Study Evaluating Desvenlafaxine Succinate Sustained Release (DVS SR) Versus Placebo in Peri- and Postmenopausal Women

• Sponsor: Wyeth is now a wholly owned subsidiary of Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00369343
• Collaborator: (none)
• Enrollment: 381
• Locations: 37
• Arms: 2
• Duration (Months): 22
• Patients Per Site: 10.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Desvenlafaxine succinate (DVS) is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). The sustained-release (SR) formulation, DVS SR, is being studied in the development program for the treatment of major depressive disorder (MDD), for vasomotor symptoms (VMS) associated with menopause, and for pain associated with peripheral diabetic neuropathy, as well as for the treatment of fibromyalgia syndrome. This study will investigate the safety, efficacy, and tolerability of DVS SR in women with MDD who are peri- and postmenopausal.

Condition or Disease	Intervention/Treatment	Phase
Depression; Depressive Disorder; Depressive Disorder, Major	Drug: Desvenlafaxine administered as a succinate salt in a sustained-release form (DVS SR); Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 381 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, 8-week, Double-blind, Placebo-controlled Study Followed by a 6-month Open-label Extension to Evaluate the Efficacy and Safety of DVS SR in Peri- and Postmenopausal Women With Major Depressive Disorder
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Nov 1, 2007
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A	Drug: Desvenlafaxine administered as a succinate salt in a sustained-release form (DVS SR); DVS-SR 50-200mg, daily (QD), tablet form, treatment period up to 34 weeks
Placebo Comparator: B	Drug: Placebo; Placebo, daily (QD), tablet form, treatment period up to 8 weeks

Outcome Measures

Primary Outcome Measures

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

   HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with 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 With Each Clinical Global Impression Improvement (CGI-I) Score [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).

2. Percentage of Patients Achieving Remission [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. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total score of 50.

3. Percentage of Patients Achieving Response to Treatment [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. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total score of 50.

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

   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 score minus baseline adjusted mean score.

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

   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.

6. Change in Hamilton Psychiatric Rating Scale for Depression (HAM-D17) Score From Open Label Baseline to 6 Months [open label baseline and 6 months]

   HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total s core of 50. Change= Final Evaluation mean HAM-D17 minus baseline mean HAM-D17.

7. Clinical Global Impression Improvement (CGI-I) Score [6 months]

   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)

8. Percentage of Patients Achieving Remission [6 months]

   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. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total s core of 50.

9. Percentage of Patients Achieving a Response to Treatment [6 months]

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

10. Change in Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) Score From Open Label Baseline to 6 Months [open label baseline to 6 months]

    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= Final Evaluation mean HAM-A score minus baseline mean score.

11. Change in Dimension Health State EuroQol (EQ-5D) Score From Open Label Baseline to 6 Months [open label baseline to 6 months]

    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.

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

    DESS: 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" (1) and 0 for "old and unchanged symptom," "absent," or "old symptom but improved" for a total possible range of 0 to 43. A higher score indicates more symptoms.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Peri- and 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 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		Birmingham	Alabama	United States	35226
2		Little Rock	Arkansas	United States	72223
3		Springdale	Arkansas	United States	72762
4		Palo Alto	California	United States	94305
5		San Diego	California	United States	92103
6		New London	Connecticut	United States	06320
7		Bradenton	Florida	United States	34208
8		Miami	Florida	United States	33133
9		Tampa	Florida	United States	33613
10		Winter Park	Florida	United States	32789
11		Atlanta	Georgia	United States	30308
12		Sandy Springs	Georgia	United States	30328
13		Savannah	Georgia	United States	31406
14		Smyrna	Georgia	United States	30080
15		Idaho Falls	Idaho	United States	83404
16		Chicago	Illinois	United States	60634
17		Indianapolis	Indiana	United States	46202
18		Terre Haute	Indiana	United States	47802
19		Shreveport	Louisiana	United States	71101
20		Rockville	Maryland	United States	20852
21		Omaha	Nebraska	United States	68131
22		Cherry Hill	New Jersey	United States	08002
23		Brooklyn	New York	United States	11235
24		Minot	North Dakota	United States	58701
25		Beachwood	Ohio	United States	44122
26		Dayton	Ohio	United States	45408
27		Toledo	Ohio	United States	43623
28		Oklahoma City	Oklahoma	United States	73118
29		Tulsa	Oklahoma	United States	74135
30		Philadelphia	Pennsylvania	United States	19131
31		Hilton Head Island	South Carolina	United States	29926
32		Austin	Texas	United States	78756
33		Houston	Texas	United States	77007
34		Richmond	Virginia	United States	23229
35		Richmond	Virginia	United States	23230
36		Seattle	Washington	United States	98105
37		Brown Deer	Wisconsin	United States	53223

