Study Evaluating Desvenlafaxine Succinate Sustained Release (DVS SR) vs. Escitalopram in Postmenopausal Women

• Sponsor: Wyeth is now a wholly owned subsidiary of Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00406640
• Collaborator: (none)
• Enrollment: 595
• Locations: 70
• Arms: 2
• Duration (Months): 22
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Desvenlafaxine succinate (DVS) is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). This study will investigate the safety, efficacy, and tolerability of DVS SR versus escitalopram in women with major depressive disorder (MDD) who are postmenopausal.

Condition or Disease	Intervention/Treatment	Phase
Depression; Depressive Disorder; Depressive Disorder, Major	Drug: Desvenlafaxine succinate sustained-release (DVS SR); Drug: Escitalopram	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 595 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, 8-Week Double-Blind Acute Phase Followed By a 6-Month Continuation Phase (Open-Label Or Double-Blind) Study to Evaluate the Efficacy, Safety, and Tolerability of DVS SR Versus Escitalopram in Postmenopausal Women With Major Depressive Disorder
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Oct 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A	Drug: Desvenlafaxine succinate sustained-release (DVS SR); flexible dose of DVS 50-100 or 200 mg every day during 56 days. Extension until 6 months.
Active Comparator: B	Drug: Escitalopram; Flexible dose of Escitalopram 10 or 20 mg every day during 56 days. Extension until 6 months.

Outcome Measures

Primary Outcome Measures

1. Change in Hamilton Psychiatric Rating Scale for Depression (HAM-D17) Score From Baseline to Week 8 [Baseline and 8 weeks]

   HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Items are scored on either a 3 point (0 to 2) or a 5 point scale (0 to 4) with 0=none/absent and 4=most severe,for a maximum total score of 50. Change= 8 week adjusted mean HAM-D17 minus baseline adjusted mean HAM-D17.

Secondary Outcome Measures

1. Percentage of Patients Achieving Response to Treatment at Final On-therapy Evaluation (Acute Phase) [8 weeks]

   A response is defined as ≥ 50% decrease from baseline on Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.

2. Percentage of Patients Achieving Remission at Final On-therapy Evaluation (Acute Phase) [8 weeks]

   Remission is defined as a Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score of ≤ 7. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.

3. Clinical Global Impression Improvement (CGI-I) Score at 8 Weeks [8 weeks]

   CGI-I is a global rating scale that measures disease improvement. Using a 7-point scale, the clinician rates how much the patient's illness has improved or worsened relative to the baseline status (1= very much improved; 7= very much worse).

4. Change in Clinical Global Impression Severity (CGI-S) Score From Baseline to Week [Baseline and 8 weeks]

   CGI-S is a global rating scale that measures the severity of a patient's disease. Using a 7-point scale, the clinician rates the severity of the patient's mental illness at the time of the assessment, relative to the clinician's experience with patients who have the same diagnosis (1= normal; 7= extremely ill).

5. Change in Hamilton Psychiatric Rating Scale for Anxiety From Baseline to Week 8 (HAM-A) Score [Baseline and Week 8]

   The HAM-A is a standardized, clinician-administered rating scale that assesses 14 items characteristically associated with major anxiety disorders. Items are scaled 0 - 4 (0=none and 4=very severe), with a maximum total score of 56. Change= 8 week adjusted mean HAM-A total score minus baseline adjusted mean total score.

6. Change in Dimension Health State EuroQol (EQ-5D) Score From Baseline to Week 8 [Baseline and week 8]

   EQ-5D is a standardized, subject-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme problems) and a single index value characterizing current health status using a 100-point visual analog scale (0=worst, 100=best). EQ-5D summary index is obtained with a formula that weights each level of the dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health). Change=8 week score minus baseline score.

7. Percentage of Responders Maintaining Response to Treatment at Final On-therapy Evaluation (Double Blind Continuation Phase) [6 months]

   Patients achieving a response to treatment at the end of the 8-week acute double blind (DB) phase continued the same treatment in a 6-month DB continuation phase and were evaluated to see if the response was maintained. A response is defined as ≥ 50% decrease from baseline on Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.

