (Week 8), delayed intervention participants were subdivided by response to treatment (165 non-responders, 83 responders) and adverse events experienced by these participants are reported here.
Arm/Group Title	Escitalopram (Acute Treatment)		Delayed Intervention (Double Blind)		Early Intervention (Double Blind)		Delayed Intervention Responders		Delayed Intervention Non-Responders
Arm/Group Description	Escitalopram 10 mg per day for 4 weeks (one 10 mg-capsule)		Escitalopram 10 to 20 mg per day for 4 weeks (one or two 10 mg capsule[s]). Then, non-responders switched to duloxetine 60 or 120 mg per day for 8 weeks, and responders continued on escitalopram 10 to 20 mg per day for 8 weeks.		Duloxetine flexible dose (60 or 120 milligram [mg] daily) for 12 weeks.		Escitalopram 10 to 20 mg per day for 8 weeks.		Duloxetine 60 or 120 mg per day for 8 weeks.
All Cause Mortality
	Escitalopram (Acute Treatment)		Delayed Intervention (Double Blind)		Early Intervention (Double Blind)		Delayed Intervention Responders		Delayed Intervention Non-Responders
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Escitalopram (Acute Treatment)		Delayed Intervention (Double Blind)		Early Intervention (Double Blind)		Delayed Intervention Responders		Delayed Intervention Non-Responders
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/840 (0.5%)		4/284 (1.4%)		8/282 (2.8%)		1/83 (1.2%)		1/165 (0.6%)
Cardiac disorders
Angina pectoris	0/840 (0%)	0	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Gastrointestinal disorders
Constipation	1/840 (0.1%)	1	0/284 (0%)	0	0/282 (0%)	0	0/83 (0%)	0	0/165 (0%)	0
Crohn's disease	0/840 (0%)	0	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Infections and infestations
Kidney infection	0/840 (0%)	0	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Injury, poisoning and procedural complications
Drug exposure during pregnancy	1/840 (0.1%)	1	0/284 (0%)	0	0/282 (0%)	0	0/83 (0%)	0	0/165 (0%)	0
Eye injury	0/840 (0%)	0	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Investigations
Intraocular pressure increased	0/840 (0%)	0	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/840 (0%)	0	1/284 (0.4%)	1	0/282 (0%)	0	0/83 (0%)	0	1/165 (0.6%)	1
Pancreatic carcinoma	0/840 (0%)	0	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Nervous system disorders
Cerebral haemorrhage	0/840 (0%)	0	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Psychiatric disorders
Abnormal behaviour	0/840 (0%)	0	1/284 (0.4%)	1	0/282 (0%)	0	0/83 (0%)	0	0/165 (0%)	0
Confusional state	0/840 (0%)	0	1/284 (0.4%)	1	0/282 (0%)	0	0/83 (0%)	0	0/165 (0%)	0
Depression	1/840 (0.1%)	1	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Insomnia	0/840 (0%)	0	1/284 (0.4%)	1	0/282 (0%)	0	0/83 (0%)	0	0/165 (0%)	0
Major depression	0/840 (0%)	0	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Suicidal ideation	1/840 (0.1%)	1	0/284 (0%)	0	0/282 (0%)	0	0/83 (0%)	0	0/165 (0%)	0
Suicide attempt	0/840 (0%)	0	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Renal and urinary disorders
Urinary retention	0/840 (0%)	0	0/284 (0%)	0	1/282 (0.4%)	1	0/83 (0%)	0	0/165 (0%)	0
Other (Not Including Serious) Adverse Events
	Escitalopram (Acute Treatment)		Delayed Intervention (Double Blind)		Early Intervention (Double Blind)		Delayed Intervention Responders		Delayed Intervention Non-Responders
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	245/840 (29.2%)		99/284 (34.9%)		110/282 (39%)		33/83 (39.8%)		60/165 (36.4%)
Gastrointestinal disorders
Abdominal pain upper	10/840 (1.2%)	10	4/284 (1.4%)	4	1/282 (0.4%)	1	1/83 (1.2%)	1	3/165 (1.8%)	3
Constipation	14/840 (1.7%)	14	2/284 (0.7%)	2	7/282 (2.5%)	7	0/83 (0%)	0	2/165 (1.2%)	2
Diarrhoea	16/840 (1.9%)	16	6/284 (2.1%)	6	7/282 (2.5%)	7	1/83 (1.2%)	1	4/165 (2.4%)	4