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Wyeth is now a wholly owned subsidiary of Pfizer
• ClinicalTrials.gov Identifier: NCT00369343
• Other Study ID Numbers: 3151A1-403
• First Posted: Aug 29, 2006
• Last Update Posted: May 7, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by Wyeth is now a wholly owned subsidiary of Pfizer: Major Depressive Disorder; vasomotor symptoms; menopause; diabetic neuropathy; fibromyalgia
• Additional relevant MeSH terms: Disease; Depression; Depressive Disorder; Depressive Disorder, Major; Desvenlafaxine Succinate

Study Results

Participant Flow

Recruitment Details	Patients were recruited in the United States from September 2006 to September 2007.
Pre-assignment Detail	Patients were screened over 4 weeks.

Arm/Group Title	Desvenlafaxine Succinate Sustained-Release (DVS SR)	Placebo
Arm/Group Description	Double-blind Phase Days 1 to 7: 50 mg/day (one 50 mg tablet) Days 8 to 14: 100 mg/day (one 100 mg tables) Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.	Double-blind Phase Placebo administered daily for 8 weeks Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg/day for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.
Period Title: Double-blind Phase
STARTED	256	125
COMPLETED	212	109
NOT COMPLETED	44	16
Period Title: Double-blind Phase
STARTED	212	109
COMPLETED	155	79
NOT COMPLETED	57	30

Baseline Characteristics

Arm/Group Title	Desvenlafaxine Succinate Sustained-Release (DVS SR)	Placebo	Total
Arm/Group Description	Double-blind Phase Days 1 to 7: 50 mg/day (one 50 mg tablet) Days 8 to 14: 100 mg/day (one 100 mg tables) Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.	Double-blind Phase Placebo administered daily for 8 weeks Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg/day for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.	Total of all reporting groups
Overall Participants	256	125	381
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.01 (6.50)	52.56 (7.17)	52.19 (6.72)
Sex: Female, Male (Count of Participants)
Female	256 100%	125 100%	381 100%
Male	0 0%	0 0%	0 0%

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 a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total score of 50. Change= 8 week adjusted mean HAM-D17 minus baseline adjusted mean HAM-D17
Time Frame	Baseline to 8 weeks

Outcome Measure Data

Analysis Population Description

Double-blind phase; modified intent to treat population, which included all randomized patients with a baseline HAM-D17 score ≥18, who took ≥1 dose of study drug and had ≥1 post-baseline HAM-D17 evaluation. Mixed model repeated measures (MMRM) modeling included all available observed data for each patient and no missing values were imputed.

Arm/Group Title	Desvenlafaxine Succinate Sustained-Release (DVS SR)	Placebo
Arm/Group Description	Double-blind Phase Days 1 to 7: 50 mg/day (one 50 mg tablet) Days 8 to 14: 100 mg/day (one 100 mg tables) Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.	Double-blind Phase Placebo administered daily for 8 weeks Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg/day for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.
Measure Participants	157	81
Mean (Standard Error) [units on scale]	-12.64 (0.53)	-8.33 (0.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-Release (DVS SR), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Models Repeated Measures (MMRM) used baseline as a covariate and factors for center, week and treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.32
	Confidence Interval	() 95%; 2.53 to 6.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	DVS SR adjusted mean change minus placebo adjusted mean change.

2. Secondary Outcome

Title	Percentage of Patients With Each Clinical Global Impression Improvement (CGI-I) Score
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

Double-blind phase, modified intent to treat population, which included all randomized patients with a baseline HAM-D17 score ≥18, took ≥1 dose of study drug and had ≥1 post-baseline HAM-D17 evaluation. Missing data handled by last observation carried forward (LOCF).