8. Percentage of Responders Achieving Remission at Final On-therapy Evaluation (Double Blind Continuation Phase) [6 months]

   Patients achieving a response to treatment at the end of the 8-week acute double blind (DB) phase continued the same treatment in a 6-month DB continuation phase and were evaluated to see if remission was achieved. Remission is defined as a Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score of ≤ 7. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.

9. Percentage of Responders Improving Response to Remission During 6-month Double Blind Continuation Phase [6 months]

   Patients achieving a response to treatment (Responders) at the end of the 8-week acute double blind (DB) phase continued into a 6-month DB phase. Responders without remission at 8 weeks were assessed for remission status during the 6-month continuation. Remission defined as a Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score ≤ 7. HAM-D17 is a standardized, clinician-administered rating scale assessing 17 items characteristically associated with major depression. Individual items scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.

10. Percentage of Non-Responders Achieving Response at Final Evaluation of 6-month Open-Label (OL)Extension Phase [6 months]

    Patients who didn't achieve a response to treatment at the end of the 8-week acute double blind phase entered into an OL treatment phase with DVS SR for 6 months and were evaluated to see if a response was achieved. A response is defined as ≥ 50% decrease from baseline on Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.

11. Percentage of Non-Responders Achieving Remission at Final Evaluation of 6-month Open-Label Extension Phase [6 months]

    Patients who did not achieve a response to treatment at the end of the 8-week acute double blind phase entered into an open label (OL) treatment phase with DVS SR for 6 months and were evaluated to see if remission was achieved. Remission is defined as a Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score of ≤ 7. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.

12. Discontinuation-Emergent Signs and Symptoms (DESS) Total Score [6 months]

    DESS is a clinician-administered 43-item assessment that evaluates discontinuation-emergent symptoms resulting from the withdrawal from test article. The DESS total score is the sum of the number of new symptoms and old (but worse) symptoms that appeared during tapering of the test article. A higher score indicates more symptoms. The DESS score was assessed by status of taper.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 70 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Postmenopausal women between the ages of 40 and 70 years, inclusive.

• A primary diagnosis of MDD, single or recurrent episode, without psychotic features using the modified MINI International Neuropsychiatric Interview (MINI).

• Montgomery-Asberg Depression Rating Scale (MADRS) total score > or = 22 at the screening and baseline visit.

Exclusion Criteria:

• Use of oral estrogen-, progestin-, androgen-, or Selective Estrogen Receptor Modulator (SERM)-containing drug products 8 weeks before baseline.

• Current (within 12 months) psychoactive substance abuse or dependence (including alcohol), manic episode, post-traumatic stress disorder, obsessive-compulsive disorder, or a lifetime diagnosis of bipolar or psychotic disorder.

• A history or active presence of clinically important medical disease.

