Study Evaluating The Safety And Efficacy Of Desvenlafaxine Succinate For Vasomotor Symptoms In Menopausal Women

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00683800
• Collaborator: (none)
• Enrollment: 2,186
• Locations: 121
• Arms: 2
• Duration (Months): 23
• Patients Per Site: 18.1
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the efficacy and safety of Desvenlafaxine Succinate (DVS) Sustained Release (SR), in comparison to placebo for the treatment of Vasomotor Symptoms (VMS) in menopausal women.

Condition or Disease	Intervention/Treatment	Phase
Vasomotor Symptoms	Drug: desvenlafaxine succinate (DVS) SR; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2186 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Randomized, Placebo-Controlled Study Assessing The Safety And Efficacy Of DVS SR For The Treatment Of Vasomotor Symptoms Associated With Menopause
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 desvenlafaxine succinate (DVS) SR	Drug: desvenlafaxine succinate (DVS) SR; Titration with 50 mg tablets once daily for 7 days, then 100mg tablets once daily from day 8 to day 365, then taper with 50 mg tablets once daily for 7 days, followed by 25 mg tablets once daily for 7 days.
Placebo Comparator: 2 Placebo	Drug: Placebo; Titration with 50 mg placebo tablets once daily for 7 days, then 100mg placebo tablets once daily from day 8 to day 365, then taper with 50 mg placebo tablets once daily for 7 days, followed by 25 mg placebo tablets once daily for 7 days.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Average Daily Number of Moderate to Severe Hot Flushes at Week 4 [Baseline and Week 4]

   The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity.

2. Change From Baseline in the Average Daily Number of Moderate to Severe Hot Flushes at Week 12 [Baseline and Week 12]

   The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity.

3. Change From Baseline in the Average Daily Severity of Hot Flushes at Week 4 [Baseline and Week 4]

   Severity ranged from mild (sensation of heat without sweating); moderate (sensation of heat with sweating; able to continue activity) to severe (sensation of heat with sweating; causing cessation of activity). The average daily severity of hot flushes for each time period was calculated as (1*Number of mild+2*Number of moderate+3*Number of severe)/(Total number of hot flushes). For the days with no hot flushes, the severity score was set as 0. As this was derived from the count data, there was no maximum; the minimum score was 0; the higher values showed worse outcomes.

4. Change From Baseline in the Average Daily Severity of Hot Flushes at Week 12 [Baseline and Week 12]

   Severity ranged from mild (sensation of heat without sweating); moderate (sensation of heat with sweating; able to continue activity) to severe (sensation of heat with sweating; causing cessation of activity). The average daily severity of hot flushes for each time period was calculated as (1*Number of mild+2*Number of moderate+3*Number of severe)/(Total number of hot flushes). For the days with no hot flushes, the severity score was set as 0. As this was derived from the count data, there was no maximum; the minimum score was 0; the higher values showed worse outcomes.

5. Number of Participants With All Adjudicated Ischemic Cardiovascular (CV) Events [Baseline up to Month 12]

   Adjudicated ischemic cardiovascular events were a composite of: a) Coronary Heart Disease (CHD)-related death; b) New Myocardial Infarction (MI) (non-procedure-related MI); c) Documented new onset of unstable angina requiring hospitalization; d) Unscheduled coronary revascularization procedures (percutaneous coronary intervention) or bypass grafting.

Secondary Outcome Measures

1. Number of Participants With a Minimal Clinically Meaningful Decrease in the Average Daily Number of Hot Flushes [Baseline and Week 12]

   A mean decrease from baseline of at least 5.35 moderate to severe hot flushes at week 12 in the participants was considered clinically meaningful.

2. Percentage of Participants With at Least 50% Reduction From Baseline in the Number of Moderate and Severe Hot Flushes [Baseline, Week 4 and Week 12]

   The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity.

3. Percentage of Participants With at Least 75% Reduction From Baseline in the Number of Moderate and Severe Hot Flushes [Baseline, Week 4 and Week 12]

   The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity.

4. Median Time to the First Day of 3 Consecutive Days of at Least 50% Reduction in Hot Flushes [Week 12]

   Time to response was defined as the time-to-first 50% reduction in the average daily number of moderate to severe hot flushes over 3 consecutive days.

5. Change From Baseline in Adjusted Means in the Number of Moderate and Severe Hot Flushes at Month 6 and Month 12 [Baseline, Month 6 and Month 12]

   The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity. Adjusted mean was calculated by using change from baseline as response variable, treatment as factor, and baseline as covariate using the observed cases.

6. Change From Baseline in Adjusted Means in the Hot Flush Severity Score at Month 6 and Month 12 [Baseline, Month 6 and Month 12]

   Severity: mild (heat sensation without sweating); moderate (heat sensation with sweating; able to continue activity); severe (heat sensation with sweating; causing cessation of activity). Average daily severity of hot flushes= (1*Number of mild+2*Number of moderate+3*Number of severe)/(Total number of hot flushes). Days with no hot flushes: severity score=0. As it was derived from count data, there was no maximum; minimum score=0; higher values= worse outcomes. Adjusted mean: calculated using change from baseline=response variable, treatment=factor and baseline=covariate using observed cases.

7. Change From Baseline in the Total Greene Climacteric Scale (GCS) Score and GCS Subscores at Week 12 [Baseline and Week 12]

   GCS: a 21 item evaluation of symptoms which asked participants how bothered they were with particular symptom at the moment. Each item was scored as 0 = Not at all, 1 = A little, 2 = Quite a bit, and 3 = Extremely. A total score was derived from the sum of the 21 items (range 0-63). GCS was also used to generate 6 individual scores (psychological symptoms [range 0-33], anxiety [range 0-18], depression [range 0-15], somatic symptoms [range 0-21], vasomotor symptoms [range 0-6], and sexual dysfunction [range 0-3]). A decrease in the total climacteric score indicated an improvement in symptoms.

8. Change From Baseline in the Total Greene Climacteric Scale (GCS) Score and GCS Subscores at Month 6 [Baseline and Month 6]

   GCS: a 21 item evaluation of symptoms which asked participants how bothered they were with particular symptom at the moment. Each item was scored as 0 = Not at all, 1 = A little, 2 = Quite a bit, and 3 = Extremely. A total score was derived from the sum of the 21 items (range 0-63). GCS was also used to generate 6 individual scores (psychological symptoms [range 0-33], anxiety [range 0-18], depression [range 0-15], somatic symptoms [range 0-21], vasomotor symptoms [range 0-6], and sexual dysfunction [range 0-3]). A decrease in the total climacteric score indicated an improvement in symptoms.

9. Change From Baseline in the Total Greene Climacteric Scale (GCS) Score and GCS Subscores at Month 12 [Baseline and Month 12]

   GCS: a 21 item evaluation of symptoms which asked participants how bothered they were with particular symptom at the moment. Each item was scored as 0 = Not at all, 1 = A little, 2 = Quite a bit, and 3 = Extremely. A total score was derived from the sum of the 21 items (range 0-63). GCS was also used to generate 6 individual scores (psychological symptoms [range 0-33], anxiety [range 0-18], depression [range 0-15], somatic symptoms [range 0-21], vasomotor symptoms [range 0-6], and sexual dysfunction [range 0-3]). A decrease in the total climacteric score indicated an improvement in symptoms.

10. Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for Main Study Efficacy Population at Week 12 [Week 12]

    PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).

11. Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for Main Study Efficacy Population at Month 6 [Month 6]

    PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).

12. Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for Main Study Efficacy Population at Month 12 [Month 12]

    PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).

13. Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for MITT Population of Efficacy Substudy at Week 12 [Week 12]

    PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).

14. Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for MITT Population of Efficacy Substudy at Month 6 [Month 6]

    PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).

15. Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for MITT Population of Efficacy Substudy at Month 12 [Month 12]

    PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).

16. Percentage of Participants With Categorical Scores on Patient Global Impression Change (PGI-C) for Main Study Efficacy Population at Week 12 [Week 12]

    PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).

17. Percentage of Participants With Categorical Scores on Patient Global Impression Change (PGI-C) for Main Study Efficacy Population at Month 6 [Month 6]

    PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).

18. Percentage of Participants With Categorical Scores Based on Patient Global Impression Change (PGI-C) for Main Study Efficacy Population at Month 12 [Month 12]

    PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).

19. Percentage of Participants With Categorical Scores on Patient Global Impression Change (PGI-C) for MITT Population of Efficacy Substudy at Week 12 [Week 12]

    PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).

20. Percentage of Participants With Categorical Scores on Patient Global Impression Change (PGI-C) for MITT Population of Efficacy Substudy at Month 6 [Month 6]

    PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).

21. Percentage of Participants With Categorical Scores Based on Patient Global Impression Change (PGI-C) for MITT Population of Efficacy Substudy at Month 12 [Month 12]

    PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).

Other Outcome Measures

1. Number of Participants With Adjudicated Cerebrovascular Events - Any Stroke [Baseline up to Month 12]

   Adjudicated cerebrovascular events were identified using Standardized MedDRA Query (SMQ), for "central nervous system haemorrhages and cerebrovascular conditions". Primary assessments included: 1) definite stroke, 2) probable stroke, 3) probable transient ischemic attack (TIA), and 4) no stroke or TIA.

2. Number of Participants With Adjudicated Cerebrovascular Events - Probable TIA [Baseline up to Month 12]

   Adjudicated cerebrovascular events were identified using Standardized MedDRA Query (SMQ), for "central nervous system haemorrhages and cerebrovascular conditions". Primary assessments included: 1) definite stroke, 2) probable stroke, 3) probable transient ischemic attack (TIA), and 4) no stroke or TIA.

3. Number of Participants With Ischemic Heart Disease [Baseline up to Month 12]

   Potential ischaemic cardiac events were identified using the Standardized MedDRA Query (SMQ) "Ischemic Heart Disease".

4. Number of Participants With Hepatic Events [Baseline up to Month 12]

   Hepatic events were defined as incidence of increased Liver Function Test (AST [aspartate aminotransferase] or ALT [alanine aminotransferase]) levels greater than 5 times the ULN (upper limit of normal).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Generally healthy, postmenopausal women who seek treatment for hot flushes

• Body Mass Index (BMI) less than or equal to 34 kg/m^2

Exclusion Criteria:

• Hypersensitivity to Venlafaxine

• Myocardial infarction an/or unstable angina within 6 months of screening

• History of seizure disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Birmingham	Alabama	United States	35235
2	Pfizer Investigational Site	Mobile	Alabama	United States	36608
3	Pfizer Investigational Site	Montgomery	Alabama	United States	36106
4	Pfizer Investigational Site	Glendale	Arizona	United States	85308
5	Pfizer Investigational Site	Peoria	Arizona	United States	85381
6	Pfizer Investigational Site	Tucson	Arizona	United States	85710
7	Pfizer Investigational Site	Tucson	Arizona	United States	85712
8	Pfizer Investigational Site	Tucson	Arizona	United States	85715
9	Pfizer Investigational Site	Jonesboro	Arkansas	United States	72401
10	Pfizer Investigational Site	Little Rock	Arkansas	United States	72205
11	Pfizer Investigational Site	Little Rock	Arkansas	United States	72223
12	Pfizer Investigational Site	San Diego	California	United States	92103
13	Pfizer Investigational Site	San Diego	California	United States	92108
14	Pfizer Investigational Site	San Diego	California	United States	92123
15	Pfizer Investigational Site	Vista	California	United States	92083
16	Pfizer Investigational Site	Walnut Creek	California	United States	94598
17	Pfizer Investigational Site	Colorado Springs	Colorado	United States	80910
18	Pfizer Investigational Site	Denver	Colorado	United States	80218
19	Pfizer Investigational Site	Englewood	Colorado	United States	80112
20	Pfizer Investigational Site	Longmont	Colorado	United States	80501
21	Pfizer Investigational Site	New London	Connecticut	United States	06320
22	Pfizer Investigational Site	Newark	Delaware	United States	19713
23	Pfizer Investigational Site	Brooksville	Florida	United States	34601
24	Pfizer Investigational Site	Clearwater	Florida	United States	33759
25	Pfizer Investigational Site	Clearwater	Florida	United States	33761
26	Pfizer Investigational Site	Daytona Beach	Florida	United States	32114
27	Pfizer Investigational Site	Fort Myers	Florida	United States	33916
28	Pfizer Investigational Site	Gainesville	Florida	United States	32610
29	Pfizer Investigational Site	Lake Worth	Florida	United States	33461
30	Pfizer Investigational Site	New Port Richey	Florida	United States	34652
31	Pfizer Investigational Site	Palm Harbor	Florida	United States	34684
32	Pfizer Investigational Site	Pembroke Pines	Florida	United States	33024
33	Pfizer Investigational Site	South Miami	Florida	United States	33143
34	Pfizer Investigational Site	Tampa	Florida	United States	33606
35	Pfizer Investigational Site	West Palm Beach	Florida	United States	33409
36	Pfizer Investigational Site	Atlanta	Georgia	United States	30342
37	Pfizer Investigational Site	Decatur	Georgia	United States	30033
38	Pfizer Investigational Site	Decatur	Georgia	United States	30319
39	Pfizer Investigational Site	Savannah	Georgia	United States	31406
40	Pfizer Investigational Site	Boise	Idaho	United States	83702
41	Pfizer Investigational Site	Idaho Falls	Idaho	United States	83404
42	Pfizer Investigational Site	Indianapolis	Indiana	United States	46202
43	Pfizer Investigational Site	Indianapolis	Indiana	United States	46260
44	Pfizer Investigational Site	South Bend	Indiana	United States	46601
45	Pfizer Investigational Site	Overland Park	Kansas	United States	66210
46	Pfizer Investigational Site	Lexington	Kentucky	United States	40509
47	Pfizer Investigational Site	Louisville	Kentucky	United States	40291
48	Pfizer Investigational Site	New Orleans	Louisiana	United States	70114
49	Pfizer Investigational Site	Scarborough	Maine	United States	04074
50	Pfizer Investigational Site	Ann Arbor	Michigan	United States	48106
51	Pfizer Investigational Site	Brooklyn Center	Minnesota	United States	55430
52	Pfizer Investigational Site	Creve Coeur	Missouri	United States	63141
53	Pfizer Investigational Site	Billings	Montana	United States	59101
54	Pfizer Investigational Site	Billings	Montana	United States	59102
55	Pfizer Investigational Site	Lincoln	Nebraska	United States	68510
56	Pfizer Investigational Site	Las Vegas	Nevada	United States	89109
57	Pfizer Investigational Site	Las Vegas	Nevada	United States	89146
58	Pfizer Investigational Site	Reno	Nevada	United States	89502
59	Pfizer Investigational Site	Lebanon	New Hampshire	United States	03756
60	Pfizer Investigational Site	New Brunswick	New Jersey	United States	08901
61	Pfizer Investigational Site	Albuquerque	New Mexico	United States	87102
62	Pfizer Investigational Site	New York	New York	United States	10032
63	Pfizer Investigational Site	Winston-Salem	North Carolina	United States	27103
64	Pfizer Investigational Site	Bismarck	North Dakota	United States	58501
65	Pfizer Investigational Site	Fargo	North Dakota	United States	58104
66	Pfizer Investigational Site	Jamestown	North Dakota	United States	58401
67	Pfizer Investigational Site	Akron	Ohio	United States	44311
68	Pfizer Investigational Site	Cincinnati	Ohio	United States	45267-0457
69	Pfizer Investigational Site	Cleveland	Ohio	United States	44122
70	Pfizer Investigational Site	Englewood	Ohio	United States	45322
71	Pfizer Investigational Site	Oklahoma City	Oklahoma	United States	73112-4481
72	Pfizer Investigational Site	Eugene	Oregon	United States	97401
73	Pfizer Investigational Site	Medford	Oregon	United States	97504
74	Pfizer Investigational Site	Erie	Pennsylvania	United States	16502
75	Pfizer Investigational Site	Erie	Pennsylvania	United States	16507-1411
76	Pfizer Investigational Site	Jenkintown	Pennsylvania	United States	19046
77	Pfizer Investigational Site	Philadelphia	Pennsylvania	United States	19114
78	Pfizer Investigational Site	Pittsburgh	Pennsylvania	United States	15206
79	Pfizer Investigational Site	Wexford	Pennsylvania	United States	15090
80	Pfizer Investigational Site	Warwick	Rhode Island	United States	02886
81	Pfizer Investigational Site	Greer	South Carolina	United States	29651
82	Pfizer Investigational Site	Hilton Head Island	South Carolina	United States	29926
83	Pfizer Investigational Site	Sioux Falls	South Dakota	United States	57104
84	Pfizer Investigational Site	Sioux Falls	South Dakota	United States	57105
85	Pfizer Investigational Site	Watertown	South Dakota	United States	57201
86	Pfizer Investigational Site	Chattanooga	Tennessee	United States	37404
87	Pfizer Investigational Site	Knoxville	Tennessee	United States	37920
88	Pfizer Investigational Site	Nashville	Tennessee	United States	37203
89	Pfizer Investigational Site	Dallas	Texas	United States	75234
90	Pfizer Investigational Site	Houston	Texas	United States	77030
91	Pfizer Investigational Site	Midland	Texas	United States	79705
92	Pfizer Investigational Site	Plano	Texas	United States	75093
93	Pfizer Investigational Site	San Antonio	Texas	United States	78229
94	Pfizer Investigational Site	Waco	Texas	United States	76712
95	Pfizer Investigational Site	Salt Lake City	Utah	United States	84117
96	Pfizer Investigational Site	Sandy	Utah	United States	84070
97	Pfizer Investigational Site	Burlington	Vermont	United States	05401
98	Pfizer Investigational Site	Norfolk	Virginia	United States	23502
99	Pfizer Investigational Site	Norfolk	Virginia	United States	23507
100	Pfizer Investigational Site	Richmond	Virginia	United States	23294
101	Pfizer Investigational Site	Seattle	Washington	United States	98105
102	Pfizer Investigational Site	Menomonee Falls	Wisconsin	United States	53051
103	Pfizer Investigational Site	Calgary	Alberta	Canada	T2N 4L7
104	Pfizer Investigational Site	Coquitlam	British Columbia	Canada	V3K 3V9
105	Pfizer Investigational Site	Surrey	British Columbia	Canada	V4A 2H9
106	Pfizer Investigational Site	Winnipeg	Manitoba	Canada	R3T 2E8
107	Pfizer Investigational Site	Antigonish	Nova Scotia	Canada	B2G 2C2
108	Pfizer Investigational Site	Corunna	Ontario	Canada	N0N 1G0
109	Pfizer Investigational Site	Ottawa	Ontario	Canada	K1H 7W9
110	Pfizer Investigational Site	Sarnia	Ontario	Canada	N7T 4X3
111	Pfizer Investigational Site	Toronto	Ontario	Canada	M4S 1Y2
112	Pfizer Investigational Site	Toronto	Ontario	Canada	M5B 1W8
113	Pfizer Investigational Site	Toronto	Ontario	Canada	M9W 4L6
114	Pfizer Investigational Site	Gatineau	Quebec	Canada	J9A 1K7
115	Pfizer Investigational Site	L'Ancienne-Lorette	Quebec	Canada	G2E 2X1
116	Pfizer Investigational Site	Pointe Claire	Quebec	Canada	H9R 4S3
117	Pfizer Investigational Site	Saint-Janvier	Quebec	Canada	J7J 2K8
118	Pfizer Investigational Site	Shawinigan	Quebec	Canada	G9N 2H6
119	Pfizer Investigational Site	Sherbrooke	Quebec	Canada	J1H 4J6
120	Pfizer Investigational Site	St-Romuald	Quebec	Canada	G6W 5M6
121	Pfizer Investigational Site	Quebec		Canada	G1S 2L6