Arm/Group Title	Desvenlafaxine Succinate Sustained-Release (DVS SR)	Placebo
Arm/Group Description	Double-blind Phase Days 1 to 7: 50 mg/day (one 50 mg tablet) Days 8 to 14: 100 mg/day (one 100 mg tables) Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.	Double-blind Phase Placebo administered daily for 8 weeks Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg/day for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.
Measure Participants	186	97
1 (very much improved)	42.5	22.7
2 (much improved)	25.3	18.6
3 (minimally improved)	16.7	17.5
4 (no change)	13.4	32.0
5 (minimally worse)	1.1	7.2
6 (much worse)	0.5	2.1
7 (very much worse)	0.5	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-Release (DVS SR), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	DVS SR compared to Placebo for CGI-I scores of either 1 (very much improved) or 2 (much improved).
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Percentage of Patients Achieving Remission
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. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total score of 50.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Double-blind phase, modified intent to treat population, which included all randomized patients with a baseline HAM-D17 score ≥18, took ≥1 dose of study drug and had ≥1 post-baseline HAM-D17 evaluation. Missing data handled by last observation carried forward (LOCF).

Arm/Group Title	Desvenlafaxine Succinate Sustained-Release (DVS SR)	Placebo
Arm/Group Description	Double-blind Phase Days 1 to 7: 50 mg/day (one 50 mg tablet) Days 8 to 14: 100 mg/day (one 100 mg tables) Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.	Double-blind Phase Placebo administered daily for 8 weeks Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg/day for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.
Measure Participants	186	98
Number [percentage of patients]	38.2	22.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-Release (DVS SR), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	DVS SR compared with Placebo.
	Method	Chi-squared
	Comments	Logistic regression model with treatment and site as factors and baseline score as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.132
	Confidence Interval	() 95%; 1.22 to 3.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted odds ratio of DVS SR to Placebo. Odds ratio adjusted for baseline, treatment and site.

4. Secondary Outcome

Title	Percentage of Patients Achieving Response to Treatment
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. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total score of 50.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Double-blind phase, modified intent to treat population, which included all randomized patients with a baseline HAM-D17 score ≥18, took ≥1 dose of study drug and had ≥1 post-baseline HAM-D17 evaluation. Missing data handled by last observation carried forward (LOCF).

Arm/Group Title	Desvenlafaxine Succinate Sustained-Release (DVS SR)	Placebo
Arm/Group Description	Double-blind Phase Days 1 to 7: 50 mg/day (one 50 mg tablet) Days 8 to 14: 100 mg/day (one 100 mg tables) Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.	Double-blind Phase Placebo administered daily for 8 weeks Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg/day for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.
Measure Participants	186	98
Number [percentage of patients]	58.6	31.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-Release (DVS SR), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	DVS SR compared with Placebo.
	Method	Chi-squared
	Comments	Logistic regression model with treatment and site as factors and baseline score as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.125
	Confidence Interval	() 95%; 1.85 to 5.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted odds ratio of DVS SR to Placebo. Odd ratio adjusted for baseline, treatment and site.

5. Secondary Outcome

Title	Change in Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) Score From Baseline to Week 8
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 score minus baseline adjusted mean score.
Time Frame	Baseline to 8 weeks

Outcome Measure Data

Analysis Population Description

Double-blind phase; modified intent to treat population, which included all randomized patients with a baseline HAM-D17 score ≥18, took ≥1 dose of study drug and had ≥1 post-baseline HAM-D17 evaluation. Mixed model repeated measures (MMRM) modeling included all available observed data for each patient and no missing values were imputed.

Arm/Group Title	Desvenlafaxine Succinate Sustained-Release (DVS SR)	Placebo
Arm/Group Description	Double-blind Phase Days 1 to 7: 50 mg/day (one 50 mg tablet) Days 8 to 14: 100 mg/day (one 100 mg tables) Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.	Double-blind Phase Placebo administered daily for 8 weeks Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg/day for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.
Measure Participants	158	81
Mean (Standard Error) [units on scale]	-8.62 (0.44)	-5.89 (0.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-Release (DVS SR), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Mixed model Repeated Measures (MMRM) analysis adjusted mean score for baseline score, time and center.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.74
	Confidence Interval	() 95%; 1.24 to 4.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted mean difference = Placebo adjusted mean score minus DVS SR adjusted mean score.