Additional criteria apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Peoria	Arizona	United States	85381
2		Pasadena	California	United States	91107
3		San Diego	California	United States	92103
4		San Diego	California	United States	92108
5		Denver	Colorado	United States	80212
6		Cromwell	Connecticut	United States	06416
7		Farmington	Connecticut	United States	06030
8		Waterbury	Connecticut	United States	06708
9		Brooksville	Florida	United States	34613
10		Coral Springs	Florida	United States	33065
11		Fort Meyers	Florida	United States	33912
12		Gainesville	Florida	United States	32607
13		Maitland	Florida	United States	32751
14		Atlanta	Georgia	United States	30328
15		Roswell	Georgia	United States	30076
16		Northfield	Illinois	United States	60093
17		Oak Brook	Illinois	United States	60523
18		Overland Park	Kansas	United States	66211
19		Witchita	Kansas	United States	67214
20		New Orleans	Louisiana	United States	70115
21		Shreveport	Louisiana	United States	71130
22		Baltimore	Maryland	United States	21208
23		Boston	Massachusetts	United States	02114
24		Fall River	Massachusetts	United States	02721
25		St. Paul	Minnesota	United States	55101
26		Las Vegas	Nevada	United States	89106
27		Piscataway	New Jersey	United States	08854
28		Elmsford	New York	United States	10523
29		Holliswood	New York	United States	11423
30		New York	New York	United States	10032
31		New York	New York	United States	10128
32		Syracuse	New York	United States	13210
33		Raleigh	North Carolina	United States	27612
34		Oklahoma City	Oklahoma	United States	73103
35		Philadelphia	Pennsylvania	United States	19104
36		Pittsburgh	Pennsylvania	United States	15206
37		Pittsburgh	Pennsylvania	United States	15213
38		East Providence	Rhode Island	United States	02914
39		Lincoln	Rhode Island	United States	02865
40		Charleston	South Carolina	United States	29407
41		Columbia	South Carolina	United States	29201
42		Mt. Pleasant	South Carolina	United States	29464
43		Memphis	Tennessee	United States	38117
44		Bellaire	Texas	United States	77401
45		Dallas	Texas	United States	75235
46		Denton	Texas	United States	76201
47		Houston	Texas	United States	77090
48		Burlington	Vermont	United States	05401
49		Charlottesville	Virginia	United States	22903
50		Richmond	Virginia	United States	23230
51		Morgantown	West Virginia	United States	26506
52		Middleton	Wisconsin	United States	53562
53		Buenos Aires		Argentina	1062
54		Buenos Aires		Argentina	1119
55		Buenos Aires		Argentina	1126
56		Buenos Aires		Argentina	1205
57		Buenos Aires		Argentina	1221
58		Buenos Aires		Argentina	1414
59		Buenos Aires		Argentina	1425
60		La Plata		Argentina	1900
61		Mendoza		Argentina	5500
62		Santiago		Chile
63		Barranquilla		Colombia
64		Bogota		Colombia
65		Bucamaranga		Colombia
66		Mexico City		Mexico
67		Monterrey		Mexico
68		Tobasco		Mexico
69		Chiclayo		Peru
70		Lima		Peru

Sponsors and Collaborators

• Wyeth is now a wholly owned subsidiary of Pfizer

Investigators

• Study Director: Medical Monitor, Wyeth is now a wholly owned subsidiary of Pfizer
• Principal Investigator: Trial Manager, For Argentina: [e-mail]
• Principal Investigator: Trial Manager, For Chile: [e-mail]
• Principal Investigator: Trial Manager, For Mexico: [e-mail]

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00406640
• Other Study ID Numbers: 3151A1-402
• First Posted: Dec 4, 2006
• Last Update Posted: Jun 29, 2010
• Last Verified: May 1, 2010

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

Study Results

Participant Flow

Recruitment Details	Subjects were recruited in Argentina, Chile, Colombia, Mexico and the United States from December 2006 to January 2008.
Pre-assignment Detail	Subjects were screened up to 4 weeks.

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)	Escitalopram
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.
Period Title: Acute Phase
STARTED	296	299
COMPLETED	245	256
NOT COMPLETED	51	43
Period Title: Acute Phase
STARTED	172	188
COMPLETED	139	151
NOT COMPLETED	33	37
Period Title: Acute Phase
STARTED	69	60
COMPLETED	47	36
NOT COMPLETED	22	24

Baseline Characteristics

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)	Escitalopram	Total
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.	Total of all reporting groups
Overall Participants	296	299	595
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.78 (6.13)	56.15 (6.25)	55.97 (6.19)
Sex: Female, Male (Count of Participants)
Female	296 100%	299 100%	595 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	211 71.3%	219 73.2%	430 72.3%
Mexico	10 3.4%	9 3%	19 3.2%
Argentina	43 14.5%	42 14%	85 14.3%
Chile	11 3.7%	9 3%	20 3.4%
Colombia	21 7.1%	20 6.7%	41 6.9%

Outcome Measures

1. Primary Outcome

Title	Change in Hamilton Psychiatric Rating Scale for Depression (HAM-D17) Score From Baseline to Week 8
Description	HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Items are scored on either a 3 point (0 to 2) or a 5 point scale (0 to 4) with 0=none/absent and 4=most severe,for a maximum total score of 50. Change= 8 week adjusted mean HAM-D17 minus baseline adjusted mean HAM-D17.
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Acute Double-blind phase; all randomized patients with a baseline HAM-D17 score ≥ 18, who took at least 1 dose of study drug and had at least 1 post-baseline HAM-D17 evaluation.