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00683800
• Other Study ID Numbers: 3151A2-3353; B2061011
• First Posted: May 23, 2008
• Last Update Posted: Aug 17, 2011
• Last Verified: Jul 1, 2011

• Keywords provided by , ,: Menopause; Hot Flush; Hot Flash; Desvenlafaxine succinate Sustained Release
• Additional relevant MeSH terms: Desvenlafaxine Succinate

Study Results

Participant Flow

Pre-assignment Detail	A total of 3784 participants were screened, of which 1598 participants were screen failures and 2186 participants were randomly assigned to treatment.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Period Title: Overall Study
STARTED	1101	1085
Treated	1066	1052
COMPLETED	669	719
NOT COMPLETED	432	366

Baseline Characteristics

Arm/Group Title	DVS SR 100 mg	Placebo	Total
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.	Total of all reporting groups
Overall Participants	1066	1052	2118
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.95 (4.90)	53.59 (4.91)	53.77 (4.90)
Sex: Female, Male (Count of Participants)
Female	1066 100%	1052 100%	2118 100%
Male	0 0%	0 0%	0 0%
Daily number of moderate and severe hot flushes (Hot Flushes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Hot Flushes]	11.67 (5.62)	11.91 (5.71)	11.79 (5.66)
Daily severity score of hot flushes (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	2.36 (0.34)	2.39 (0.35)	2.37 (0.34)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Average Daily Number of Moderate to Severe Hot Flushes at Week 4
Description	The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat(MITT) population: Participants randomized into efficacy substudy; at least 1 dose of study drug, vasomotor symptoms on at least 1 day of baseline period and 1 day of on-therapy period during initial 12 weeks. Last observation carried forward (LOCF) method was used. 1 participant in each group did not have data till Week 4.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	183	180
Mean (Standard Error) [Hot Flushes]	-6.52 (0.33)	-3.64 (0.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	An analysis of covariance with treatment as factor and baseline value as a covariate was used to compare DVS SR 100 mg with matching placebo. The comparison was performed at significance level of p=0.05 (two sided).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-2.89
	Confidence Interval	(2-Sided) 95%; -3.80 to -1.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in the Average Daily Number of Moderate to Severe Hot Flushes at Week 12
Description	The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

MITT population included all participants who were randomized into efficacy substudy, had at least 1 dose of study drug, had vasomotor symptoms recorded on at least 1 day of baseline period and at least 1 day of on-therapy period during initial 12 weeks of therapy. Assessment was done using last observation carried forward (LOCF) method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	184	181
Mean (Standard Error) [Hot Flushes]	-7.31 (0.35)	-4.52 (0.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	An analysis of covariance with treatment as factor and baseline value as a covariate was used to compare DVS SR 100 mg with matching placebo. The comparison was performed at significance level of p=0.05 (two sided).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-2.79
	Confidence Interval	(2-Sided) 95%; -3.77 to -1.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in the Average Daily Severity of Hot Flushes at Week 4
Description	Severity ranged from mild (sensation of heat without sweating); moderate (sensation of heat with sweating; able to continue activity) to severe (sensation of heat with sweating; causing cessation of activity). The average daily severity of hot flushes for each time period was calculated as (1*Number of mild+2*Number of moderate+3*Number of severe)/(Total number of hot flushes). For the days with no hot flushes, the severity score was set as 0. As this was derived from the count data, there was no maximum; the minimum score was 0; the higher values showed worse outcomes.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

MITT population: All participants randomized into efficacy substudy, had at least 1 dose of study drug, had vasomotor symptoms recorded on at least 1 day of baseline period and at least 1 day of on-therapy period during initial 12 weeks of therapy. Assessment was done using LOCF method. 1 participant in each group did not have data till Week 4.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	183	180
Mean (Standard Error) [Units on a Scale]	-0.47 (0.04)	-0.19 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	An analysis of covariance with treatment as factor and baseline value as a covariate was used to compare DVS SR 100 mg with matching placebo. The comparison was performed at significance level of p=0.05 (two sided).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Change From Baseline in the Average Daily Severity of Hot Flushes at Week 12
Description	Severity ranged from mild (sensation of heat without sweating); moderate (sensation of heat with sweating; able to continue activity) to severe (sensation of heat with sweating; causing cessation of activity). The average daily severity of hot flushes for each time period was calculated as (1*Number of mild+2*Number of moderate+3*Number of severe)/(Total number of hot flushes). For the days with no hot flushes, the severity score was set as 0. As this was derived from the count data, there was no maximum; the minimum score was 0; the higher values showed worse outcomes.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

MITT population included all participants who were randomized into efficacy substudy, had at least 1 dose of study drug, had vasomotor symptoms recorded on at least 1 day of baseline period and at least 1 day of on-therapy period during initial 12 weeks of therapy. Assessment was done using last observation carried forward (LOCF) method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	184	181
Mean (Standard Error) [Units on a Scale]	-0.59 (0.05)	-0.28 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	An analysis of covariance with treatment as factor and baseline value as a covariate was used to compare DVS SR 100 mg with matching placebo. The comparison was performed at significance level of p=0.05 (two sided).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -0.44 to -0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Number of Participants With All Adjudicated Ischemic Cardiovascular (CV) Events
Description	Adjudicated ischemic cardiovascular events were a composite of: a) Coronary Heart Disease (CHD)-related death; b) New Myocardial Infarction (MI) (non-procedure-related MI); c) Documented new onset of unstable angina requiring hospitalization; d) Unscheduled coronary revascularization procedures (percutaneous coronary intervention) or bypass grafting.
Time Frame	Baseline up to Month 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study medication.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	1066	1052
Any ischemic CV event	0 0%	1 0.1%
CHD related death	0 0%	0 0%
New MI	0 0%	1 0.1%
New Onset of Unstable Angina	0 0%	0 0%
Unscheduled Coronary Revascularization Procedures	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	Excess risk of DVS SR 100 mg over placebo per 1000 woman-years of exposure, defined as the difference in the exposure adjusted rates between the treatment groups, was obtained.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Wald Formula
	Estimated Value	-1.07
	Confidence Interval	(2-Sided) 90%; -2.86 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 90% CI for excess risk was obtained using the Wald Formula.

6. Secondary Outcome

Title	Number of Participants With a Minimal Clinically Meaningful Decrease in the Average Daily Number of Hot Flushes
Description	A mean decrease from baseline of at least 5.35 moderate to severe hot flushes at week 12 in the participants was considered clinically meaningful.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

MITT population included all participants who were randomized into efficacy substudy, had at least 1 dose of study drug, had vasomotor symptoms recorded on at least 1 day of baseline period and at least 1 day of on-therapy period during initial 12 weeks of therapy. Assessment was done using last observation carried forward (LOCF) method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	184	181
Number [Participants]	117 11%	75 7.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	The proportion of participants achieving a response as defined by minimal clinically important difference (MCID) at week 12 was compared between DVS and placebo treatment groups with a Cochran-Mantel-Haenszel test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

7. Secondary Outcome

Title	Percentage of Participants With at Least 50% Reduction From Baseline in the Number of Moderate and Severe Hot Flushes
Description	The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity.
Time Frame	Baseline, Week 4 and Week 12

Outcome Measure Data

Analysis Population Description

MITT population included all participants who were randomized into efficacy substudy, had at least 1 dose of study drug, had vasomotor symptoms recorded on at least 1 day of baseline period and at least 1 day of on-therapy period during initial 12 weeks of therapy. Assessment was done using last observation carried forward (LOCF) method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	184	181
Week 4	58.47 5.5%	28.89 2.7%
Week 12	67.93 6.4%	44.20 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	The proportion of participants achieving at least 50% hot flush reduction from baseline at 4-week was compared between DVS and placebo treatment groups with a logistic regression model with treatment as factor and baseline value as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.47
	Confidence Interval	(2-Sided) 95%; 2.24 to 5.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	The proportion of participants achieving at least 50% hot flush reduction from baseline at 12-week was compared between DVS and placebo treatment groups with a logistic regression model with treatment as factor and baseline value as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.67
	Confidence Interval	(2-Sided) 95%; 1.75 to 4.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants With at Least 75% Reduction From Baseline in the Number of Moderate and Severe Hot Flushes
Description	The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity.
Time Frame	Baseline, Week 4 and Week 12

Outcome Measure Data

Analysis Population Description

MITT population included all participants who were randomized into efficacy substudy, had at least 1 dose of study drug, had vasomotor symptoms recorded on at least 1 day of baseline period and at least 1 day of on-therapy period during initial 12 weeks of therapy. Assessment was done using last observation carried forward (LOCF) method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	184	181
Week 4	32.79 3.1%	10.00 1%
Week 12	41.30 3.9%	18.23 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	The proportion of participants achieving at least 75% hot flush reduction from baseline at 4-week was compared between DVS and placebo treatment groups with a logistic regression model with treatment as factor and baseline value as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.39
	Confidence Interval	(2-Sided) 95%; 2.47 to 7.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	The proportion of participants achieving at least 75% hot flush reduction from baseline at 12-week was compared between DVS and placebo treatment groups with a logistic regression model with treatment as factor and baseline value as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.16
	Confidence Interval	(2-Sided) 95%; 1.96 to 5.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Median Time to the First Day of 3 Consecutive Days of at Least 50% Reduction in Hot Flushes
Description	Time to response was defined as the time-to-first 50% reduction in the average daily number of moderate to severe hot flushes over 3 consecutive days.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

MITT population included all participants who were randomized into efficacy substudy, had at least 1 dose of study drug, had vasomotor symptoms recorded on at least 1 day of baseline period and at least 1 day of on-therapy period during initial 12 weeks of therapy.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	184	181
Median (95% Confidence Interval) [Days]	13.0	48.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A log-rank test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments

10. Secondary Outcome

Title	Change From Baseline in Adjusted Means in the Number of Moderate and Severe Hot Flushes at Month 6 and Month 12
Description	The average daily number of moderate and severe hot flushes was calculated as the sum of the number of moderate and severe hot flushes on each day divided by the number of days with data. Moderate hot flushes: sensation of heat with sweating; able to continue activity; and severe hot flushes: sensation of heat with sweating; causing cessation of activity. Adjusted mean was calculated by using change from baseline as response variable, treatment as factor, and baseline as covariate using the observed cases.
Time Frame	Baseline, Month 6 and Month 12

Outcome Measure Data

Analysis Population Description

MITT participants of the efficacy sub-study population who had non-missing average daily number of moderate and severe hot flushes. The assessment was done using observed values. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the time point for each group respectively.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	184	181
Month 6 (n= 125, 124)	-8.65 (0.37)	-6.61 (0.37)
Month 12 (n= 112, 102)	-7.98 (0.46)	-5.17 (0.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	An analysis of covariance with treatment as factor and baseline value as a covariate was used to compare DVS SR 100 mg with matching placebo. The comparison was performed at significance level of p=0.05 (two sided). (At month 6)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-2.04
	Confidence Interval	(2-Sided) 95%; -3.07 to -1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	An analysis of covariance with treatment as factor and baseline value as a covariate was used to compare DVS SR 100 mg with matching placebo. The comparison was performed at significance level of p=0.05 (two sided). (At month 12)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-2.81
	Confidence Interval	(2-Sided) 95%; -4.12 to -1.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in Adjusted Means in the Hot Flush Severity Score at Month 6 and Month 12
Description	Severity: mild (heat sensation without sweating); moderate (heat sensation with sweating; able to continue activity); severe (heat sensation with sweating; causing cessation of activity). Average daily severity of hot flushes= (1*Number of mild+2*Number of moderate+3*Number of severe)/(Total number of hot flushes). Days with no hot flushes: severity score=0. As it was derived from count data, there was no maximum; minimum score=0; higher values= worse outcomes. Adjusted mean: calculated using change from baseline=response variable, treatment=factor and baseline=covariate using observed cases.
Time Frame	Baseline, Month 6 and Month 12