6. 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 to 8 weeks

Outcome Measure Data

Analysis Population Description

Double-blind phase; modified intent to treat population, which included all randomized patients with a baseline HAM-D17 score ≥18, took ≥1 dose of study drug and had ≥1 post-baseline HAM-D17 evaluation.

Arm/Group Title	Desvenlafaxine Succinate Sustained-Release (DVS SR)	Placebo
Arm/Group Description	Double-blind Phase Days 1 to 7: 50 mg/day (one 50 mg tablet) Days 8 to 14: 100 mg/day (one 100 mg tables) Days 15 to 56: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.	Double-blind Phase Placebo administered daily for 8 weeks Open-label Phase Days 57-63: 100 mg/day (one 100 mg tablet) Days 64-238: At the discretion of the investigator, patients assigned 100 mg/day (one 100 mg tablet) or 200 mg/day (two 100 mg tablets) Taper Phase Day 239 or at discontinuation: If patient taking 200 mg/day, then decreased to 100 mg/day for 7 days, and then decreased to 50 mg/day for 7 days. Patients taking 100 mg/day decreased to 50 mg/day for 7 days.
Measure Participants	158	81
Mean (Standard Error) [units on scale]	0.18 (0.02)	0.06 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-Release (DVS SR), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Mixed Model Repeated Measures (MMRM) with treatment and site as factors and baseline as covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.12
	Confidence Interval	() 95%; -0.18 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted mean difference = Placebo adjusted mean score minus DVS SR adjusted mean score.

7. Secondary Outcome

Title	Change in Hamilton Psychiatric Rating Scale for Depression (HAM-D17) Score From Open Label Baseline to 6 Months
Description	HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total s core of 50. Change= Final Evaluation mean HAM-D17 minus baseline mean HAM-D17.
Time Frame	open label baseline and 6 months

Outcome Measure Data

Analysis Population Description

Open-label phase safety population: All patients who completed the double-blind phase, elected to continue treatment in the open-label phase, and received at least 1 dose of study drug in the open-label phase. One patient did not have a baseline and at least 1 on therapy assessment.

Arm/Group Title	DVS SR / DVS SR	Placebo / DVS SR
Arm/Group Description	Patients were in the DVS SR arm during both the double-blind and open-label phase.	Patients were in the Placebo arm during the double-blind phase and the DVS SR arm during the open-label phase.
Measure Participants	207	103
Mean (Standard Deviation) [units on scale]	-12.52 (7.17)	-12.45 (6.85)

8. Secondary Outcome

Title	Clinical Global Impression Improvement (CGI-I) Score
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	6 months

Outcome Measure Data

Analysis Population Description

Open-label phase safety population: All patients who completed the double-blind phase, elected to continue treatment in the open-label phase, and received at least 1 dose of study drug in the open-label phase.

Arm/Group Title	DVS SR / DVS SR	Placebo / DVS SR
Arm/Group Description	Patients were in the DVS SR arm during both the double-blind and open-label phase.	Patients were in the Placebo arm during the double-blind phase and the DVS SR arm during the open-label phase.
Measure Participants	208	103
Mean (Standard Deviation) [units on scale]	1.55 (1.00)	1.56 (0.99)

9. Secondary Outcome

Title	Percentage of Patients Achieving Remission
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. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total s core of 50.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Open-label phase safety population: All patients who completed the double-blind phase, elected to continue treatment in the open-label phase, and received at least 1 dose of study drug in the open-label phase. One patient did not have a baseline and at least 1 on therapy assessment.