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)	Escitalopram
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.
Measure Participants	185	203
Mean (Standard Error) [units on scale]	-13.63 (0.42)	-14.30 (0.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR compared with ESC
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.243
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Models Repeated Measures (MMRM) with baseline score as a covariant and factors for center, week and treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.67
	Confidence Interval	() 95%; -0.46 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	DVS SR adjusted mean change minus ESC adjusted mean change.

2. Secondary Outcome

Title	Percentage of Patients Achieving Response to Treatment at Final On-therapy Evaluation (Acute Phase)
Description	A response is defined as ≥ 50% decrease from baseline on Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Acute double-blind phase; all randomized patients with a baseline HAM-D17 score ≥18, who took at least 1 dose of study drug and had at least 1 post-baseline HAM-D17 evaluation.

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)	Escitalopram
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.
Measure Participants	224	237
Number [percentage of patients]	64.3	73.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR compared with ESC.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.077
	Comments
	Method	Chi-squared
	Comments	Logistic regression model with treatment and site as factors and baseline score as a covariant.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.608
	Confidence Interval	() 95%; 0.40 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated odds ratio of DVS SR to ESC. Odd ratio adjusted for baseline, treatment and site.

3. Secondary Outcome

Title	Percentage of Patients Achieving Remission at Final On-therapy Evaluation (Acute Phase)
Description	Remission is defined as a Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score of ≤ 7. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Acute double-blind phase; all randomized patients with a baseline HAM-D17 score ≥18, who took at least 1 dose of study drug and had at least 1 post-baseline HAM-D17 evaluation.

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)	Escitalopram
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.
Measure Participants	224	237
Number [Percentage of patients]	37.9	48.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR compared with ESC.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0054
	Comments
	Method	Chi-squared
	Comments	Logistic regression model with treatment and site as factors and baseline score as a covariant.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.571
	Confidence Interval	() 95%; 0.39 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated odds ratio of DVS SR to ESC. Odds ratio adjusted for baseline, treatment and site.

4. Secondary Outcome

Title	Clinical Global Impression Improvement (CGI-I) Score at 8 Weeks
Description	CGI-I is a global rating scale that measures disease improvement. Using a 7-point scale, the clinician rates how much the patient's illness has improved or worsened relative to the baseline status (1= very much improved; 7= very much worse).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Acute double-blind phase; all randomized patients with a baseline HAM-D17 score ≥18, took at least1 dose of study drug and had at least1 post-baseline HAM-D17 evaluation.

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)	Escitalopram
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.
Measure Participants	185	203
Mean (Standard Error) [units on scale]	1.93 (0.08)	1.81 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR compared with ESC
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.260
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Models Repeated Measures (MMRM) with baseline score as a covariant and factors for center, week and treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.12
	Confidence Interval	() 95%; -0.09 to 0.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	DVS SR minus ESC adjusted mean

5. Secondary Outcome

Title	Change in Clinical Global Impression Severity (CGI-S) Score From Baseline to Week
Description	CGI-S is a global rating scale that measures the severity of a patient's disease. Using a 7-point scale, the clinician rates the severity of the patient's mental illness at the time of the assessment, relative to the clinician's experience with patients who have the same diagnosis (1= normal; 7= extremely ill).
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Acute double-blind phase; all randomized patients with a baseline HAM-D17 score ≥18, took at least1 dose of study drug and had at least1 post-baseline HAM-D17 evaluation.