Outcome Measure Data

Analysis Population Description

MITT participants of the efficacy sub-study population who had non-missing average daily number of moderate and severe hot flushes. The assessment was done using observed values. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the time point for each group respectively.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	184	181
Month 6 (n= 125, 124)	-0.87 (0.07)	-0.56 (0.07)
Month 12 (n= 112, 102)	-0.78 (0.07)	-0.45 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	An analysis of covariance with treatment as factor and baseline value as a covariate was used to compare DVS SR 100 mg with matching placebo. The comparison was performed at significance level of p=0.05 (two sided). (At month 6)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -0.51 to -0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	An analysis of covariance with treatment as factor and baseline value as a covariate was used to compare DVS SR 100 mg with matching placebo. The comparison was performed at significance level of p=0.05 (two sided). (At month 12)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline in the Total Greene Climacteric Scale (GCS) Score and GCS Subscores at Week 12
Description	GCS: a 21 item evaluation of symptoms which asked participants how bothered they were with particular symptom at the moment. Each item was scored as 0 = Not at all, 1 = A little, 2 = Quite a bit, and 3 = Extremely. A total score was derived from the sum of the 21 items (range 0-63). GCS was also used to generate 6 individual scores (psychological symptoms [range 0-33], anxiety [range 0-18], depression [range 0-15], somatic symptoms [range 0-21], vasomotor symptoms [range 0-6], and sexual dysfunction [range 0-3]). A decrease in the total climacteric score indicated an improvement in symptoms.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Main study efficacy population included all participants who were randomized; had at least 1 dose of study medication; and had a baseline and at least 1 on therapy Greene Climacteric Scale (GCS) assessment or at least 1 on therapy Patient Global Impression (PGI) assessment.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	964	986
Baseline: Total Score	22.48 (0.28)	22.04 (0.28)
Baseline: Anxiety Scale	6.43 (0.10)	6.36 (0.10)
Baseline: Depression Scale	4.92 (0.10)	4.84 (0.09)
Baseline: Sexual Dysfunction Scale	1.60 (0.03)	1.65 (0.03)
Baseline: Psychological Scale	11.35 (0.18)	11.19 (0.18)
Baseline: Somatic Scale	4.54 (0.11)	4.21 (0.11)
Baseline: Vasomotor Scale	4.99 (0.04)	4.99 (0.04)
Week 12: Total Score	-9.18 (0.25)	-6.84 (0.25)
Week 12: Anxiety Scale	-2.81 (0.09)	-2.06 (0.09)
Week 12: Depression Scale	-2.23 (0.08)	-1.55 (0.08)
Week 12: Sexual Dysfunction Scale	-0.41 (0.03)	-0.36 (0.03)
Week 12: Psychological Scale	-5.04 (0.15)	-3.62 (0.15)
Week 12: Somatic Scale	-1.24 (0.09)	-1.02 (0.09)
Week 12: Vasomotor Scale	-2.50 (0.05)	-1.85 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Week 12: Change from baseline of the GCS Total score was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-2.34
	Confidence Interval	(2-Sided) 95%; -3.05 to -1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Week 12: Change from baseline of the GCS Anxiety scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.75
	Confidence Interval	(2-Sided) 95%; -0.99 to -0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Week 12: Change from baseline of the GCS Depression scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.67
	Confidence Interval	(2-Sided) 95%; -0.89 to -0.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Week 12: Change from baseline of the GCS Sexual Dysfunction scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.162
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Week 12: Change from baseline of the GCS Psychological scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 was outcome variable, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-1.42
	Confidence Interval	(2-Sided) 95%; -1.84 to -1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Week 12: Change from baseline of the GCS Somatic scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.066
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.46 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Week 12: Change from baseline of the GCS Vasomotor scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 95%; -0.79 to -0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline in the Total Greene Climacteric Scale (GCS) Score and GCS Subscores at Month 6
Description	GCS: a 21 item evaluation of symptoms which asked participants how bothered they were with particular symptom at the moment. Each item was scored as 0 = Not at all, 1 = A little, 2 = Quite a bit, and 3 = Extremely. A total score was derived from the sum of the 21 items (range 0-63). GCS was also used to generate 6 individual scores (psychological symptoms [range 0-33], anxiety [range 0-18], depression [range 0-15], somatic symptoms [range 0-21], vasomotor symptoms [range 0-6], and sexual dysfunction [range 0-3]). A decrease in the total climacteric score indicated an improvement in symptoms.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Main study efficacy population included all participants who were randomized; had at least 1 dose of study medication; and had a baseline and at least 1 on therapy GCS assessment or at least 1 on therapy PGI assessment.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	796	836
Total Score	-9.84 (0.25)	-7.97 (0.25)
Anxiety Scale	-3.06 (0.09)	-2.41 (0.09)
Depression Scale	-2.35 (0.08)	-1.77 (0.08)
Sexual Dysfunction Scale	-0.46 (0.03)	-0.41 (0.03)
Psychological Scale	-5.39 (0.15)	-4.15 (0.15)
Somatic Scale	-1.49 (0.08)	-1.31 (0.08)
Vasomotor Scale	-2.55 (0.06)	-2.14 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 6: Change from baseline of the GCS Total score was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-1.87
	Confidence Interval	(2-Sided) 95%; -2.57 to -1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 6: Change from baseline of the GCS Anxiety scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.65
	Confidence Interval	(2-Sided) 95%; -0.90 to -0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 6: Change from baseline of the GCS Depression scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95%; -0.80 to -0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 6: Change from baseline of the GCS Sexual Dysfunction scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.282
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 6: Change from baseline of the GCS Psychological scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-1.24
	Confidence Interval	(2-Sided) 95%; -1.66 to -0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 6: Change from baseline of the GCS Somatic scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.140
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 6: Change from baseline of the GCS Vasomotor scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6, and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in the Total Greene Climacteric Scale (GCS) Score and GCS Subscores at Month 12
Description	GCS: a 21 item evaluation of symptoms which asked participants how bothered they were with particular symptom at the moment. Each item was scored as 0 = Not at all, 1 = A little, 2 = Quite a bit, and 3 = Extremely. A total score was derived from the sum of the 21 items (range 0-63). GCS was also used to generate 6 individual scores (psychological symptoms [range 0-33], anxiety [range 0-18], depression [range 0-15], somatic symptoms [range 0-21], vasomotor symptoms [range 0-6], and sexual dysfunction [range 0-3]). A decrease in the total climacteric score indicated an improvement in symptoms.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Main study efficacy population included all participants who were randomized; had at least 1 dose of study medication; and had a baseline and at least 1 on therapy GCS assessment or at least 1 on therapy PGI assessment.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	673	718
Total Score	-10.60 (0.26)	-8.89 (0.25)
Anxiety Scale	-3.25 (0.09)	-2.69 (0.09)
Depression Scale	-2.66 (0.08)	-2.04 (0.08)
Sexual Dysfunction Scale	-0.51 (0.03)	-0.43 (0.03)
Psychological Scale	-5.88 (0.16)	-4.70 (0.15)
Somatic Scale	-1.63 (0.09)	-1.61 (0.08)
Vasomotor Scale	-2.64 (0.06)	-2.19 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 12: Change from baseline of the GCS Total score was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6 and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-1.71
	Confidence Interval	(2-Sided) 95%; -2.42 to -1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 12: Change from baseline of the GCS Anxiety scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6 and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95%; -0.81 to -0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 12: Change from baseline of the GCS Depression scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6 and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -0.83 to -0.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 12: Change from baseline of the GCS Sexual Dysfunction scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6 and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.082
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 12: Change from baseline of the GCS Psychological scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6 and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-1.18
	Confidence Interval	(2-Sided) 95%; -1.61 to -0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 12: Change from baseline of the GCS Somatic scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6 and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.865
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	For Month 12: Change from baseline of the GCS Vasomotor scale subscore was analyzed using a Mixed-effects model repeated measures (MMRM), for which changes from baseline at week 12, month 6 and month 12 were outcome variables, with treatment, week, and interaction between treatment and week as fixed effects with participant as a random effect, and with the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.45
	Confidence Interval	(2-Sided) 95%; -0.61 to -0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for Main Study Efficacy Population at Week 12
Description	PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Main study efficacy population included all participants who were randomized; had at least 1 dose of study medication; and had a baseline and at least 1 on therapy GCS assessment or at least 1 on therapy PGI assessment. Assessment was done using LOCF method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	961	982
1= None	8.8 0.8%	5.0 0.5%
2= Minimal	27.8 2.6%	18.5 1.8%
3= Mild	28.9 2.7%	26.5 2.5%
4= Moderate	24.9 2.3%	33.8 3.2%
5= Severe	9.6 0.9%	16.2 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

16. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for Main Study Efficacy Population at Month 6
Description	PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

Main study efficacy population included all participants who were randomized; had at least 1 dose of study medication; and had a baseline and at least 1 on therapy GCS assessment or at least 1 on therapy PGI assessment. Assessment was done using LOCF method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	963	986
1= None	8.5 0.8%	5.7 0.5%
2= Minimal	32.2 3%	25.5 2.4%
3= Mild	27.3 2.6%	23.1 2.2%
4= Moderate	22.9 2.1%	31.1 3%
5= Severe	9.0 0.8%	14.6 1.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

17. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for Main Study Efficacy Population at Month 12
Description	PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Main study efficacy population included all participants who were randomized; had at least 1 dose of study medication; and had a baseline and at least 1 on therapy GCS assessment or at least 1 on therapy PGI assessment. Assessment was done using LOCF method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	963	986
1= None	10.1 0.9%	7.1 0.7%
2= Minimal	32.2 3%	27.8 2.6%
3= Mild	25.9 2.4%	21.0 2%
4= Moderate	21.6 2%	29.7 2.8%
5= Severe	10.3 1%	14.4 1.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

18. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for MITT Population of Efficacy Substudy at Week 12
Description	PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

MITT population: All participants randomized into efficacy substudy; at least 1 dose of study drug, vasomotor symptoms recorded on at least 1 day of baseline period and 1 day of on-therapy period during initial 12 weeks of therapy. LOCF method was used. Participants analyzed included those who were evaluated for this particular scale.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	172	175
1= None	8.1 0.8%	1.7 0.2%
2= Minimal	20.3 1.9%	10.9 1%
3= Mild	29.1 2.7%	16.6 1.6%
4= Moderate	24.4 2.3%	42.9 4.1%
5= Severe	18.0 1.7%	28.0 2.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

19. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for MITT Population of Efficacy Substudy at Month 6
Description	PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

MITT population: All participants randomized into efficacy substudy; at least 1 dose of study drug, vasomotor symptoms recorded on at least 1 day of baseline period and 1 day of on-therapy period during initial 12 weeks of therapy. LOCF method was used. Participants analyzed included those who were evaluated for this particular scale.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	172	175
1= None	12.2 1.1%	2.9 0.3%
2= Minimal	29.7 2.8%	18.3 1.7%
3= Mild	27.3 2.6%	17.7 1.7%
4= Moderate	16.9 1.6%	34.3 3.3%
5= Severe	14.0 1.3%	26.9 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

20. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Symptom Rating (PGI-R) for MITT Population of Efficacy Substudy at Month 12
Description	PGI-R scale was intended to assess the study participant's perception of symptoms. Participants were requested to identify the severity of their hot flush symptoms. It was a 5-scale which ranged from 1 (None) to 5 (Severe).
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

MITT population: All participants randomized into efficacy substudy; at least 1 dose of study drug, vasomotor symptoms recorded on at least 1 day of baseline period and 1 day of on-therapy period during initial 12 weeks of therapy. LOCF method was used. Participants analyzed included those who were evaluated for this particular scale.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	172	175
1= None	9.3 0.9%	4.0 0.4%
2= Minimal	28.5 2.7%	17.1 1.6%
3= Mild	26.7 2.5%	12.6 1.2%
4= Moderate	18.0 1.7%	39.4 3.7%
5= Severe	17.4 1.6%	26.9 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

21. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Change (PGI-C) for Main Study Efficacy Population at Week 12
Description	PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Main study efficacy population included all participants who were randomized; had at least 1 dose of study medication; and had a baseline and at least 1 on therapy GCS assessment or at least 1 on therapy PGI assessment. Assessment was done using LOCF method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	962	983
1= Very Much Improved	25.8 2.4%	13.1 1.2%
2= Much Improved	32.3 3%	25.5 2.4%
3= Minimally Improved	23.3 2.2%	25.1 2.4%
4= No Change	11.5 1.1%	29.3 2.8%
5= Minimally Worse	4.1 0.4%	4.5 0.4%
6= Much Worse	2.2 0.2%	1.7 0.2%
7= Very Much Worse	0.8 0.1%	0.7 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

22. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Change (PGI-C) for Main Study Efficacy Population at Month 6
Description	PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

Main study efficacy population included all participants who were randomized; had at least 1 dose of study medication; and had a baseline and at least 1 on therapy GCS assessment or at least 1 on therapy PGI assessment. Assessment was done using LOCF method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	963	986
1= Very Much Improved	28.9 2.7%	17.1 1.6%
2= Much Improved	32.3 3%	27.7 2.6%
3= Minimally Improved	20.5 1.9%	20.6 2%
4= No Change	11.6 1.1%	26.2 2.5%
5= Minimally Worse	3.5 0.3%	5.2 0.5%
6= Much Worse	2.1 0.2%	2.6 0.2%
7= Very Much Worse	1.1 0.1%	0.6 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

23. Secondary Outcome

Title	Percentage of Participants With Categorical Scores Based on Patient Global Impression Change (PGI-C) for Main Study Efficacy Population at Month 12
Description	PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Main study efficacy population included all participants who were randomized; had at least 1 dose of study medication; and had a baseline and at least 1 on therapy GCS assessment or at least 1 on therapy PGI assessment. Assessment was done using LOCF method.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	963	986
1= Very Much Improved	31.0 2.9%	19.9 1.9%
2= Much Improved	29.2 2.7%	24.5 2.3%
3= Minimally Improved	21.1 2%	21.5 2%
4= No Change	12.7 1.2%	26.8 2.5%
5= Minimally Worse	2.4 0.2%	4.4 0.4%
6= Much Worse	2.7 0.3%	2.0 0.2%
7= Very Much Worse	0.9 0.1%	0.9 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

24. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Change (PGI-C) for MITT Population of Efficacy Substudy at Week 12
Description	PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

MITT population: All participants randomized into efficacy substudy; at least 1 dose of study drug, vasomotor symptoms recorded on at least 1 day of baseline period and 1 day of on-therapy period during initial 12 weeks of therapy. LOCF method was used. Participants analyzed included those who were evaluated for this particular scale.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	172	175
1= Very Much Improved	26.7 2.5%	7.4 0.7%
2= Much Improved	35.5 3.3%	22.3 2.1%
3= Minimally Improved	17.4 1.6%	29.7 2.8%
4= No Change	12.8 1.2%	34.3 3.3%
5= Minimally Worse	2.9 0.3%	4.6 0.4%
6= Much Worse	3.5 0.3%	1.7 0.2%
7= Very Much Worse	1.2 0.1%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

25. Secondary Outcome

Title	Percentage of Participants With Categorical Scores on Patient Global Impression Change (PGI-C) for MITT Population of Efficacy Substudy at Month 6
Description	PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

MITT population: All participants randomized into efficacy substudy; at least 1 dose of study drug, vasomotor symptoms recorded on at least 1 day of baseline period and 1 day of on-therapy period during initial 12 weeks of therapy. LOCF method was used. Participants analyzed included those who were evaluated for this particular scale.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	172	175
1= Very Much Improved	34.9 3.3%	14.9 1.4%
2= Much Improved	32.6 3.1%	25.7 2.4%
3= Minimally Improved	15.7 1.5%	23.4 2.2%
4= No Change	11.0 1%	29.7 2.8%
5= Minimally Worse	2.3 0.2%	4.0 0.4%
6= Much Worse	2.9 0.3%	2.3 0.2%
7= Very Much Worse	0.6 0.1%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

26. Secondary Outcome

Title	Percentage of Participants With Categorical Scores Based on Patient Global Impression Change (PGI-C) for MITT Population of Efficacy Substudy at Month 12
Description	PGI-C score was intended to assess the study participant's perception of changes in hot flushes. It was 7-point scale which ranged from 1 (Very Much Improved) to 7 (Very Much Worse).
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

MITT population: All participants randomized into efficacy substudy; at least 1 dose of study drug, vasomotor symptoms recorded on at least 1 day of baseline period and 1 day of on-therapy period during initial 12 weeks of therapy. LOCF method was used. Participants analyzed included those who were evaluated for this particular scale.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	172	175
1= Very Much Improved	37.2 3.5%	13.7 1.3%
2= Much Improved	24.4 2.3%	18.3 1.7%
3= Minimally Improved	21.5 2%	25.1 2.4%
4= No Change	10.5 1%	36.0 3.4%
5= Minimally Worse	1.2 0.1%	5.1 0.5%
6= Much Worse	4.1 0.4%	1.7 0.2%
7= Very Much Worse	1.2 0.1%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	A Cochran-Mantel-Haenszel row mean score test was used to compare the treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

27. Other Pre-specified Outcome

Title	Number of Participants With Adjudicated Cerebrovascular Events - Any Stroke
Description	Adjudicated cerebrovascular events were identified using Standardized MedDRA Query (SMQ), for "central nervous system haemorrhages and cerebrovascular conditions". Primary assessments included: 1) definite stroke, 2) probable stroke, 3) probable transient ischemic attack (TIA), and 4) no stroke or TIA.
Time Frame	Baseline up to Month 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study medication.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	1066	1052
Any Stroke (Definite or Probable)	1 0.1%	0 0%
Definite Stroke	0 0%	0 0%
Probable Stroke	1 0.1%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	Excess risk over placebo of DVS SR 100 mg per 1000 woman-years of exposure, defined as the difference in the exposure adjusted rates between the treatment groups, was obtained.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Wald Formula
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 90%; -0.68 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 90% CI for excess risk is obtained using the Wald Formula.