Arm/Group Title	DVS SR / DVS SR	Placebo / DVS SR
Arm/Group Description	Patients were in the DVS SR arm during both the double-blind and open-label phase.	Patients were in the Placebo arm during the double-blind phase and the DVS SR arm during the open-label phase.
Measure Participants	207	103
Number [percentage of patients]	55.6	48.5

10. Secondary Outcome

Title	Percentage of Patients Achieving a Response to Treatment
Description	A responder is defined as a patient with ≥ 50% decrease from baseline on Hamilton Psychiatric Rating Scale for Depression - 17-item (HAM-D17) score. HAM-D17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression. Items are scored on a 0 to 2-4 scale (0=none/absent and 4=most severe) with a maximum total score of 50.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Open-label phase safety population: All patients who completed the double-blind phase, elected to continue treatment in the open-label phase, and received at least 1 dose of study drug in the open-label phase. One patient did not have a baseline and at least 1 on therapy assessment.

Arm/Group Title	DVS SR / DVS SR	Placebo / DVS SR
Arm/Group Description	Patients were in the DVS SR arm during both the double-blind and open-label phase.	Patients were in the Placebo arm during the double-blind phase and the DVS SR arm during the open-label phase.
Measure Participants	207	103
Number [percentage of patients responding]	70.5	66.0

11. Secondary Outcome

Title	Change in Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) Score From Open Label Baseline to 6 Months
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= Final Evaluation mean HAM-A score minus baseline mean score.
Time Frame	open label baseline to 6 months

Outcome Measure Data

Analysis Population Description

Open-label phase safety population: All patients who completed the double-blind phase, elected to continue treatment in the open-label phase, and received at least 1 dose of study drug in the open-label phase. One patient did not have a baseline and at least 1 on therapy assessment.

Arm/Group Title	DVS SR / DVS SR	Placebo / DVS SR
Arm/Group Description	Patients were in the DVS SR arm during both the double-blind and open-label phase.	Patients were in the Placebo arm during the double-blind phase and the DVS SR arm during the open-label phase.
Measure Participants	207	103
Mean (Standard Deviation) [units on scale]	-10.95 (6.90)	-10.38 (5.64)

12. Secondary Outcome

Title	Change in Dimension Health State EuroQol (EQ-5D) Score From Open Label Baseline to 6 Months
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	open label baseline to 6 months

Outcome Measure Data

Analysis Population Description

Open-label phase safety population: All patients who completed the double-blind phase, elected to continue treatment in the open-label phase, and received at least 1 dose of study drug in the open-label phase. One patient did not have a baseline and at least 1 on therapy assessment.

Arm/Group Title	DVS SR / DVS SR	Placebo / DVS SR
Arm/Group Description	Patients were in the DVS SR arm during both the double-blind and open-label phase.	Patients were in the Placebo arm during the double-blind phase and the DVS SR arm during the open-label phase.
Measure Participants	208	102
Mean (Standard Deviation) [units on scale]	0.19 (0.26)	0.22 (0.31)

13. Secondary Outcome

Title	Discontinuation-Emergent Signs and Symptoms (DESS) Total Score
Description	DESS: 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" (1) and 0 for "old and unchanged symptom," "absent," or "old symptom but improved" for a total possible range of 0 to 43. A higher score indicates more symptoms.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Open-label (OL) safety population: Patients completed double-blind and continued in OL with ≥1 dose study drug. Excluded patients lost to follow-up and discontinued with <4 wks therapy. Patients analyzed varied by time (0mg, 100mg, 200mg): Early Termination (n=9,98,207); Taper week 1 (n=4,76,193); Taper week 2 (n=5,75,195); Post-taper (n=5,71,192)