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)	Escitalopram
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.
Measure Participants	185	203
Mean (Standard Error) [units on scale]	-2.09 (0.09)	-2.22 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.239
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Models Repeated Measures (MMRM) with baseline score as a covariant and factors for center, week and treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.14
	Confidence Interval	() 95%; -0.09 to 0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	DVS SR minus ESC adjusted mean

6. Secondary Outcome

Title	Change in Hamilton Psychiatric Rating Scale for Anxiety From Baseline to Week 8 (HAM-A) Score
Description	The HAM-A is a standardized, clinician-administered rating scale that assesses 14 items characteristically associated with major anxiety disorders. Items are scaled 0 - 4 (0=none and 4=very severe), with a maximum total score of 56. Change= 8 week adjusted mean HAM-A total score minus baseline adjusted mean total score.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Acute Double-blind phase; all randomized patients with a baseline HAM-D17 score ≥ 18, who took at least 1 dose of study drug and had at least 1 post-baseline HAM-D17 evaluation.

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)	Escitalopram
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.
Measure Participants	185	203
Mean (Standard Deviation) [units on scale]	-11.37 (0.42)	-11.73 (0.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR compared to ESC
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.516
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed model Repeated Measures (MMRM) analysis adjusted mean score for baseline score, time and center.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.37
	Confidence Interval	() 95%; -0.75 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	DVS SR adjusted mean change minus ESC adjusted mean change.

7. Secondary Outcome

Title	Change in Dimension Health State EuroQol (EQ-5D) Score From Baseline to Week 8
Description	EQ-5D is a standardized, subject-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme problems) and a single index value characterizing current health status using a 100-point visual analog scale (0=worst, 100=best). EQ-5D summary index is obtained with a formula that weights each level of the dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health). Change=8 week score minus baseline score.
Time Frame	Baseline and week 8

Outcome Measure Data

Analysis Population Description

Acute Double-blind phase; all randomized patients with a baseline HAM-D17 score ≥ 18, who took at least 1 dose of study drug and had at least 1 post-baseline HAM-D17 evaluation.

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)	Escitalopram
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.
Measure Participants	179	189
Mean (Standard Error) [units on scale]	0.25 (0.02)	0.24 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR compared to ESC
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.635
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Model Repeated Measures (MMRM) with treatment, time and site as factors and baseline as covariant.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.01
	Confidence Interval	() 95%; -0.03 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	DVS SR adjusted mean change minus ESC adjusted mean change

8. Secondary Outcome

Title	Percentage of Responders Maintaining Response to Treatment at Final On-therapy Evaluation (Double Blind Continuation Phase)
Description	Patients achieving a response to treatment at the end of the 8-week acute double blind (DB) phase continued the same treatment in a 6-month DB continuation phase and were evaluated to see if the response was maintained. A response is defined as ≥ 50% decrease from baseline on Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline HAM-D17 score ≥18, who took at least 1 dose of study drug, had at least 1 post-baseline HAM-D17 evaluation, achieved a response to treatment (≥50% reduction of HAM-D17 total score from baseline) at the end of the acute phase (week 8) and continued treatment in the double blind continuation phase.

Arm/Group Title	DVS SR Responders / DVS SR DB	ESC Responders / ESC DB
Arm/Group Description	Patients who received DVS SR during the acute double blind phase (weeks 1-8), achieved a response to treatment (defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase and continued on DVS SR during the 6-month Double Blind Continuation phase.	Patients who received ESC during the acute double blind phase (weeks 1-8), achieved a response to treatment (defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase and continued on ESC during the 6-month Double Blind Continuation phase.
Measure Participants	137	160
Number [percentage of responders]	81.8	80.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR compared with ESC.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.702
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.12
	Confidence Interval	() 95%; 0.63 to 2.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated odds ratio of DVS SR to ESC. Odd ratio adjusted for baseline, treatment and site.

9. Secondary Outcome

Title	Percentage of Responders Achieving Remission at Final On-therapy Evaluation (Double Blind Continuation Phase)
Description	Patients achieving a response to treatment at the end of the 8-week acute double blind (DB) phase continued the same treatment in a 6-month DB continuation phase and were evaluated to see if remission was achieved. Remission is defined as a Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score of ≤ 7. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized patients with a baseline HAM-D17 score ≥18, who took at least 1 dose of study drug, had at least 1 post-baseline HAM-D17 evaluation, achieved a response to treatment (≥50% reduction of HAM-D17 total score from baseline) at the end of the acute phase (week 8) and continued treatment in the double blind continuation phase.