28. Other Pre-specified Outcome

Title	Number of Participants With Adjudicated Cerebrovascular Events - Probable TIA
Description	Adjudicated cerebrovascular events were identified using Standardized MedDRA Query (SMQ), for "central nervous system haemorrhages and cerebrovascular conditions". Primary assessments included: 1) definite stroke, 2) probable stroke, 3) probable transient ischemic attack (TIA), and 4) no stroke or TIA.
Time Frame	Baseline up to Month 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study medication.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	1066	1052
Number [Participants]	1 0.1%	0 0%

29. Other Pre-specified Outcome

Title	Number of Participants With Ischemic Heart Disease
Description	Potential ischaemic cardiac events were identified using the Standardized MedDRA Query (SMQ) "Ischemic Heart Disease".
Time Frame	Baseline up to Month 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study medication.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	1066	1052
Number [Participants]	4 0.4%	2 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	Excess risk over placebo of DVS SR 100 mg per 1000 woman-years of exposure, defined as the difference in the exposure adjusted rates between the treatment groups, was obtained.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Wald Formula
	Estimated Value	2.31
	Confidence Interval	(2-Sided) 90%; -2.08 to 6.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 90% CI for excess risk is obtained using the Wald Formula.

30. Other Pre-specified Outcome

Title	Number of Participants With Hepatic Events
Description	Hepatic events were defined as incidence of increased Liver Function Test (AST [aspartate aminotransferase] or ALT [alanine aminotransferase]) levels greater than 5 times the ULN (upper limit of normal).
Time Frame	Baseline up to Month 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study medication.

Arm/Group Title	DVS SR 100 mg	Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.	Matching placebo tablets daily until Day 365 or early withdrawal.
Measure Participants	1066	1052
Number [Participants]	2 0.2%	2 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DVS SR 100 mg, Placebo
	Comments	Excess risk over placebo of DVS SR 100 mg per 1000 woman-years of exposure, defined as the difference in the exposure adjusted rates between the treatment groups, was obtained.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Wald Formula
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 90%; -3.51 to 3.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 90% CI for excess risk is obtained using the Wald Formula.