Arm/Group Title	0 mg	100 mg	200 mg
Arm/Group Description	Placebo	DVS SR 100mg dosage was reduced to DVS SR 50mg for 7 days.	DVS SR 200mg dosage was reduced to DVS SR 100mg for 7 days and then further reduced to DVS SR 50mg from days 8 to 14.
Measure Participants	9	98	207
End of 8 week DB / OL phase or early termination	4.00 (5.05)	2.07 (4.03)	1.27 (3.40)
Taper week 1	2.00 (2.16)	3.32 (4.35)	2.47 (3.61)
Taper week 2	1.40 (3.13)	5.29 (5.96)	3.76 (4.71)
Post-taper	0.60 (0.89)	1.41 (2.18)	2.46 (3.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-Release (DVS SR), Placebo
	Comments	100mg vs. Placebo (0mg) post taper
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.553
	Comments	t-test adjusted by multiple comparison
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Desvenlafaxine Succinate Sustained-Release (DVS SR), 200 mg
	Comments	200mg vs. Placebo (0mg) post taper
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments	t-test adjusted by multiple comparison
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	Double-blind DVS SR		Double-blind Placebo		Open-label DVS SR/ DVS SR		Open-label Placebo/DVS SR
Arm/Group Description	Days 1 to 7: Patients will be instructed to take 1-50mg tablet per day Days 8 to 14: Patients will be instructed to take 1-100mg tablet per day Days 15 to 56: At the discretion of the investigator, patients may be assigned to 100mg or 200mg tablets per day		Placebo administered daily for 8 weeks		Patients were in the DVS SR arm during both the double-blind and open-label phase.		Patients were in the Placebo arm during the double-blind phase and the DVS SR arm during the open-label phase.
All Cause Mortality
	Double-blind DVS SR		Double-blind Placebo		Open-label DVS SR/ DVS SR		Open-label Placebo/DVS SR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Double-blind DVS SR		Double-blind Placebo		Open-label DVS SR/ DVS SR		Open-label Placebo/DVS SR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/ (NaN)		2/ (NaN)		12/ (NaN)		2/ (NaN)
Blood and lymphatic system disorders
Coagulation disorder	0/256 (0%)		0/125 (0%)		1/208 (0.5%)		0/103 (0%)
Cardiac disorders
Hypertension	1/256 (0.4%)		0/125 (0%)		0/208 (0%)		0/103 (0%)
Cerebrovascular disorder	0/256 (0%)		1/125 (0.8%)		0/208 (0%)		0/103 (0%)
Supraventricular tachycardia	0/256 (0%)		0/125 (0%)		1/208 (0.5%)		0/103 (0%)
General disorders
Infection	1/256 (0.4%)		0/125 (0%)		0/208 (0%)		0/103 (0%)
Medication error	1/256 (0.4%)		0/125 (0%)		0/208 (0%)		0/103 (0%)
Chest pain	1/256 (0.4%)		0/125 (0%)		0/208 (0%)		1/103 (1%)
Accidental overdose	0/256 (0%)		0/125 (0%)		3/208 (1.4%)		0/103 (0%)
Overdose	0/256 (0%)		0/125 (0%)		2/208 (1%)		0/103 (0%)
Allergic reaction	0/256 (0%)		0/125 (0%)		1/208 (0.5%)		0/103 (0%)
Nervous system disorders
Psychotic depression	1/256 (0.4%)		0/125 (0%)		0/208 (0%)		0/103 (0%)
Psychosis	0/256 (0%)		0/125 (0%)		1/208 (0.5%)		0/103 (0%)
Reproductive system and breast disorders
Uterine fibroids enlarged	0/256 (0%)		0/125 (0%)		0/208 (0%)		1/103 (1%)
Endometrial carcinoma	0/256 (0%)		0/125 (0%)		1/208 (0.5%)		0/103 (0%)
Breast carcinoma	0/256 (0%)		0/125 (0%)		1/208 (0.5%)		0/103 (0%)