Arm/Group Title	DVS SR Responders / DVS SR DB	ESC Responders / ESC DB
Arm/Group Description	Patients who received DVS SR during the acute double blind phase (weeks 1-8), achieved a response to treatment (defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase and continued on DVS SR during the 6-month Double Blind Continuation phase.	Patients who received ESC during the acute double blind phase (weeks 1-8), achieved a response to treatment (defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase and continued on ESC during the 6-month Double Blind Continuation phase.
Measure Participants	137	160
Number [percentage of responders]	67.9	61.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR compared with ESC.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.234
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.34
	Confidence Interval	() 95%; 0.83 to 2.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated odds ratio of DVS SR to ESC. Odd ratio adjusted for baseline, treatment and site.

10. Secondary Outcome

Title	Percentage of Responders Improving Response to Remission During 6-month Double Blind Continuation Phase
Description	Patients achieving a response to treatment (Responders) at the end of the 8-week acute double blind (DB) phase continued into a 6-month DB phase. Responders without remission at 8 weeks were assessed for remission status during the 6-month continuation. Remission defined as a Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score ≤ 7. HAM-D17 is a standardized, clinician-administered rating scale assessing 17 items characteristically associated with major depression. Individual items scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized patients with baseline HAM-D17 score ≥18, who took ≥1 dose study drug, had ≥1 post-baseline HAM-D17 evaluation, achieved a response to treatment (≥50% reduction of HAM-D17 total score from baseline) but not remission (HAM-D17 score ≤ 7) at the end of the acute phase and continued treatment in the 6-month DB continuation phase.

Arm/Group Title	DVS SR Responders / DVS SR DB	ESC Responders / ESC DB
Arm/Group Description	Patients who received DVS SR during the acute double blind phase (weeks 1-8), achieved a response to treatment (defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase and continued on DVS SR during the 6-month Double Blind Continuation phase.	Patients who received ESC during the acute double blind phase (weeks 1-8), achieved a response to treatment (defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase and continued on ESC during the 6-month Double Blind Continuation phase.
Measure Participants	54	55
Number [percentage of responders]	88.9	81.8

11. Secondary Outcome

Title	Percentage of Non-Responders Achieving Response at Final Evaluation of 6-month Open-Label (OL)Extension Phase
Description	Patients who didn't achieve a response to treatment at the end of the 8-week acute double blind phase entered into an OL treatment phase with DVS SR for 6 months and were evaluated to see if a response was achieved. A response is defined as ≥ 50% decrease from baseline on Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized patients who took at least 1 dose of study drug, who did not achieve a response to treatment (≥50% reduction of HAM-D17 total score from baseline) at the end of the acute phase (week 8), entered into the open label extension phase and had baseline and at least 1 post-baseline HAM-D17 evaluation in the acute and open label phase.

Arm/Group Title	DVS SR Non-Responders / DVS SR OL	ESC Non-Responders / DVS SR OL
Arm/Group Description	Patients who received DVS SR during the acute double blind phase (weeks 1-8), did not achieve a response to treatment (response defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase; entered into open label (OL) treatment with DVS SR during 6-month Open Label Extension phase.	Patients who received ESC during the acute double blind phase (weeks 1-8), did not achieve a response to treatment (response defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase; entered into open label (OL) treatment with DVS SR during 6-month Open Label Extension phase.
Measure Participants	185	203
Number [Percentage of Non-Responders]	39.1	50.8

12. Secondary Outcome

Title	Percentage of Non-Responders Achieving Remission at Final Evaluation of 6-month Open-Label Extension Phase
Description	Patients who did not achieve a response to treatment at the end of the 8-week acute double blind phase entered into an open label (OL) treatment phase with DVS SR for 6 months and were evaluated to see if remission was achieved. Remission is defined as a Hamilton Psychiatric Rating Scale for Depression (HAM-D17) score of ≤ 7. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Individual items are scored on a 0 to 2 or 4 scale (0=none/absent and 4=most severe) for a maximum total score of 50.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized patients who took at least 1 dose of study drug, who did not achieve a response to treatment (≥50% reduction of HAM-D17 total score from baseline) at the end of the acute phase (week 8), entered into the open label extension phase and had baseline and at least 1 post-baseline HAM-D17 evaluation in the acute and open label phase.