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	DVS SR 100 mg		Placebo
Arm/Group Description	Desvenlafaxine Succinate Sustained Release (DVS SR) 100 milligram (mg) tablets daily until Day 365 or early withdrawal.		Matching placebo tablets daily until Day 365 or early withdrawal.
All Cause Mortality
	DVS SR 100 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	DVS SR 100 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/1066 (4%)		36/1052 (3.4%)
Blood and lymphatic system disorders
Anaemia	1/1066 (0.1%)		0/1052 (0%)
Cardiac disorders
Acute myocardial infarction	0/1066 (0%)		1/1052 (0.1%)
Angina pectoris	1/1066 (0.1%)		0/1052 (0%)
Atrial fibrillation	1/1066 (0.1%)		0/1052 (0%)
Coronary artery occlusion	0/1066 (0%)		1/1052 (0.1%)
Palpitations	0/1066 (0%)		1/1052 (0.1%)
Congenital, familial and genetic disorders
Cerebrovascular arteriovenous malformation	0/1066 (0%)		1/1052 (0.1%)
Ear and labyrinth disorders
Vertigo	0/1066 (0%)		1/1052 (0.1%)
Eye disorders
Glaucoma	0/1066 (0%)		1/1052 (0.1%)
Narrow anterior chamber angle	1/1066 (0.1%)		0/1052 (0%)
Retinal haemorrhage	1/1066 (0.1%)		0/1052 (0%)
Gastrointestinal disorders
Abdominal pain	0/1066 (0%)		1/1052 (0.1%)
Colitis ischaemic	0/1066 (0%)		1/1052 (0.1%)
Diverticular perforation	0/1066 (0%)		1/1052 (0.1%)
Gastrooesophageal reflux disease	0/1066 (0%)		1/1052 (0.1%)
Ileus	1/1066 (0.1%)		0/1052 (0%)
Ileus paralytic	1/1066 (0.1%)		0/1052 (0%)
Lower gastrointestinal haemorrhage	1/1066 (0.1%)		1/1052 (0.1%)
Stomatitis	1/1066 (0.1%)		0/1052 (0%)
Swollen tongue	1/1066 (0.1%)		0/1052 (0%)
Upper gastrointestinal haemorrhage	1/1066 (0.1%)		0/1052 (0%)
General disorders
Chest pain	0/1066 (0%)		1/1052 (0.1%)
Drug therapeutic incompatibility	1/1066 (0.1%)		0/1052 (0%)
Fatigue	1/1066 (0.1%)		0/1052 (0%)
Non-cardiac chest pain	0/1066 (0%)		2/1052 (0.2%)
Hepatobiliary disorders
Biliary dyskinesia	1/1066 (0.1%)		0/1052 (0%)
Cholecystitis	2/1066 (0.2%)		0/1052 (0%)
Infections and infestations
Cellulitis	1/1066 (0.1%)		0/1052 (0%)
Diverticulitis	0/1066 (0%)		1/1052 (0.1%)
Enterocolitis viral	0/1066 (0%)		1/1052 (0.1%)
Escherichia sepsis	1/1066 (0.1%)		0/1052 (0%)
Herpes zoster	0/1066 (0%)		1/1052 (0.1%)
Laryngitis	0/1066 (0%)		1/1052 (0.1%)
Pneumonia	1/1066 (0.1%)		1/1052 (0.1%)
Pyelonephritis	1/1066 (0.1%)		0/1052 (0%)
Subcutaneous abscess	1/1066 (0.1%)		0/1052 (0%)
Injury, poisoning and procedural complications
Drug toxicity	0/1066 (0%)		1/1052 (0.1%)
Hand fracture	1/1066 (0.1%)		0/1052 (0%)
Injury	0/1066 (0%)		1/1052 (0.1%)
Intentional overdose	2/1066 (0.2%)		2/1052 (0.2%)
Limb injury	1/1066 (0.1%)		0/1052 (0%)
Patella fracture	0/1066 (0%)		1/1052 (0.1%)
Radius fracture	1/1066 (0.1%)		0/1052 (0%)
Traumatic intracranial haemorrhage	1/1066 (0.1%)		0/1052 (0%)
Ulna fracture	1/1066 (0.1%)		0/1052 (0%)
Investigations
Blood creatine phosphokinase MB increased	1/1066 (0.1%)		0/1052 (0%)
Blood pressure increased	1/1066 (0.1%)		0/1052 (0%)
Cardiac stress test abnormal	0/1066 (0%)		1/1052 (0.1%)
Electrocardiogram T wave abnormal	1/1066 (0.1%)		0/1052 (0%)
Electrocardiogram T wave inversion	1/1066 (0.1%)		0/1052 (0%)
Electrocardiogram abnormal	0/1066 (0%)		1/1052 (0.1%)
Metabolism and nutrition disorders
Hypokalaemia	1/1066 (0.1%)		0/1052 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/1066 (0.1%)		1/1052 (0.1%)
Bunion	2/1066 (0.2%)		0/1052 (0%)
Flank pain	1/1066 (0.1%)		0/1052 (0%)
Foot deformity	1/1066 (0.1%)		0/1052 (0%)
Intervertebral disc protrusion	1/1066 (0.1%)		0/1052 (0%)
Knee deformity	1/1066 (0.1%)		0/1052 (0%)
Musculoskeletal chest pain	0/1066 (0%)		1/1052 (0.1%)
Osteoarthritis	1/1066 (0.1%)		0/1052 (0%)
Pain in extremity	1/1066 (0.1%)		0/1052 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/1066 (0.1%)		3/1052 (0.3%)
Breast cancer	0/1066 (0%)		2/1052 (0.2%)
Carcinoid tumour pulmonary	0/1066 (0%)		1/1052 (0.1%)
Dermatofibrosarcoma	0/1066 (0%)		1/1052 (0.1%)
Lung adenocarcinoma	0/1066 (0%)		1/1052 (0.1%)
Malignant melanoma in situ	0/1066 (0%)		1/1052 (0.1%)
Multiple myeloma	0/1066 (0%)		1/1052 (0.1%)
Non-small cell lung cancer stage III	0/1066 (0%)		1/1052 (0.1%)
Ovarian cancer recurrent	1/1066 (0.1%)		0/1052 (0%)
Pancreatic carcinoma metastatic	1/1066 (0.1%)		0/1052 (0%)
Squamous cell carcinoma of skin	4/1066 (0.4%)		1/1052 (0.1%)
Thyroid cancer	1/1066 (0.1%)		0/1052 (0%)
Transitional cell carcinoma	1/1066 (0.1%)		0/1052 (0%)
Uterine leiomyoma	1/1066 (0.1%)		0/1052 (0%)
Nervous system disorders
Ageusia	1/1066 (0.1%)		0/1052 (0%)
Carotid artery occlusion	0/1066 (0%)		1/1052 (0.1%)
Cerebral haematoma	1/1066 (0.1%)		0/1052 (0%)
Cervical myelopathy	0/1066 (0%)		1/1052 (0.1%)
Convulsion	1/1066 (0.1%)		0/1052 (0%)
Dysarthria	2/1066 (0.2%)		0/1052 (0%)
Hypoaesthesia	1/1066 (0.1%)		0/1052 (0%)
Migraine	1/1066 (0.1%)		0/1052 (0%)
Paraesthesia	1/1066 (0.1%)		0/1052 (0%)
Presyncope	0/1066 (0%)		1/1052 (0.1%)
Transient ischaemic attack	1/1066 (0.1%)		0/1052 (0%)
Psychiatric disorders
Major depression	1/1066 (0.1%)		0/1052 (0%)
Mental status changes	2/1066 (0.2%)		0/1052 (0%)
Renal and urinary disorders
Nephrolithiasis	1/1066 (0.1%)		0/1052 (0%)
Renal failure acute	1/1066 (0.1%)		0/1052 (0%)
Reproductive system and breast disorders
Endometrial hyperplasia	0/1066 (0%)		1/1052 (0.1%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/1066 (0.1%)		0/1052 (0%)
Asthma	1/1066 (0.1%)		0/1052 (0%)
Chronic obstructive pulmonary disease	1/1066 (0.1%)		0/1052 (0%)
Non-cardiogenic pulmonary oedema	1/1066 (0.1%)		0/1052 (0%)
Pulmonary embolism	1/1066 (0.1%)		0/1052 (0%)
Skin and subcutaneous tissue disorders
Erythema	1/1066 (0.1%)		0/1052 (0%)
Pruritus	1/1066 (0.1%)		0/1052 (0%)
Rash	1/1066 (0.1%)		0/1052 (0%)
Vascular disorders
Hypertension	1/1066 (0.1%)		0/1052 (0%)
Other (Not Including Serious) Adverse Events
	DVS SR 100 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	941/1066 (88.3%)		872/1052 (82.9%)
Blood and lymphatic system disorders
Anaemia	7/1066 (0.7%)		5/1052 (0.5%)
Leukopenia	3/1066 (0.3%)		4/1052 (0.4%)
Lymph node pain	0/1066 (0%)		1/1052 (0.1%)
Lymphadenitis	0/1066 (0%)		1/1052 (0.1%)
Lymphadenopathy	4/1066 (0.4%)		7/1052 (0.7%)
Neutropenia	2/1066 (0.2%)		3/1052 (0.3%)
Pancytopenia	1/1066 (0.1%)		0/1052 (0%)
Pernicious anaemia	1/1066 (0.1%)		0/1052 (0%)
Splenic granuloma	0/1066 (0%)		1/1052 (0.1%)
Thrombocytopenia	0/1066 (0%)		1/1052 (0.1%)
Cardiac disorders
Aortic valve incompetence	0/1066 (0%)		1/1052 (0.1%)
Arrhythmia	1/1066 (0.1%)		0/1052 (0%)
Atrial fibrillation	2/1066 (0.2%)		0/1052 (0%)
Atrioventricular block first degree	1/1066 (0.1%)		1/1052 (0.1%)
Bundle branch block left	0/1066 (0%)		1/1052 (0.1%)
Cardiac flutter	0/1066 (0%)		2/1052 (0.2%)
Conduction disorder	1/1066 (0.1%)		0/1052 (0%)
Palpitations	35/1066 (3.3%)		33/1052 (3.1%)
Pulmonary valve incompetence	0/1066 (0%)		1/1052 (0.1%)
Right atrial dilatation	1/1066 (0.1%)		0/1052 (0%)
Sinus tachycardia	1/1066 (0.1%)		0/1052 (0%)
Supraventricular extrasystoles	1/1066 (0.1%)		0/1052 (0%)
Tachycardia	7/1066 (0.7%)		7/1052 (0.7%)
Ventricular extrasystoles	4/1066 (0.4%)		0/1052 (0%)
Congenital, familial and genetic disorders
Keratosis follicular	1/1066 (0.1%)		0/1052 (0%)
Mixed hyperlipidaemia	2/1066 (0.2%)		2/1052 (0.2%)
Ear and labyrinth disorders
Cerumen impaction	2/1066 (0.2%)		0/1052 (0%)
Conductive deafness	1/1066 (0.1%)		0/1052 (0%)
Deafness	3/1066 (0.3%)		1/1052 (0.1%)
Ear canal stenosis	1/1066 (0.1%)		0/1052 (0%)
Ear congestion	2/1066 (0.2%)		0/1052 (0%)
Ear discomfort	2/1066 (0.2%)		4/1052 (0.4%)
Ear disorder	3/1066 (0.3%)		0/1052 (0%)
Ear haemorrhage	1/1066 (0.1%)		0/1052 (0%)
Ear pain	16/1066 (1.5%)		8/1052 (0.8%)
Ear pruritus	1/1066 (0.1%)		1/1052 (0.1%)
Eustachian tube dysfunction	0/1066 (0%)		1/1052 (0.1%)
Meniere's disease	2/1066 (0.2%)		0/1052 (0%)
Middle ear effusion	3/1066 (0.3%)		2/1052 (0.2%)
Motion sickness	4/1066 (0.4%)		5/1052 (0.5%)
Otosclerosis	1/1066 (0.1%)		0/1052 (0%)
Tinnitus	36/1066 (3.4%)		4/1052 (0.4%)
Tympanic membrane disorder	1/1066 (0.1%)		0/1052 (0%)
Vertigo	43/1066 (4%)		8/1052 (0.8%)
Vertigo positional	1/1066 (0.1%)		0/1052 (0%)
Endocrine disorders
Goitre	3/1066 (0.3%)		5/1052 (0.5%)
Hyperthyroidism	1/1066 (0.1%)		0/1052 (0%)
Hypothyroidism	3/1066 (0.3%)		11/1052 (1%)
Eye disorders
Altered visual depth perception	1/1066 (0.1%)		0/1052 (0%)
Angle closure glaucoma	1/1066 (0.1%)		0/1052 (0%)
Asthenopia	1/1066 (0.1%)		0/1052 (0%)
Astigmatism	1/1066 (0.1%)		0/1052 (0%)
Blepharitis	1/1066 (0.1%)		3/1052 (0.3%)
Blepharospasm	3/1066 (0.3%)		4/1052 (0.4%)
Cataract	2/1066 (0.2%)		3/1052 (0.3%)
Conjunctival haemorrhage	2/1066 (0.2%)		0/1052 (0%)
Conjunctivitis	6/1066 (0.6%)		2/1052 (0.2%)
Dry eye	3/1066 (0.3%)		0/1052 (0%)
Episcleritis	1/1066 (0.1%)		0/1052 (0%)
Eye irritation	2/1066 (0.2%)		3/1052 (0.3%)
Eye pain	6/1066 (0.6%)		1/1052 (0.1%)
Eye pruritus	2/1066 (0.2%)		8/1052 (0.8%)
Eye swelling	1/1066 (0.1%)		1/1052 (0.1%)
Eyelid cyst	0/1066 (0%)		2/1052 (0.2%)
Eyelid oedema	0/1066 (0%)		1/1052 (0.1%)
Eyelid ptosis	0/1066 (0%)		1/1052 (0.1%)
Glaucoma	2/1066 (0.2%)		0/1052 (0%)
Iritis	0/1066 (0%)		1/1052 (0.1%)
Keratoconjunctivitis sicca	2/1066 (0.2%)		0/1052 (0%)
Lacrimation increased	3/1066 (0.3%)		3/1052 (0.3%)
Macular degeneration	1/1066 (0.1%)		1/1052 (0.1%)
Macular oedema	0/1066 (0%)		1/1052 (0.1%)
Mydriasis	6/1066 (0.6%)		1/1052 (0.1%)
Myopia	0/1066 (0%)		1/1052 (0.1%)
Narrow anterior chamber angle	1/1066 (0.1%)		0/1052 (0%)
Night blindness	1/1066 (0.1%)		0/1052 (0%)
Ocular hyperaemia	4/1066 (0.4%)		0/1052 (0%)
Photophobia	1/1066 (0.1%)		0/1052 (0%)
Photopsia	1/1066 (0.1%)		0/1052 (0%)
Pinguecula	1/1066 (0.1%)		0/1052 (0%)
Presbyopia	1/1066 (0.1%)		0/1052 (0%)
Pupil fixed	1/1066 (0.1%)		0/1052 (0%)
Retinal aneurysm	1/1066 (0.1%)		1/1052 (0.1%)
Retinopathy hypertensive	1/1066 (0.1%)		0/1052 (0%)
Scleral hyperaemia	0/1066 (0%)		1/1052 (0.1%)
Ulcerative keratitis	0/1066 (0%)		1/1052 (0.1%)
Vision blurred	25/1066 (2.3%)		10/1052 (1%)
Visual acuity reduced	3/1066 (0.3%)		1/1052 (0.1%)
Visual impairment	4/1066 (0.4%)		0/1052 (0%)
Vitreous degeneration	1/1066 (0.1%)		0/1052 (0%)
Vitreous detachment	2/1066 (0.2%)		0/1052 (0%)
Vitreous floaters	1/1066 (0.1%)		3/1052 (0.3%)
Gastrointestinal disorders
Abdominal discomfort	22/1066 (2.1%)		20/1052 (1.9%)
Abdominal distension	16/1066 (1.5%)		8/1052 (0.8%)
Abdominal mass	1/1066 (0.1%)		0/1052 (0%)
Abdominal pain	23/1066 (2.2%)		24/1052 (2.3%)
Abdominal pain lower	2/1066 (0.2%)		7/1052 (0.7%)
Abdominal pain upper	39/1066 (3.7%)		41/1052 (3.9%)
Abdominal tenderness	2/1066 (0.2%)		2/1052 (0.2%)
Abnormal faeces	1/1066 (0.1%)		0/1052 (0%)
Anal fissure	0/1066 (0%)		1/1052 (0.1%)
Aphthous stomatitis	4/1066 (0.4%)		0/1052 (0%)
Bowel movement irregularity	2/1066 (0.2%)		1/1052 (0.1%)
Change of bowel habit	2/1066 (0.2%)		0/1052 (0%)
Cheilitis	1/1066 (0.1%)		0/1052 (0%)
Coeliac disease	0/1066 (0%)		1/1052 (0.1%)
Colitis	1/1066 (0.1%)		1/1052 (0.1%)
Colitis microscopic	0/1066 (0%)		1/1052 (0.1%)
Colonic polyp	0/1066 (0%)		1/1052 (0.1%)
Constipation	118/1066 (11.1%)		40/1052 (3.8%)
Crohn's disease	0/1066 (0%)		1/1052 (0.1%)
Dental caries	8/1066 (0.8%)		4/1052 (0.4%)
Diarrhoea	79/1066 (7.4%)		56/1052 (5.3%)
Diarrhoea haemorrhagic	0/1066 (0%)		1/1052 (0.1%)
Diverticulum	2/1066 (0.2%)		3/1052 (0.3%)
Dry mouth	88/1066 (8.3%)		15/1052 (1.4%)
Duodenal ulcer	1/1066 (0.1%)		0/1052 (0%)
Dyspepsia	63/1066 (5.9%)		50/1052 (4.8%)
Dysphagia	0/1066 (0%)		2/1052 (0.2%)
Enterocolitis haemorrhagic	1/1066 (0.1%)		0/1052 (0%)
Eructation	1/1066 (0.1%)		1/1052 (0.1%)
Faeces discoloured	0/1066 (0%)		1/1052 (0.1%)
Faeces hard	1/1066 (0.1%)		0/1052 (0%)
Flatulence	20/1066 (1.9%)		5/1052 (0.5%)