Dry mouth	26/840 (3.1%)	28	3/284 (1.1%)	3	10/282 (3.5%)	10	2/83 (2.4%)	2	1/165 (0.6%)	1
Dyspepsia	0/840 (0%)	0	2/284 (0.7%)	2	2/282 (0.7%)	2	1/83 (1.2%)	1	1/165 (0.6%)	1
Flatulence	3/840 (0.4%)	3	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Gastric disorder	1/840 (0.1%)	1	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Nausea	63/840 (7.5%)	63	5/284 (1.8%)	5	14/282 (5%)	14	1/83 (1.2%)	1	4/165 (2.4%)	4
Vomiting	5/840 (0.6%)	5	2/284 (0.7%)	2	0/282 (0%)	0	1/83 (1.2%)	1	1/165 (0.6%)	1
General disorders
Fatigue	7/840 (0.8%)	7	7/284 (2.5%)	7	6/282 (2.1%)	6	4/83 (4.8%)	4	2/165 (1.2%)	2
Malaise	2/840 (0.2%)	2	2/284 (0.7%)	2	0/282 (0%)	0	0/83 (0%)	0	2/165 (1.2%)	2
Immune system disorders
Seasonal allergy	1/840 (0.1%)	1	2/284 (0.7%)	2	1/282 (0.4%)	1	0/83 (0%)	0	2/165 (1.2%)	2
Infections and infestations
Influenza	3/840 (0.4%)	3	3/284 (1.1%)	3	5/282 (1.8%)	5	2/83 (2.4%)	2	1/165 (0.6%)	1
Nasopharyngitis	10/840 (1.2%)	10	12/284 (4.2%)	13	5/282 (1.8%)	5	3/83 (3.6%)	4	9/165 (5.5%)	9
Investigations
Biopsy uterus	0/840 (0%)	0	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Blood pressure diastolic decreased	3/840 (0.4%)	3	2/284 (0.7%)	2	5/282 (1.8%)	5	1/83 (1.2%)	1	0/165 (0%)	0
Weight decreased	4/840 (0.5%)	4	4/284 (1.4%)	4	1/282 (0.4%)	1	2/83 (2.4%)	2	2/165 (1.2%)	2
Weight increased	1/840 (0.1%)	1	2/284 (0.7%)	2	0/282 (0%)	0	2/83 (2.4%)	2	0/165 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/840 (0.1%)	1	2/284 (0.7%)	3	1/282 (0.4%)	1	1/83 (1.2%)	2	1/165 (0.6%)	1
Back pain	3/840 (0.4%)	4	5/284 (1.8%)	5	2/282 (0.7%)	2	1/83 (1.2%)	1	4/165 (2.4%)	4
Muscle contracture	0/840 (0%)	0	2/284 (0.7%)	2	0/282 (0%)	0	0/83 (0%)	0	2/165 (1.2%)	2
Nervous system disorders
Dizziness	15/840 (1.8%)	15	5/284 (1.8%)	5	11/282 (3.9%)	11	3/83 (3.6%)	3	2/165 (1.2%)	2
Headache	43/840 (5.1%)	51	24/284 (8.5%)	28	22/282 (7.8%)	43	5/83 (6%)	7	17/165 (10.3%)	19
Somnolence	6/840 (0.7%)	6	2/284 (0.7%)	2	0/282 (0%)	0	0/83 (0%)	0	2/165 (1.2%)	2
Tension headache	0/840 (0%)	0	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Tremor	7/840 (0.8%)	7	2/284 (0.7%)	2	3/282 (1.1%)	3	1/83 (1.2%)	1	1/165 (0.6%)	1
Psychiatric disorders
Anxiety	10/840 (1.2%)	10	3/284 (1.1%)	4	2/282 (0.7%)	2	1/83 (1.2%)	1	2/165 (1.2%)	3
Insomnia	10/840 (1.2%)	10	4/284 (1.4%)	4	6/282 (2.1%)	9	1/83 (1.2%)	1	3/165 (1.8%)	3
Loss of libido	3/840 (0.4%)	3	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Panic attack	2/840 (0.2%)	2	2/284 (0.7%)	2	0/282 (0%)	0	1/83 (1.2%)	1	1/165 (0.6%)	1
Renal and urinary disorders
Urinary retention	0/840 (0%)	0	2/284 (0.7%)	2	0/282 (0%)	0	0/83 (0%)	0	2/165 (1.2%)	2
Reproductive system and breast disorders
Ejaculation delayed	1/840 (0.1%)	1	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Metrorrhagia	1/840 (0.1%)	1	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Vaginal haemorrhage	1/840 (0.1%)	1	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	0/840 (0%)	0	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Dyspnoea	1/840 (0.1%)	1	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/840 (0%)	0	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Hyperhidrosis	20/840 (2.4%)	20	6/284 (2.1%)	6	12/282 (4.3%)	12	5/83 (6%)	5	1/165 (0.6%)	1
Night sweats	0/840 (0%)	0	2/284 (0.7%)	2	2/282 (0.7%)	2	0/83 (0%)	0	2/165 (1.2%)	2
Vascular disorders
Diastolic hypertension	1/840 (0.1%)	1	1/284 (0.4%)	1	0/282 (0%)	0	1/83 (1.2%)	1	0/165 (0%)	0
Hot flush	2/840 (0.2%)	2	0/284 (0%)	0	5/282 (1.8%)	5	0/83 (0%)	0	0/165 (0%)	0
Hypertension	19/840 (2.3%)	19	2/284 (0.7%)	2	5/282 (1.8%)	5	0/83 (0%)	0	2/165 (1.2%)	2
Hypotension	5/840 (0.6%)	5	2/284 (0.7%)	3	1/282 (0.4%)	1	1/83 (1.2%)	2	1/165 (0.6%)	1

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.