Arm/Group Title	DVS SR Non-Responders / DVS SR OL	ESC Non-Responders / DVS SR OL
Arm/Group Description	Patients who received DVS SR during the acute double blind phase (weeks 1-8), did not achieve a response to treatment (response defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase; entered into open label (OL) treatment with DVS SR during 6-month Open Label Extension phase.	Patients who received ESC during the acute double blind phase (weeks 1-8), did not achieve a response to treatment (response defined as HAM-D17 improved ≥50% from baseline) at the end of the acute phase; entered into open label (OL) treatment with DVS SR during 6-month Open Label Extension phase.
Measure Participants	64	59
Number [Percentage of Non-Responders]	40.6	47.5

13. Secondary Outcome

Title	Discontinuation-Emergent Signs and Symptoms (DESS) Total Score
Description	DESS is a clinician-administered 43-item assessment that evaluates discontinuation-emergent symptoms resulting from the withdrawal from test article. The DESS total score is the sum of the number of new symptoms and old (but worse) symptoms that appeared during tapering of the test article. A higher score indicates more symptoms. The DESS score was assessed by status of taper.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Safety population: Randomized patients who took ≥1 dose study drug. Excluded patients lost to follow-up and discontinued with < 4 wks therapy. Patients analyzed varied by time (DVS SR, ESC): End of Therapy (n=264, 267); Taper week 1 (n=217, 227); Taper week 2 (n=222, 223); Post-taper (n=219, 223).