Food poisoning	3/1066 (0.3%)		2/1052 (0.2%)
Frequent bowel movements	3/1066 (0.3%)		0/1052 (0%)
Gastritis	4/1066 (0.4%)		2/1052 (0.2%)
Gastrointestinal haemorrhage	0/1066 (0%)		1/1052 (0.1%)
Gastrointestinal pain	3/1066 (0.3%)		0/1052 (0%)
Gastrooesophageal reflux disease	20/1066 (1.9%)		18/1052 (1.7%)
Gingival erosion	0/1066 (0%)		1/1052 (0.1%)
Gingival pain	2/1066 (0.2%)		3/1052 (0.3%)
Gingival swelling	0/1066 (0%)		1/1052 (0.1%)
Gingival ulceration	1/1066 (0.1%)		1/1052 (0.1%)
Glossodynia	2/1066 (0.2%)		0/1052 (0%)
Haematochezia	3/1066 (0.3%)		1/1052 (0.1%)
Haemorrhoidal haemorrhage	0/1066 (0%)		3/1052 (0.3%)
Haemorrhoids	6/1066 (0.6%)		8/1052 (0.8%)
Hiatus hernia	1/1066 (0.1%)		3/1052 (0.3%)
Hyperchlorhydria	0/1066 (0%)		1/1052 (0.1%)
Hypoaesthesia oral	0/1066 (0%)		1/1052 (0.1%)
Infrequent bowel movements	1/1066 (0.1%)		0/1052 (0%)
Irritable bowel syndrome	0/1066 (0%)		1/1052 (0.1%)
Lip blister	0/1066 (0%)		1/1052 (0.1%)
Lip swelling	1/1066 (0.1%)		0/1052 (0%)
Lower gastrointestinal haemorrhage	0/1066 (0%)		1/1052 (0.1%)
Mouth ulceration	0/1066 (0%)		1/1052 (0.1%)
Nausea	279/1066 (26.2%)		89/1052 (8.5%)
Odynophagia	1/1066 (0.1%)		0/1052 (0%)
Oesophageal pain	1/1066 (0.1%)		0/1052 (0%)
Oesophageal ulcer	0/1066 (0%)		1/1052 (0.1%)
Oesophagitis	0/1066 (0%)		1/1052 (0.1%)
Oral disorder	2/1066 (0.2%)		1/1052 (0.1%)
Oral pain	7/1066 (0.7%)		0/1052 (0%)
Oral pruritus	1/1066 (0.1%)		0/1052 (0%)
Paraesthesia oral	2/1066 (0.2%)		1/1052 (0.1%)
Peptic ulcer	0/1066 (0%)		1/1052 (0.1%)
Periodontal disease	1/1066 (0.1%)		0/1052 (0%)
Periodontitis	0/1066 (0%)		1/1052 (0.1%)
Polyp colorectal	0/1066 (0%)		2/1052 (0.2%)
Proctalgia	0/1066 (0%)		1/1052 (0.1%)
Proctitis	1/1066 (0.1%)		0/1052 (0%)
Rectal haemorrhage	1/1066 (0.1%)		3/1052 (0.3%)
Retching	1/1066 (0.1%)		0/1052 (0%)
Salivary gland enlargement	1/1066 (0.1%)		0/1052 (0%)
Salivary gland pain	0/1066 (0%)		1/1052 (0.1%)
Salivary hypersecretion	1/1066 (0.1%)		0/1052 (0%)
Sensitivity of teeth	1/1066 (0.1%)		0/1052 (0%)
Stomatitis	3/1066 (0.3%)		0/1052 (0%)
Swollen tongue	0/1066 (0%)		2/1052 (0.2%)
Tongue dry	1/1066 (0.1%)		0/1052 (0%)
Tooth discolouration	1/1066 (0.1%)		0/1052 (0%)
Tooth impacted	1/1066 (0.1%)		0/1052 (0%)
Tooth loss	0/1066 (0%)		1/1052 (0.1%)
Toothache	37/1066 (3.5%)		30/1052 (2.9%)
Vomiting	50/1066 (4.7%)		26/1052 (2.5%)
General disorders
Asthenia	27/1066 (2.5%)		11/1052 (1%)
Axillary pain	0/1066 (0%)		1/1052 (0.1%)
Chest discomfort	9/1066 (0.8%)		11/1052 (1%)
Chest pain	4/1066 (0.4%)		6/1052 (0.6%)
Chills	28/1066 (2.6%)		8/1052 (0.8%)
Cyst	3/1066 (0.3%)		2/1052 (0.2%)
Device breakage	0/1066 (0%)		1/1052 (0.1%)
Device malfunction	0/1066 (0%)		1/1052 (0.1%)
Drug intolerance	0/1066 (0%)		1/1052 (0.1%)
Drug withdrawal syndrome	0/1066 (0%)		1/1052 (0.1%)
Energy increased	3/1066 (0.3%)		1/1052 (0.1%)
Facial pain	1/1066 (0.1%)		0/1052 (0%)
Fatigue	109/1066 (10.2%)		35/1052 (3.3%)
Feeling abnormal	6/1066 (0.6%)		3/1052 (0.3%)
Feeling cold	2/1066 (0.2%)		2/1052 (0.2%)
Feeling drunk	1/1066 (0.1%)		0/1052 (0%)
Feeling hot	1/1066 (0.1%)		3/1052 (0.3%)
Feeling jittery	18/1066 (1.7%)		1/1052 (0.1%)
Feeling of body temperature change	0/1066 (0%)		2/1052 (0.2%)
Generalised oedema	1/1066 (0.1%)		0/1052 (0%)
Hangover	2/1066 (0.2%)		0/1052 (0%)
Hunger	1/1066 (0.1%)		0/1052 (0%)
Impaired healing	2/1066 (0.2%)		0/1052 (0%)
Implant site reaction	1/1066 (0.1%)		0/1052 (0%)
Inflammation	1/1066 (0.1%)		0/1052 (0%)
Influenza like illness	13/1066 (1.2%)		14/1052 (1.3%)
Injection site haematoma	1/1066 (0.1%)		0/1052 (0%)
Injection site pain	2/1066 (0.2%)		2/1052 (0.2%)
Irritability	32/1066 (3%)		19/1052 (1.8%)
Local swelling	0/1066 (0%)		1/1052 (0.1%)
Malaise	8/1066 (0.8%)		4/1052 (0.4%)
Mass	0/1066 (0%)		2/1052 (0.2%)
Medical device pain	0/1066 (0%)		1/1052 (0.1%)
Nodule	2/1066 (0.2%)		1/1052 (0.1%)
Non-cardiac chest pain	8/1066 (0.8%)		9/1052 (0.9%)
Oedema	0/1066 (0%)		2/1052 (0.2%)
Oedema peripheral	12/1066 (1.1%)		14/1052 (1.3%)
Pain	41/1066 (3.8%)		40/1052 (3.8%)
Pyrexia	21/1066 (2%)		21/1052 (2%)
Rebound effect	0/1066 (0%)		1/1052 (0.1%)
Sluggishness	2/1066 (0.2%)		0/1052 (0%)
Temperature intolerance	1/1066 (0.1%)		1/1052 (0.1%)
Therapeutic response unexpected	1/1066 (0.1%)		0/1052 (0%)
Thirst	3/1066 (0.3%)		5/1052 (0.5%)
Ulcer	0/1066 (0%)		1/1052 (0.1%)
Unevaluable event	1/1066 (0.1%)		0/1052 (0%)
Vaccination site induration	0/1066 (0%)		1/1052 (0.1%)
Vessel puncture site haematoma	1/1066 (0.1%)		0/1052 (0%)
Vessel puncture site pain	1/1066 (0.1%)		0/1052 (0%)
Vestibulitis	1/1066 (0.1%)		0/1052 (0%)
Hepatobiliary disorders
Cholecystitis	1/1066 (0.1%)		0/1052 (0%)
Gallbladder pain	0/1066 (0%)		1/1052 (0.1%)
Hepatic cirrhosis	1/1066 (0.1%)		0/1052 (0%)
Hepatic cyst	0/1066 (0%)		2/1052 (0.2%)
Immune system disorders
Allergy to animal	1/1066 (0.1%)		0/1052 (0%)
Allergy to arthropod sting	1/1066 (0.1%)		1/1052 (0.1%)
Allergy to chemicals	0/1066 (0%)		1/1052 (0.1%)
Allergy to plants	2/1066 (0.2%)		1/1052 (0.1%)
Allergy to vaccine	1/1066 (0.1%)		1/1052 (0.1%)
Contrast media allergy	0/1066 (0%)		1/1052 (0.1%)
Drug hypersensitivity	2/1066 (0.2%)		1/1052 (0.1%)
Food allergy	0/1066 (0%)		2/1052 (0.2%)
House dust allergy	0/1066 (0%)		1/1052 (0.1%)
Hypersensitivity	7/1066 (0.7%)		5/1052 (0.5%)
Sarcoidosis	0/1066 (0%)		1/1052 (0.1%)
Seasonal allergy	17/1066 (1.6%)		22/1052 (2.1%)
Infections and infestations
Abdominal abscess	0/1066 (0%)		1/1052 (0.1%)
Abscess	0/1066 (0%)		1/1052 (0.1%)
Abscess intestinal	0/1066 (0%)		1/1052 (0.1%)
Abscess limb	0/1066 (0%)		1/1052 (0.1%)
Acute sinusitis	0/1066 (0%)		1/1052 (0.1%)
Anal abscess	0/1066 (0%)		1/1052 (0.1%)
Anal fungal infection	0/1066 (0%)		1/1052 (0.1%)
Asymptomatic bacteriuria	1/1066 (0.1%)		0/1052 (0%)
Bacterial infection	3/1066 (0.3%)		0/1052 (0%)
Breast abscess	0/1066 (0%)		1/1052 (0.1%)
Breast cellulitis	1/1066 (0.1%)		0/1052 (0%)
Breast infection	0/1066 (0%)		1/1052 (0.1%)
Bronchitis	34/1066 (3.2%)		35/1052 (3.3%)
Bronchitis viral	2/1066 (0.2%)		0/1052 (0%)
Bronchopneumonia	1/1066 (0.1%)		1/1052 (0.1%)
Cellulitis	2/1066 (0.2%)		2/1052 (0.2%)
Cervicitis	0/1066 (0%)		2/1052 (0.2%)
Conjunctivitis bacterial	1/1066 (0.1%)		0/1052 (0%)
Conjunctivitis infective	1/1066 (0.1%)		0/1052 (0%)
Cystitis	14/1066 (1.3%)		15/1052 (1.4%)
Diverticulitis	2/1066 (0.2%)		6/1052 (0.6%)
Ear infection	12/1066 (1.1%)		17/1052 (1.6%)
Ear infection viral	1/1066 (0.1%)		0/1052 (0%)
Eye abscess	0/1066 (0%)		1/1052 (0.1%)
Eye infection	9/1066 (0.8%)		4/1052 (0.4%)
Eye infection viral	1/1066 (0.1%)		0/1052 (0%)
Folliculitis	5/1066 (0.5%)		1/1052 (0.1%)
Fungal infection	2/1066 (0.2%)		7/1052 (0.7%)
Fungal skin infection	2/1066 (0.2%)		1/1052 (0.1%)
Furuncle	2/1066 (0.2%)		3/1052 (0.3%)
Gastroenteritis	9/1066 (0.8%)		6/1052 (0.6%)
Gastroenteritis viral	24/1066 (2.3%)		15/1052 (1.4%)
Gastrointestinal infection	0/1066 (0%)		1/1052 (0.1%)
Gastrointestinal viral infection	6/1066 (0.6%)		1/1052 (0.1%)
Genital herpes	1/1066 (0.1%)		2/1052 (0.2%)
Gingival infection	4/1066 (0.4%)		2/1052 (0.2%)
H1N1 influenza	0/1066 (0%)		2/1052 (0.2%)
Helicobacter infection	3/1066 (0.3%)		3/1052 (0.3%)
Herpes ophthalmic	0/1066 (0%)		1/1052 (0.1%)
Herpes simplex	0/1066 (0%)		1/1052 (0.1%)
Herpes zoster	5/1066 (0.5%)		9/1052 (0.9%)
Hordeolum	2/1066 (0.2%)		1/1052 (0.1%)
Incision site infection	0/1066 (0%)		1/1052 (0.1%)
Infected bites	2/1066 (0.2%)		1/1052 (0.1%)
Infected cyst	1/1066 (0.1%)		1/1052 (0.1%)
Infected sebaceous cyst	1/1066 (0.1%)		0/1052 (0%)
Infectious mononucleosis	0/1066 (0%)		1/1052 (0.1%)
Influenza	60/1066 (5.6%)		61/1052 (5.8%)
Keratitis herpetic	1/1066 (0.1%)		0/1052 (0%)
Kidney infection	3/1066 (0.3%)		1/1052 (0.1%)
Labyrinthitis	3/1066 (0.3%)		2/1052 (0.2%)
Laryngitis	3/1066 (0.3%)		5/1052 (0.5%)
Localised infection	2/1066 (0.2%)		5/1052 (0.5%)
Lower respiratory tract infection	3/1066 (0.3%)		7/1052 (0.7%)
Lung infection	1/1066 (0.1%)		0/1052 (0%)
Lymph gland infection	1/1066 (0.1%)		0/1052 (0%)
Nasopharyngitis	162/1066 (15.2%)		168/1052 (16%)
Neurosyphilis	1/1066 (0.1%)		0/1052 (0%)
Onychomycosis	3/1066 (0.3%)		5/1052 (0.5%)
Oral candidiasis	1/1066 (0.1%)		0/1052 (0%)
Oral herpes	15/1066 (1.4%)		11/1052 (1%)
Oral infection	1/1066 (0.1%)		0/1052 (0%)
Osteomyelitis	1/1066 (0.1%)		0/1052 (0%)
Otitis externa	1/1066 (0.1%)		0/1052 (0%)
Otitis media	4/1066 (0.4%)		1/1052 (0.1%)
Paronychia	1/1066 (0.1%)		0/1052 (0%)
Parotitis	1/1066 (0.1%)		0/1052 (0%)
Pharyngitis	1/1066 (0.1%)		3/1052 (0.3%)
Pharyngitis streptococcal	6/1066 (0.6%)		6/1052 (0.6%)
Pneumonia	10/1066 (0.9%)		9/1052 (0.9%)
Pneumonia primary atypical	0/1066 (0%)		1/1052 (0.1%)
Respiratory tract infection	0/1066 (0%)		2/1052 (0.2%)
Respiratory tract infection viral	3/1066 (0.3%)		1/1052 (0.1%)
Rhinitis	3/1066 (0.3%)		8/1052 (0.8%)
Secondary syphilis	1/1066 (0.1%)		0/1052 (0%)
Sinusitis	84/1066 (7.9%)		69/1052 (6.6%)
Sinusitis bacterial	0/1066 (0%)		1/1052 (0.1%)
Skin bacterial infection	1/1066 (0.1%)		0/1052 (0%)
Skin infection	2/1066 (0.2%)		0/1052 (0%)
Staphylococcal infection	1/1066 (0.1%)		3/1052 (0.3%)
Staphylococcal skin infection	1/1066 (0.1%)		0/1052 (0%)
Subcutaneous abscess	0/1066 (0%)		2/1052 (0.2%)
Tinea infection	0/1066 (0%)		1/1052 (0.1%)
Tinea pedis	3/1066 (0.3%)		1/1052 (0.1%)
Tonsillitis	3/1066 (0.3%)		0/1052 (0%)
Tooth abscess	16/1066 (1.5%)		12/1052 (1.1%)
Tooth infection	10/1066 (0.9%)		9/1052 (0.9%)
Upper respiratory tract infection	85/1066 (8%)		91/1052 (8.7%)
Urethritis	0/1066 (0%)		1/1052 (0.1%)
Urinary tract infection	36/1066 (3.4%)		61/1052 (5.8%)
Vaginal abscess	0/1066 (0%)		1/1052 (0.1%)
Vaginal infection	4/1066 (0.4%)		3/1052 (0.3%)
Vaginitis bacterial	5/1066 (0.5%)		10/1052 (1%)
Viral infection	3/1066 (0.3%)		6/1052 (0.6%)
Viral labyrinthitis	0/1066 (0%)		1/1052 (0.1%)
Viral pharyngitis	1/1066 (0.1%)		0/1052 (0%)
Viral upper respiratory tract infection	8/1066 (0.8%)		7/1052 (0.7%)
Vulval cellulitis	1/1066 (0.1%)		0/1052 (0%)
Vulvovaginal candidiasis	1/1066 (0.1%)		2/1052 (0.2%)
Vulvovaginal mycotic infection	3/1066 (0.3%)		13/1052 (1.2%)
Vulvovaginitis trichomonal	1/1066 (0.1%)		0/1052 (0%)
Injury, poisoning and procedural complications
Accidental overdose	2/1066 (0.2%)		8/1052 (0.8%)
Animal bite	3/1066 (0.3%)		1/1052 (0.1%)
Animal scratch	1/1066 (0.1%)		0/1052 (0%)
Ankle fracture	3/1066 (0.3%)		0/1052 (0%)
Arthropod bite	7/1066 (0.7%)		8/1052 (0.8%)
Arthropod sting	6/1066 (0.6%)		6/1052 (0.6%)
Avulsion fracture	1/1066 (0.1%)		0/1052 (0%)
Back injury	1/1066 (0.1%)		2/1052 (0.2%)
Burns third degree	0/1066 (0%)		1/1052 (0.1%)
Clavicle fracture	0/1066 (0%)		1/1052 (0.1%)
Concussion	2/1066 (0.2%)		0/1052 (0%)
Contusion	25/1066 (2.3%)		8/1052 (0.8%)
Corneal abrasion	0/1066 (0%)		1/1052 (0.1%)
Epicondylitis	3/1066 (0.3%)		4/1052 (0.4%)
Excoriation	4/1066 (0.4%)		2/1052 (0.2%)
Facial bones fracture	0/1066 (0%)		2/1052 (0.2%)
Fall	12/1066 (1.1%)		5/1052 (0.5%)
Foot fracture	4/1066 (0.4%)		11/1052 (1%)
Foreign body	0/1066 (0%)		1/1052 (0.1%)
Fracture displacement	0/1066 (0%)		1/1052 (0.1%)
Hand fracture	4/1066 (0.4%)		0/1052 (0%)
Head injury	1/1066 (0.1%)		1/1052 (0.1%)
Incisional hernia	0/1066 (0%)		1/1052 (0.1%)
Incorrect dose administered	2/1066 (0.2%)		1/1052 (0.1%)
Joint dislocation	5/1066 (0.5%)		1/1052 (0.1%)
Joint injury	6/1066 (0.6%)		5/1052 (0.5%)
Joint sprain	13/1066 (1.2%)		16/1052 (1.5%)
Ligament rupture	1/1066 (0.1%)		0/1052 (0%)
Ligament sprain	1/1066 (0.1%)		0/1052 (0%)
Limb injury	5/1066 (0.5%)		3/1052 (0.3%)
Medication error	57/1066 (5.3%)		49/1052 (4.7%)
Meniscus lesion	1/1066 (0.1%)		1/1052 (0.1%)
Muscle injury	2/1066 (0.2%)		1/1052 (0.1%)
Muscle rupture	1/1066 (0.1%)		0/1052 (0%)
Muscle strain	18/1066 (1.7%)		24/1052 (2.3%)