Skin and subcutaneous tissue disorders
Skin carcinoma	0/256 (0%)		1/125 (0.8%)		0/208 (0%)		0/103 (0%)
Skin melanoma	0/256 (0%)		0/125 (0%)		1/208 (0.5%)		0/103 (0%)
Vascular disorders
Cerebral ischemia	0/256 (0%)		0/125 (0%)		1/208 (0.5%)		0/103 (0%)
Deep vein thrombosis	0/256 (0%)		0/125 (0%)		1/208 (0.5%)		0/103 (0%)
Other (Not Including Serious) Adverse Events
	Double-blind DVS SR		Double-blind Placebo		Open-label DVS SR/ DVS SR		Open-label Placebo/DVS SR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	217/ (NaN)		94/ (NaN)		198/ (NaN)		97/ (NaN)
Ear and labyrinth disorders
Tinnitus	0/256 (0%)		0/125 (0%)		15/208 (7.2%)		2/103 (1.9%)
Eye disorders
Abnormal vision	0/256 (0%)		0/125 (0%)		13/208 (6.3%)		5/103 (4.9%)
Gastrointestinal disorders
Anorexia	15/256 (5.9%)		1/125 (0.8%)		12/208 (5.8%)		6/103 (5.8%)
Constipation	36/256 (14.1%)		8/125 (6.4%)		37/208 (17.8%)		22/103 (21.4%)
Diarrhea	22/256 (8.6%)		13/125 (10.4%)		33/208 (15.9%)		15/103 (14.6%)
Dry mouth	61/256 (23.8%)		12/125 (9.6%)		56/208 (26.9%)		23/103 (22.3%)
Dyspepsia	16/256 (6.3%)		2/125 (1.6%)		20/208 (9.6%)		4/103 (3.9%)
Nausea	43/256 (16.8%)		15/125 (12%)		52/208 (25%)		32/103 (31.1%)
Vomiting	0/256 (0%)		0/125 (0%)		7/208 (3.4%)		9/103 (8.7%)
General disorders
Abdominal pain	11/256 (4.3%)		8/125 (6.4%)		21/208 (10.1%)		8/103 (7.8%)
Asthenia	17/256 (6.6%)		10/125 (8%)		21/208 (10.1%)		11/103 (10.7%)
Headache	68/256 (26.6%)		26/125 (20.8%)		82/208 (39.4%)		43/103 (41.7%)
Infection	16/256 (6.3%)		10/125 (8%)		40/208 (19.2%)		18/103 (17.5%)
Pain	8/256 (3.1%)		7/125 (5.6%)		20/208 (9.6%)		12/103 (11.7%)
Accidental injury	0/256 (0%)		0/125 (0%)		35/208 (16.8%)		12/103 (11.7%)
Back pain	0/256 (0%)		0/125 (0%)		13/208 (6.3%)		6/103 (5.8%)
Flu syndrome	0/256 (0%)		0/125 (0%)		11/208 (5.3%)		5/103 (4.9%)
Metabolism and nutrition disorders
Weight gain	0/256 (0%)		0/125 (0%)		17/208 (8.2%)		9/103 (8.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/256 (0%)		0/125 (0%)		18/208 (8.7%)		6/103 (5.8%)
Nervous system disorders
Dizziness	29/256 (11.3%)		9/125 (7.2%)		6/208 (2.9%)		6/103 (5.8%)
Insomnia	29/256 (11.3%)		8/125 (6.4%)		32/208 (15.4%)		16/103 (15.5%)
Nervousness	13/256 (5.1%)		4/125 (3.2%)		14/208 (6.7%)		7/103 (6.8%)
Somnolence	37/256 (14.5%)		9/125 (7.2%)		27/208 (13%)		15/103 (14.6%)
Abnormal dreams	0/256 (0%)		0/125 (0%)		15/208 (7.2%)		1/103 (1%)
Anxiety	0/256 (0%)		0/125 (0%)		6/208 (2.9%)		6/103 (5.8%)
Hostility	0/256 (0%)		0/125 (0%)		3/208 (1.4%)		7/103 (6.8%)
Respiratory, thoracic and mediastinal disorders
Pharyngitis	0/256 (0%)		0/125 (0%)		12/208 (5.8%)		10/103 (9.7%)
Rhinitis	0/256 (0%)		0/125 (0%)		14/208 (6.7%)		7/103 (6.8%)
Sinusitis	0/256 (0%)		0/125 (0%)		23/208 (11.1%)		11/103 (10.7%)
Upper respiratory infection	0/256 (0%)		0/125 (0%)		19/208 (9.1%)		9/103 (8.7%)
Skin and subcutaneous tissue disorders
Sweating	17/256 (6.6%)		3/125 (2.4%)		20/208 (9.6%)		12/103 (11.7%)
Vascular disorders
Hypertension	17/256 (6.6%)		2/125 (1.6%)		21/208 (10.1%)		4/103 (3.9%)
Vasodilatation	15/256 (5.9%)		5/125 (4%)		18/208 (8.7%)		7/103 (6.8%)

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.