Arm/Group Title	Desvenlafaxine Succinate Sustained-Release (DVS SR)	Escitalopram (ESC)
Arm/Group Description	Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg/day for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.	Taper Phase Day 239 or at discontinuation: If patients taking escitalopram 20 mg/day, then decrease to 10 mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10 mg/day decreased to matching escitalopram placebo/day for 7 days.
Measure Participants	264	267
End of Therapy	1.49 (3.09)	1.52 (3.65)
Taper week 1	1.18 (2.12)	1.68 (3.28)
Taper week 2	2.29 (3.46)	3.16 (4.58)
Post-taper	1.61 (3.55)	1.48 (2.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR vs. ESC: end of therapy
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.927
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR vs. ESC: after 1 week of taper
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.055
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR vs. ESC: after 2 weeks of taper
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-release (DVS SR), Escitalopram
	Comments	DVS SR vs. ESC: after > 2 weeks of taper
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.653
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	Desvenlafaxine Succinate Sustained-release (DVS SR)		Escitalopram
Arm/Group Description	Acute Double Blind (DB) Phase Days 1 to 7: DVS SR 50 mg/day Days 8 to 14: 100 mg/day Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day or 200 mg/day 6-Month Continuation Phases Double Blind Continuation Phase for Responders (HAM-D17 improved ≥50% from baseline) Days 57-238: continue taking DVS SR 100 mg/day or 200 mg/day Open-Label (OL) Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63: DVS SR 100 mg/day Days 64-238: At the discretion of the investigator, patients assigned DVS SR 100 mg/day or 200mg/day Taper Phase Day 239 or at discontinuation: If patient taking DVS SR 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking DVS SR 100 mg/day decreased to 50 mg/day for 7 days.		Acute DB Phase Days 1-14:escitalopram 10mg/day; Days 15-56:discretion of the investigator patients assigned escitalopram 10mg/day or 20mg/day 6-Month Continuation Phases DB Continuation Phase for Responders (HAM-D17 improved 50% from baseline) Days 57-238:continue taking escitalopram 10mg/day or 20mg/day OL Extension Phase for Non-Responders (HAM-D17 improved <50% from baseline) Days 57-63:DVS SR 100mg/day; Days 64-238:At the discretion of the investigator, patients assigned DVS SR 100mg/day or 200mg/day Taper Phase Day 239 or at discontinuation:If patient taking DVS SR 200mg/day, decreased to 100mg/day for 7 days, and then decreased to 50mg/day for 7 days. Patients taking DVS SR 100mg/day decreased to 50mg/day for 7 days. If patients taking escitalopram 20mg/day, decreased to 10mg/day for 7 days and then decreased to matching escitalopram placebo/day for 7 days. Patients taking escitalopram 10mg/day decreased to matching escitalopram placebo/day for 7 days.
All Cause Mortality
	Desvenlafaxine Succinate Sustained-release (DVS SR)		Escitalopram
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Desvenlafaxine Succinate Sustained-release (DVS SR)		Escitalopram
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/ (NaN)		4/ (NaN)
Cardiac disorders
Postural hypotension	1/296 (0.3%)		0/299 (0%)
General disorders
Accidental injury	0/296 (0%)		1/299 (0.3%)
Non-specific drug reaction	1/296 (0.3%)		0/299 (0%)
Overdose	0/296 (0%)		1/299 (0.3%)
Suicide attempt	2/296 (0.7%)		0/299 (0%)
Hepatobiliary disorders
Hepatitis	1/296 (0.3%)		0/299 (0%)
Hepatomegaly	1/296 (0.3%)		0/299 (0%)
Nervous system disorders
Anxiety	1/296 (0.3%)		0/299 (0%)
Depression	1/296 (0.3%)		1/299 (0.3%)
Hypesthesia	0/296 (0%)		1/299 (0.3%)
Paresis	0/296 (0%)		1/299 (0.3%)
Other (Not Including Serious) Adverse Events
	Desvenlafaxine Succinate Sustained-release (DVS SR)		Escitalopram
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	267/ (NaN)		262/ (NaN)
Cardiac disorders
Hypertension	16/296 (5.4%)		15/299 (5%)
Eye disorders
Abnormal vision	14/296 (4.7%)		17/299 (5.7%)
Gastrointestinal disorders
Anorexia	20/296 (6.8%)		15/299 (5%)
Constipation	52/296 (17.6%)		28/299 (9.4%)
Diarrhea	26/296 (8.8%)		49/299 (16.4%)
Dry mouth	83/296 (28%)		60/299 (20.1%)
Dyspepsia	21/296 (7.1%)		27/299 (9%)
Nausea	74/296 (25%)		61/299 (20.4%)
General disorders
Abdominal pain	29/296 (9.8%)		21/299 (7%)
Asthenia	27/296 (9.1%)		23/299 (7.7%)
Back pain	16/296 (5.4%)		13/299 (4.3%)
Headache	76/296 (25.7%)		85/299 (28.4%)
Infection	17/296 (5.7%)		21/299 (7%)
Metabolism and nutrition disorders
Metabolic and nutritional	20/296 (6.8%)		13/299 (4.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal	26/296 (8.8%)		32/299 (10.7%)
Nervous system disorders
Dizziness	33/296 (11.1%)		28/299 (9.4%)
Insomina	33/296 (11.1%)		39/299 (13%)
Nervousness	21/296 (7.1%)		10/299 (3.3%)
Sommolence	42/296 (14.2%)		48/299 (16.1%)
Renal and urinary disorders
Urogenitial	24/296 (8.1%)		25/299 (8.4%)
Respiratory, thoracic and mediastinal disorders
Respiratory	29/296 (9.8%)		28/299 (9.4%)
Skin and subcutaneous tissue disorders
Sweating	43/296 (14.5%)		33/299 (11%)
Vascular disorders
Vasodilatation	12/296 (4.1%)		16/299 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The PIs agreed to allow the sponsor 60 days to review and require changes to presentations or publications but only to protect confidential information and intellectual property, and for the sponsor to file a patent application, as applicable. The PIs also agreed for data to be presented first as a joint, multi-center publication.