Patella fracture	0/1066 (0%)		1/1052 (0.1%)
Post procedural complication	0/1066 (0%)		1/1052 (0.1%)
Post procedural haematoma	0/1066 (0%)		1/1052 (0.1%)
Post procedural haemorrhage	0/1066 (0%)		1/1052 (0.1%)
Post-traumatic pain	1/1066 (0.1%)		0/1052 (0%)
Procedural dizziness	0/1066 (0%)		1/1052 (0.1%)
Procedural nausea	2/1066 (0.2%)		0/1052 (0%)
Procedural pain	15/1066 (1.4%)		21/1052 (2%)
Radius fracture	0/1066 (0%)		1/1052 (0.1%)
Renal injury	1/1066 (0.1%)		0/1052 (0%)
Rib fracture	2/1066 (0.2%)		1/1052 (0.1%)
Road traffic accident	2/1066 (0.2%)		9/1052 (0.9%)
Sciatic nerve injury	0/1066 (0%)		1/1052 (0.1%)
Scratch	1/1066 (0.1%)		1/1052 (0.1%)
Skeletal injury	2/1066 (0.2%)		2/1052 (0.2%)
Skin laceration	6/1066 (0.6%)		9/1052 (0.9%)
Splinter	1/1066 (0.1%)		0/1052 (0%)
Sternal fracture	0/1066 (0%)		1/1052 (0.1%)
Stress fracture	3/1066 (0.3%)		0/1052 (0%)
Sunburn	2/1066 (0.2%)		4/1052 (0.4%)
Superficial injury of eye	2/1066 (0.2%)		0/1052 (0%)
Thermal burn	3/1066 (0.3%)		1/1052 (0.1%)
Tooth fracture	4/1066 (0.4%)		5/1052 (0.5%)
Traumatic haematoma	1/1066 (0.1%)		0/1052 (0%)
Upper limb fracture	2/1066 (0.2%)		1/1052 (0.1%)
Vascular injury	1/1066 (0.1%)		0/1052 (0%)
Venomous bite	0/1066 (0%)		1/1052 (0.1%)
Vulva injury	1/1066 (0.1%)		0/1052 (0%)
Whiplash injury	1/1066 (0.1%)		1/1052 (0.1%)
Wound	0/1066 (0%)		3/1052 (0.3%)
Wrist fracture	3/1066 (0.3%)		2/1052 (0.2%)
Investigations
Alanine aminotransferase increased	4/1066 (0.4%)		3/1052 (0.3%)
Albumin urine present	0/1066 (0%)		2/1052 (0.2%)
Antinuclear antibody positive	0/1066 (0%)		1/1052 (0.1%)
Arthroscopy	1/1066 (0.1%)		0/1052 (0%)
Aspartate aminotransferase increased	3/1066 (0.3%)		2/1052 (0.2%)
Autoantibody positive	0/1066 (0%)		1/1052 (0.1%)
Biopsy breast	0/1066 (0%)		1/1052 (0.1%)
Blood alkaline phosphatase increased	1/1066 (0.1%)		2/1052 (0.2%)
Blood bilirubin increased	1/1066 (0.1%)		0/1052 (0%)
Blood cholesterol increased	22/1066 (2.1%)		21/1052 (2%)
Blood creatine increased	0/1066 (0%)		1/1052 (0.1%)
Blood glucose decreased	1/1066 (0.1%)		0/1052 (0%)
Blood glucose increased	3/1066 (0.3%)		2/1052 (0.2%)
Blood iron decreased	1/1066 (0.1%)		1/1052 (0.1%)
Blood potassium decreased	0/1066 (0%)		2/1052 (0.2%)
Blood pressure diastolic increased	2/1066 (0.2%)		0/1052 (0%)
Blood pressure increased	43/1066 (4%)		23/1052 (2.2%)
Blood pressure systolic increased	2/1066 (0.2%)		0/1052 (0%)
Blood thyroid stimulating hormone decreased	1/1066 (0.1%)		0/1052 (0%)
Blood thyroid stimulating hormone increased	0/1066 (0%)		1/1052 (0.1%)
Blood triglycerides increased	14/1066 (1.3%)		9/1052 (0.9%)
Blood uric acid increased	0/1066 (0%)		1/1052 (0.1%)
Blood urine present	7/1066 (0.7%)		4/1052 (0.4%)
Body temperature increased	1/1066 (0.1%)		1/1052 (0.1%)
Bone density decreased	1/1066 (0.1%)		2/1052 (0.2%)
Breath sounds abnormal	1/1066 (0.1%)		0/1052 (0%)
C-reactive protein increased	1/1066 (0.1%)		0/1052 (0%)
Cardiac murmur	1/1066 (0.1%)		2/1052 (0.2%)
Electrocardiogram PR prolongation	1/1066 (0.1%)		0/1052 (0%)
Electrocardiogram QT prolonged	1/1066 (0.1%)		0/1052 (0%)
Electrocardiogram T wave amplitude decreased	1/1066 (0.1%)		0/1052 (0%)
Electrocardiogram abnormal	3/1066 (0.3%)		3/1052 (0.3%)
Gamma-glutamyltransferase increased	3/1066 (0.3%)		0/1052 (0%)
Glycosylated haemoglobin increased	0/1066 (0%)		1/1052 (0.1%)
Haematocrit decreased	0/1066 (0%)		1/1052 (0.1%)
Haemoglobin decreased	0/1066 (0%)		1/1052 (0.1%)
Heart rate increased	13/1066 (1.2%)		5/1052 (0.5%)
Heart rate irregular	4/1066 (0.4%)		0/1052 (0%)
Heart sounds abnormal	1/1066 (0.1%)		0/1052 (0%)
Hepatic enzyme increased	1/1066 (0.1%)		3/1052 (0.3%)
Intraocular pressure increased	0/1066 (0%)		1/1052 (0.1%)
Lipids increased	5/1066 (0.5%)		3/1052 (0.3%)
Liver function test abnormal	5/1066 (0.5%)		3/1052 (0.3%)
Low density lipoprotein increased	12/1066 (1.1%)		7/1052 (0.7%)
Mammogram abnormal	1/1066 (0.1%)		2/1052 (0.2%)
Platelet count decreased	1/1066 (0.1%)		1/1052 (0.1%)
Protein total decreased	1/1066 (0.1%)		0/1052 (0%)
Protein urine present	1/1066 (0.1%)		0/1052 (0%)
Smear cervix abnormal	0/1066 (0%)		1/1052 (0.1%)
Thyroid function test abnormal	0/1066 (0%)		1/1052 (0.1%)
Tuberculin test positive	1/1066 (0.1%)		0/1052 (0%)
Urine analysis abnormal	0/1066 (0%)		1/1052 (0.1%)
Urine ketone body present	1/1066 (0.1%)		1/1052 (0.1%)
Urine output decreased	1/1066 (0.1%)		0/1052 (0%)
Very low density lipoprotein increased	5/1066 (0.5%)		2/1052 (0.2%)
Vitamin B12 decreased	0/1066 (0%)		1/1052 (0.1%)
Vitamin D decreased	1/1066 (0.1%)		1/1052 (0.1%)
Weight decreased	4/1066 (0.4%)		6/1052 (0.6%)
Weight increased	38/1066 (3.6%)		33/1052 (3.1%)
White blood cell count decreased	1/1066 (0.1%)		0/1052 (0%)
White blood cells urine	2/1066 (0.2%)		0/1052 (0%)
Metabolism and nutrition disorders
Decreased appetite	34/1066 (3.2%)		8/1052 (0.8%)
Dehydration	4/1066 (0.4%)		4/1052 (0.4%)
Diabetes mellitus	1/1066 (0.1%)		2/1052 (0.2%)
Dyslipidaemia	2/1066 (0.2%)		1/1052 (0.1%)
Fluid retention	2/1066 (0.2%)		3/1052 (0.3%)
Food craving	2/1066 (0.2%)		2/1052 (0.2%)
Gout	1/1066 (0.1%)		2/1052 (0.2%)
Hypercholesterolaemia	33/1066 (3.1%)		18/1052 (1.7%)
Hyperglycaemia	0/1066 (0%)		1/1052 (0.1%)
Hyperkalaemia	1/1066 (0.1%)		1/1052 (0.1%)
Hyperlipidaemia	12/1066 (1.1%)		7/1052 (0.7%)
Hyperphagia	1/1066 (0.1%)		0/1052 (0%)
Hyperphosphataemia	0/1066 (0%)		1/1052 (0.1%)
Hypertriglyceridaemia	9/1066 (0.8%)		3/1052 (0.3%)
Hyperuricaemia	1/1066 (0.1%)		4/1052 (0.4%)
Hypoalbuminaemia	1/1066 (0.1%)		0/1052 (0%)
Hypocalcaemia	1/1066 (0.1%)		0/1052 (0%)
Hypokalaemia	1/1066 (0.1%)		2/1052 (0.2%)
Hypovolaemia	1/1066 (0.1%)		0/1052 (0%)
Increased appetite	8/1066 (0.8%)		5/1052 (0.5%)
Lactose intolerance	0/1066 (0%)		1/1052 (0.1%)
Metabolic syndrome	1/1066 (0.1%)		0/1052 (0%)
Obesity	0/1066 (0%)		1/1052 (0.1%)
Type 2 diabetes mellitus	1/1066 (0.1%)		1/1052 (0.1%)
Vitamin B12 deficiency	1/1066 (0.1%)		1/1052 (0.1%)
Vitamin D deficiency	4/1066 (0.4%)		2/1052 (0.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	64/1066 (6%)		93/1052 (8.8%)
Arthritis	7/1066 (0.7%)		8/1052 (0.8%)
Axillary mass	0/1066 (0%)		1/1052 (0.1%)
Back pain	81/1066 (7.6%)		106/1052 (10.1%)
Bone disorder	1/1066 (0.1%)		0/1052 (0%)
Bone pain	2/1066 (0.2%)		1/1052 (0.1%)
Bunion	2/1066 (0.2%)		0/1052 (0%)
Bursitis	1/1066 (0.1%)		4/1052 (0.4%)
Chondrocalcinosis pyrophosphate	0/1066 (0%)		1/1052 (0.1%)
Coccydynia	1/1066 (0.1%)		0/1052 (0%)
Costochondritis	3/1066 (0.3%)		5/1052 (0.5%)
Dupuytren's contracture	0/1066 (0%)		1/1052 (0.1%)
Exostosis	0/1066 (0%)		3/1052 (0.3%)
Flank pain	2/1066 (0.2%)		2/1052 (0.2%)
Foot deformity	1/1066 (0.1%)		0/1052 (0%)
Groin pain	2/1066 (0.2%)		0/1052 (0%)
Intervertebral disc degeneration	2/1066 (0.2%)		1/1052 (0.1%)
Intervertebral disc protrusion	4/1066 (0.4%)		2/1052 (0.2%)
Joint crepitation	1/1066 (0.1%)		0/1052 (0%)
Joint range of motion decreased	1/1066 (0.1%)		1/1052 (0.1%)
Joint stiffness	9/1066 (0.8%)		4/1052 (0.4%)
Joint swelling	6/1066 (0.6%)		7/1052 (0.7%)
Ligamentitis	0/1066 (0%)		1/1052 (0.1%)
Monarthritis	4/1066 (0.4%)		2/1052 (0.2%)
Muscle atrophy	0/1066 (0%)		1/1052 (0.1%)
Muscle spasms	35/1066 (3.3%)		40/1052 (3.8%)
Muscle tightness	5/1066 (0.5%)		0/1052 (0%)
Muscle twitching	3/1066 (0.3%)		2/1052 (0.2%)
Muscular weakness	5/1066 (0.5%)		2/1052 (0.2%)
Musculoskeletal chest pain	10/1066 (0.9%)		4/1052 (0.4%)
Musculoskeletal discomfort	1/1066 (0.1%)		2/1052 (0.2%)
Musculoskeletal pain	27/1066 (2.5%)		36/1052 (3.4%)
Musculoskeletal stiffness	10/1066 (0.9%)		12/1052 (1.1%)
Myalgia	47/1066 (4.4%)		46/1052 (4.4%)
Neck deformity	0/1066 (0%)		1/1052 (0.1%)
Neck pain	31/1066 (2.9%)		46/1052 (4.4%)
Nodule on extremity	1/1066 (0.1%)		0/1052 (0%)
Osteitis	1/1066 (0.1%)		1/1052 (0.1%)
Osteoarthritis	7/1066 (0.7%)		3/1052 (0.3%)
Osteochondrosis	0/1066 (0%)		1/1052 (0.1%)
Osteopenia	6/1066 (0.6%)		4/1052 (0.4%)
Osteoporosis	4/1066 (0.4%)		3/1052 (0.3%)
Pain in extremity	71/1066 (6.7%)		73/1052 (6.9%)
Pain in jaw	3/1066 (0.3%)		2/1052 (0.2%)
Periarthritis	1/1066 (0.1%)		0/1052 (0%)
Plantar fasciitis	4/1066 (0.4%)		5/1052 (0.5%)
Polyarthritis	1/1066 (0.1%)		1/1052 (0.1%)
Rheumatoid arthritis	2/1066 (0.2%)		1/1052 (0.1%)
Rotator cuff syndrome	2/1066 (0.2%)		3/1052 (0.3%)
Sensation of heaviness	1/1066 (0.1%)		1/1052 (0.1%)
Spinal column stenosis	1/1066 (0.1%)		0/1052 (0%)
Spinal osteoarthritis	1/1066 (0.1%)		0/1052 (0%)
Spondylitis	2/1066 (0.2%)		0/1052 (0%)
Spondylolisthesis	0/1066 (0%)		1/1052 (0.1%)
Synovial cyst	2/1066 (0.2%)		2/1052 (0.2%)
Temporomandibular joint syndrome	0/1066 (0%)		1/1052 (0.1%)
Tendonitis	12/1066 (1.1%)		7/1052 (0.7%)
Tenosynovitis stenosans	1/1066 (0.1%)		1/1052 (0.1%)
Trigger finger	1/1066 (0.1%)		1/1052 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon	1/1066 (0.1%)		0/1052 (0%)
Adrenal adenoma	0/1066 (0%)		1/1052 (0.1%)
Basal cell carcinoma	0/1066 (0%)		1/1052 (0.1%)
Benign breast neoplasm	2/1066 (0.2%)		1/1052 (0.1%)
Benign neoplasm of bladder	1/1066 (0.1%)		0/1052 (0%)
Benign neoplasm of thyroid gland	0/1066 (0%)		2/1052 (0.2%)
Breast cancer	0/1066 (0%)		1/1052 (0.1%)
Eye naevus	0/1066 (0%)		1/1052 (0.1%)
Fibroadenoma of breast	1/1066 (0.1%)		0/1052 (0%)
Fibroma	1/1066 (0.1%)		0/1052 (0%)
Haemangioma	1/1066 (0.1%)		0/1052 (0%)
Lipoma	1/1066 (0.1%)		1/1052 (0.1%)
Lipoma of breast	1/1066 (0.1%)		0/1052 (0%)
Lung neoplasm	2/1066 (0.2%)		2/1052 (0.2%)
Melanocytic naevus	2/1066 (0.2%)		2/1052 (0.2%)
Pharyngeal neoplasm	1/1066 (0.1%)		0/1052 (0%)
Pituitary tumour	1/1066 (0.1%)		0/1052 (0%)
Pituitary tumour benign	0/1066 (0%)		1/1052 (0.1%)
Seborrhoeic keratosis	2/1066 (0.2%)		1/1052 (0.1%)
Thyroid neoplasm	1/1066 (0.1%)		4/1052 (0.4%)
Uterine leiomyoma	3/1066 (0.3%)		3/1052 (0.3%)
Uterine neoplasm	0/1066 (0%)		1/1052 (0.1%)
Nervous system disorders
Amnesia	3/1066 (0.3%)		0/1052 (0%)
Aphonia	1/1066 (0.1%)		0/1052 (0%)
Ataxia	1/1066 (0.1%)		0/1052 (0%)
Autonomic nervous system imbalance	0/1066 (0%)		1/1052 (0.1%)
Balance disorder	7/1066 (0.7%)		1/1052 (0.1%)
Burning sensation	1/1066 (0.1%)		1/1052 (0.1%)
Carotid artery occlusion	0/1066 (0%)		1/1052 (0.1%)
Carpal tunnel syndrome	7/1066 (0.7%)		5/1052 (0.5%)
Cervical myelopathy	0/1066 (0%)		1/1052 (0.1%)
Circadian rhythm sleep disorder	1/1066 (0.1%)		0/1052 (0%)
Clonus	1/1066 (0.1%)		0/1052 (0%)
Clumsiness	1/1066 (0.1%)		0/1052 (0%)
Cognitive disorder	1/1066 (0.1%)		0/1052 (0%)
Complex regional pain syndrome	0/1066 (0%)		1/1052 (0.1%)
Crying	19/1066 (1.8%)		2/1052 (0.2%)
Decreased vibratory sense	0/1066 (0%)		1/1052 (0.1%)
Disturbance in attention	21/1066 (2%)		6/1052 (0.6%)
Dizziness	207/1066 (19.4%)		64/1052 (6.1%)
Dizziness postural	1/1066 (0.1%)		1/1052 (0.1%)
Dysaesthesia	0/1066 (0%)		1/1052 (0.1%)
Dysgeusia	13/1066 (1.2%)		2/1052 (0.2%)
Exertional headache	1/1066 (0.1%)		0/1052 (0%)
Head titubation	0/1066 (0%)		1/1052 (0.1%)
Headache	332/1066 (31.1%)		262/1052 (24.9%)
Hemicephalalgia	1/1066 (0.1%)		1/1052 (0.1%)
Hyperaesthesia	1/1066 (0.1%)		0/1052 (0%)
Hypersomnia	7/1066 (0.7%)		0/1052 (0%)
Hypoaesthesia	27/1066 (2.5%)		21/1052 (2%)
Intracranial aneurysm	1/1066 (0.1%)		0/1052 (0%)
Lethargy	9/1066 (0.8%)		4/1052 (0.4%)
Loss of consciousness	1/1066 (0.1%)		0/1052 (0%)
Memory impairment	2/1066 (0.2%)		2/1052 (0.2%)
Mental impairment	1/1066 (0.1%)		0/1052 (0%)
Migraine	25/1066 (2.3%)		18/1052 (1.7%)
Migraine with aura	1/1066 (0.1%)		1/1052 (0.1%)
Multiple sclerosis	1/1066 (0.1%)		0/1052 (0%)
Multiple sclerosis relapse	0/1066 (0%)		1/1052 (0.1%)
Muscle spasticity	0/1066 (0%)		1/1052 (0.1%)
Myoclonus	1/1066 (0.1%)		0/1052 (0%)
Nerve compression	2/1066 (0.2%)		2/1052 (0.2%)
Neuralgia	0/1066 (0%)		1/1052 (0.1%)
Neuropathy peripheral	0/1066 (0%)		1/1052 (0.1%)
Paraesthesia	43/1066 (4%)		12/1052 (1.1%)
Poor quality sleep	5/1066 (0.5%)		0/1052 (0%)
Presyncope	1/1066 (0.1%)		1/1052 (0.1%)
Psychomotor hyperactivity	2/1066 (0.2%)		2/1052 (0.2%)
Radicular pain	0/1066 (0%)		1/1052 (0.1%)
Radiculopathy	1/1066 (0.1%)		0/1052 (0%)
Restless legs syndrome	6/1066 (0.6%)		3/1052 (0.3%)
Sciatica	4/1066 (0.4%)		8/1052 (0.8%)
Sedation	3/1066 (0.3%)		0/1052 (0%)
Sinus headache	45/1066 (4.2%)		35/1052 (3.3%)
Sleep phase rhythm disturbance	1/1066 (0.1%)		0/1052 (0%)
Somnolence	59/1066 (5.5%)		11/1052 (1%)
Syncope	1/1066 (0.1%)		4/1052 (0.4%)
Tension headache	8/1066 (0.8%)		9/1052 (0.9%)
Thoracic outlet syndrome	1/1066 (0.1%)		0/1052 (0%)
Tremor	22/1066 (2.1%)		6/1052 (0.6%)
Visual field defect	1/1066 (0.1%)		3/1052 (0.3%)
Psychiatric disorders
Abnormal dreams	32/1066 (3%)		7/1052 (0.7%)
Affect lability	9/1066 (0.8%)		1/1052 (0.1%)
Aggression	4/1066 (0.4%)		2/1052 (0.2%)
Agitation	10/1066 (0.9%)		4/1052 (0.4%)
Anger	2/1066 (0.2%)		4/1052 (0.4%)
Anhedonia	2/1066 (0.2%)		0/1052 (0%)
Anorgasmia	10/1066 (0.9%)		0/1052 (0%)
Anxiety	42/1066 (3.9%)		29/1052 (2.8%)
Apathy	1/1066 (0.1%)		4/1052 (0.4%)
Attention deficit/hyperactivity disorder	0/1066 (0%)		1/1052 (0.1%)
Bradyphrenia	0/1066 (0%)		1/1052 (0.1%)
Bruxism	3/1066 (0.3%)		0/1052 (0%)
Change in sustained attention	0/1066 (0%)		1/1052 (0.1%)
Confusional state	8/1066 (0.8%)		3/1052 (0.3%)
Decreased interest	1/1066 (0.1%)		0/1052 (0%)
Depressed mood	15/1066 (1.4%)		9/1052 (0.9%)
Depression	28/1066 (2.6%)		31/1052 (2.9%)
Depressive symptom	1/1066 (0.1%)		0/1052 (0%)
Derealisation	1/1066 (0.1%)		3/1052 (0.3%)
Disorientation	6/1066 (0.6%)		3/1052 (0.3%)
Dissociation	2/1066 (0.2%)		0/1052 (0%)
Disturbance in sexual arousal	2/1066 (0.2%)		0/1052 (0%)
Dysphoria	0/1066 (0%)		1/1052 (0.1%)
Emotional disorder	1/1066 (0.1%)		3/1052 (0.3%)
Emotional distress	2/1066 (0.2%)		0/1052 (0%)
Euphoric mood	2/1066 (0.2%)		0/1052 (0%)
Feelings of worthlessness	0/1066 (0%)		1/1052 (0.1%)
Frustration	1/1066 (0.1%)		0/1052 (0%)
Impatience	0/1066 (0%)		1/1052 (0.1%)
Initial insomnia	3/1066 (0.3%)		1/1052 (0.1%)
Insomnia	151/1066 (14.2%)		88/1052 (8.4%)
Intentional drug misuse	0/1066 (0%)		1/1052 (0.1%)
Libido decreased	24/1066 (2.3%)		5/1052 (0.5%)
Logorrhoea	1/1066 (0.1%)		0/1052 (0%)
Loss of libido	1/1066 (0.1%)		1/1052 (0.1%)
Major depression	1/1066 (0.1%)		0/1052 (0%)
Mental status changes	1/1066 (0.1%)		0/1052 (0%)
Middle insomnia	4/1066 (0.4%)		0/1052 (0%)
Mood altered	8/1066 (0.8%)		7/1052 (0.7%)
Mood swings	11/1066 (1%)		3/1052 (0.3%)
Nervousness	21/1066 (2%)		4/1052 (0.4%)
Nightmare	10/1066 (0.9%)		3/1052 (0.3%)
Obsessive-compulsive disorder	0/1066 (0%)		1/1052 (0.1%)
Orgasm abnormal	3/1066 (0.3%)		0/1052 (0%)
Orgasmic sensation decreased	1/1066 (0.1%)		0/1052 (0%)
Panic attack	0/1066 (0%)		2/1052 (0.2%)
Post-traumatic stress disorder	2/1066 (0.2%)		0/1052 (0%)
Psychotic disorder	1/1066 (0.1%)		0/1052 (0%)
Restlessness	5/1066 (0.5%)		5/1052 (0.5%)
Sleep disorder	6/1066 (0.6%)		3/1052 (0.3%)
Sleep talking	1/1066 (0.1%)		1/1052 (0.1%)
Sleep terror	1/1066 (0.1%)		0/1052 (0%)
Stress	4/1066 (0.4%)		2/1052 (0.2%)
Suicidal ideation	2/1066 (0.2%)		2/1052 (0.2%)
Tearfulness	3/1066 (0.3%)		1/1052 (0.1%)
Tension	1/1066 (0.1%)		2/1052 (0.2%)
Terminal insomnia	0/1066 (0%)		1/1052 (0.1%)
Thinking abnormal	3/1066 (0.3%)		0/1052 (0%)
Tic	1/1066 (0.1%)		0/1052 (0%)
Withdrawal syndrome	14/1066 (1.3%)		0/1052 (0%)
Renal and urinary disorders
Bladder discomfort	1/1066 (0.1%)		0/1052 (0%)
Bladder irritation	1/1066 (0.1%)		0/1052 (0%)
Bladder pain	1/1066 (0.1%)		1/1052 (0.1%)
Bladder prolapse	1/1066 (0.1%)		0/1052 (0%)
Bladder spasm	1/1066 (0.1%)		0/1052 (0%)
Costovertebral angle tenderness	1/1066 (0.1%)		0/1052 (0%)
Dysuria	7/1066 (0.7%)		4/1052 (0.4%)
Haematuria	12/1066 (1.1%)		13/1052 (1.2%)
Hypertonic bladder	0/1066 (0%)		1/1052 (0.1%)
Incontinence	1/1066 (0.1%)		1/1052 (0.1%)
Ketonuria	1/1066 (0.1%)		1/1052 (0.1%)
Micturition urgency	4/1066 (0.4%)		1/1052 (0.1%)
Nephrocalcinosis	1/1066 (0.1%)		0/1052 (0%)
Nephrolithiasis	2/1066 (0.2%)		6/1052 (0.6%)
Nocturia	1/1066 (0.1%)		0/1052 (0%)
Pollakiuria	5/1066 (0.5%)		6/1052 (0.6%)
Polyuria	0/1066 (0%)		1/1052 (0.1%)
Proteinuria	1/1066 (0.1%)		0/1052 (0%)
Pyuria	1/1066 (0.1%)		0/1052 (0%)
Renal cyst	0/1066 (0%)		3/1052 (0.3%)
Renal pain	1/1066 (0.1%)		2/1052 (0.2%)
Residual urine	1/1066 (0.1%)		1/1052 (0.1%)
Stress urinary incontinence	0/1066 (0%)		1/1052 (0.1%)
Trigonitis	0/1066 (0%)		1/1052 (0.1%)
Urethral caruncle	1/1066 (0.1%)		0/1052 (0%)
Urethral pain	0/1066 (0%)		1/1052 (0.1%)
Urethral prolapse	0/1066 (0%)		1/1052 (0.1%)
Urge incontinence	0/1066 (0%)		1/1052 (0.1%)
Urinary hesitation	3/1066 (0.3%)		1/1052 (0.1%)
Urinary incontinence	1/1066 (0.1%)		1/1052 (0.1%)
Urinary retention	1/1066 (0.1%)		0/1052 (0%)
Urine odour abnormal	1/1066 (0.1%)		0/1052 (0%)
Reproductive system and breast disorders
Atrophic vulvovaginitis	4/1066 (0.4%)		3/1052 (0.3%)
Breast calcifications	0/1066 (0%)		4/1052 (0.4%)
Breast cyst	1/1066 (0.1%)		2/1052 (0.2%)
Breast discharge	1/1066 (0.1%)		1/1052 (0.1%)
Breast disorder	1/1066 (0.1%)		0/1052 (0%)
Breast dysplasia	0/1066 (0%)		2/1052 (0.2%)
Breast engorgement	0/1066 (0%)		1/1052 (0.1%)
Breast mass	3/1066 (0.3%)		4/1052 (0.4%)
Breast pain	6/1066 (0.6%)		7/1052 (0.7%)
Breast swelling	0/1066 (0%)		2/1052 (0.2%)
Breast tenderness	3/1066 (0.3%)		14/1052 (1.3%)
Cervical discharge	0/1066 (0%)		1/1052 (0.1%)
Cervical dysplasia	0/1066 (0%)		1/1052 (0.1%)
Cervical polyp	3/1066 (0.3%)		1/1052 (0.1%)
Cervix disorder	0/1066 (0%)		1/1052 (0.1%)
Coital bleeding	1/1066 (0.1%)		1/1052 (0.1%)
Cystocele	3/1066 (0.3%)		3/1052 (0.3%)
Dysmenorrhoea	1/1066 (0.1%)		3/1052 (0.3%)
Dyspareunia	0/1066 (0%)		3/1052 (0.3%)
Endometrial hyperplasia	1/1066 (0.1%)		0/1052 (0%)
Genital discomfort	1/1066 (0.1%)		0/1052 (0%)
Genital haemorrhage	0/1066 (0%)		1/1052 (0.1%)
Genital rash	0/1066 (0%)		1/1052 (0.1%)
Lactation disorder	1/1066 (0.1%)		0/1052 (0%)
Menstrual disorder	0/1066 (0%)		1/1052 (0.1%)
Menstruation irregular	1/1066 (0.1%)		3/1052 (0.3%)
Metrorrhagia	1/1066 (0.1%)		3/1052 (0.3%)
Nipple pain	1/1066 (0.1%)		2/1052 (0.2%)
Ovarian cyst	2/1066 (0.2%)		1/1052 (0.1%)
Pelvic discomfort	0/1066 (0%)		1/1052 (0.1%)
Pelvic pain	3/1066 (0.3%)		4/1052 (0.4%)
Postmenopausal haemorrhage	3/1066 (0.3%)		8/1052 (0.8%)
Premenstrual syndrome	2/1066 (0.2%)		0/1052 (0%)
Pruritus genital	2/1066 (0.2%)		1/1052 (0.1%)
Rectocele	1/1066 (0.1%)		1/1052 (0.1%)
Sexual dysfunction	2/1066 (0.2%)		0/1052 (0%)
Uterine cervix stenosis	0/1066 (0%)		1/1052 (0.1%)
Uterine enlargement	1/1066 (0.1%)		1/1052 (0.1%)
Uterine haemorrhage	1/1066 (0.1%)		1/1052 (0.1%)
Uterine pain	0/1066 (0%)		1/1052 (0.1%)
Uterine polyp	1/1066 (0.1%)		1/1052 (0.1%)
Uterine prolapse	1/1066 (0.1%)		0/1052 (0%)
Vaginal discharge	10/1066 (0.9%)		4/1052 (0.4%)
Vaginal haemorrhage	30/1066 (2.8%)		22/1052 (2.1%)
Vaginal stricture	0/1066 (0%)		1/1052 (0.1%)
Vulva cyst	1/1066 (0.1%)		2/1052 (0.2%)
Vulval disorder	1/1066 (0.1%)		0/1052 (0%)
Vulvar erosion	1/1066 (0.1%)		0/1052 (0%)
Vulvovaginal discomfort	1/1066 (0.1%)		1/1052 (0.1%)
Vulvovaginal dryness	6/1066 (0.6%)		3/1052 (0.3%)
Vulvovaginal erythema	1/1066 (0.1%)		0/1052 (0%)
Vulvovaginal pruritus	2/1066 (0.2%)		5/1052 (0.5%)
Respiratory, thoracic and mediastinal disorders
Allergic sinusitis	0/1066 (0%)		3/1052 (0.3%)
Asthma	6/1066 (0.6%)		4/1052 (0.4%)
Chronic obstructive pulmonary disease	3/1066 (0.3%)		2/1052 (0.2%)
Cough	53/1066 (5%)		45/1052 (4.3%)
Dry throat	3/1066 (0.3%)		0/1052 (0%)
Dysphonia	3/1066 (0.3%)		0/1052 (0%)
Dyspnoea	12/1066 (1.1%)		9/1052 (0.9%)
Dyspnoea exertional	2/1066 (0.2%)		0/1052 (0%)
Epistaxis	13/1066 (1.2%)		10/1052 (1%)
Hiccups	1/1066 (0.1%)		0/1052 (0%)
Laryngeal oedema	1/1066 (0.1%)		0/1052 (0%)
Laryngeal polyp	1/1066 (0.1%)		0/1052 (0%)
Nasal congestion	26/1066 (2.4%)		20/1052 (1.9%)
Nasal disorder	1/1066 (0.1%)		0/1052 (0%)
Nasal dryness	1/1066 (0.1%)		0/1052 (0%)
Nasal ulcer	0/1066 (0%)		1/1052 (0.1%)
Obliterative bronchiolitis	0/1066 (0%)		1/1052 (0.1%)
Oropharyngeal pain	59/1066 (5.5%)		42/1052 (4%)
Paranasal sinus hypersecretion	2/1066 (0.2%)		2/1052 (0.2%)
Pharyngeal erythema	0/1066 (0%)		2/1052 (0.2%)
Pharyngeal oedema	1/1066 (0.1%)		0/1052 (0%)
Pleurisy	1/1066 (0.1%)		1/1052 (0.1%)
Postnasal drip	2/1066 (0.2%)		2/1052 (0.2%)
Productive cough	1/1066 (0.1%)		1/1052 (0.1%)
Pulmonary congestion	2/1066 (0.2%)		0/1052 (0%)
Respiratory tract congestion	1/1066 (0.1%)		3/1052 (0.3%)
Rhinalgia	0/1066 (0%)		3/1052 (0.3%)
Rhinitis allergic	0/1066 (0%)		3/1052 (0.3%)
Rhinorrhoea	17/1066 (1.6%)		9/1052 (0.9%)
Rhonchi	1/1066 (0.1%)		0/1052 (0%)
Sinus congestion	26/1066 (2.4%)		28/1052 (2.7%)
Sinus polyp	0/1066 (0%)		1/1052 (0.1%)
Sleep apnoea syndrome	0/1066 (0%)		2/1052 (0.2%)
Sneezing	1/1066 (0.1%)		3/1052 (0.3%)
Sputum discoloured	1/1066 (0.1%)		0/1052 (0%)
Stridor	1/1066 (0.1%)		0/1052 (0%)
Throat irritation	5/1066 (0.5%)		4/1052 (0.4%)
Throat tightness	1/1066 (0.1%)		2/1052 (0.2%)
Upper respiratory tract congestion	11/1066 (1%)		13/1052 (1.2%)
Wheezing	5/1066 (0.5%)		3/1052 (0.3%)
Yawning	12/1066 (1.1%)		1/1052 (0.1%)
Skin and subcutaneous tissue disorders
Acne	4/1066 (0.4%)		6/1052 (0.6%)
Acne cystic	1/1066 (0.1%)		0/1052 (0%)
Actinic keratosis	1/1066 (0.1%)		3/1052 (0.3%)
Alopecia	9/1066 (0.8%)		6/1052 (0.6%)
Blister	0/1066 (0%)		1/1052 (0.1%)
Campbell de Morgan spots	1/1066 (0.1%)		0/1052 (0%)
Cold sweat	3/1066 (0.3%)		0/1052 (0%)
Dermal cyst	0/1066 (0%)		2/1052 (0.2%)
Dermatitis	1/1066 (0.1%)		3/1052 (0.3%)
Dermatitis allergic	3/1066 (0.3%)		0/1052 (0%)
Dermatitis contact	10/1066 (0.9%)		12/1052 (1.1%)
Dermatosis	0/1066 (0%)		1/1052 (0.1%)
Dry skin	6/1066 (0.6%)		4/1052 (0.4%)
Dyshidrosis	2/1066 (0.2%)		0/1052 (0%)
Ecchymosis	3/1066 (0.3%)		3/1052 (0.3%)
Eczema	1/1066 (0.1%)		2/1052 (0.2%)
Erythema	1/1066 (0.1%)		1/1052 (0.1%)
Erythema nodosum	1/1066 (0.1%)		0/1052 (0%)
Hair texture abnormal	0/1066 (0%)		1/1052 (0.1%)
Hidradenitis	0/1066 (0%)		1/1052 (0.1%)
Hirsutism	0/1066 (0%)		2/1052 (0.2%)
Hyperhidrosis	30/1066 (2.8%)		8/1052 (0.8%)
Hypoaesthesia facial	0/1066 (0%)		2/1052 (0.2%)
Increased tendency to bruise	3/1066 (0.3%)		1/1052 (0.1%)
Ingrowing nail	3/1066 (0.3%)		0/1052 (0%)
Keloid scar	1/1066 (0.1%)		0/1052 (0%)
Lentigo	1/1066 (0.1%)		0/1052 (0%)
Lichen planus	0/1066 (0%)		1/1052 (0.1%)
Lichen sclerosus	0/1066 (0%)		1/1052 (0.1%)
Nail disorder	0/1066 (0%)		2/1052 (0.2%)
Nail dystrophy	1/1066 (0.1%)		0/1052 (0%)
Night sweats	27/1066 (2.5%)		14/1052 (1.3%)
Onychoclasis	1/1066 (0.1%)		0/1052 (0%)
Pain of skin	0/1066 (0%)		1/1052 (0.1%)
Photosensitivity reaction	1/1066 (0.1%)		0/1052 (0%)
Pruritus	17/1066 (1.6%)		13/1052 (1.2%)
Pruritus generalised	3/1066 (0.3%)		3/1052 (0.3%)
Psoriasis	1/1066 (0.1%)		1/1052 (0.1%)
Rash	33/1066 (3.1%)		25/1052 (2.4%)
Rash erythematous	1/1066 (0.1%)		3/1052 (0.3%)
Rash generalised	1/1066 (0.1%)		1/1052 (0.1%)
Rash macular	2/1066 (0.2%)		2/1052 (0.2%)
Rash maculo-papular	1/1066 (0.1%)		0/1052 (0%)
Rash papular	1/1066 (0.1%)		2/1052 (0.2%)
Rash pruritic	2/1066 (0.2%)		1/1052 (0.1%)
Rosacea	2/1066 (0.2%)		1/1052 (0.1%)
Scar	2/1066 (0.2%)		0/1052 (0%)
Sebaceous hyperplasia	0/1066 (0%)		1/1052 (0.1%)
Seborrhoeic dermatitis	2/1066 (0.2%)		1/1052 (0.1%)
Skin atrophy	1/1066 (0.1%)		0/1052 (0%)
Skin discolouration	1/1066 (0.1%)		0/1052 (0%)
Skin haemorrhage	1/1066 (0.1%)		0/1052 (0%)
Skin hyperpigmentation	1/1066 (0.1%)		1/1052 (0.1%)
Skin induration	0/1066 (0%)		1/1052 (0.1%)
Skin irritation	2/1066 (0.2%)		2/1052 (0.2%)
Skin lesion	5/1066 (0.5%)		2/1052 (0.2%)
Skin nodule	0/1066 (0%)		1/1052 (0.1%)
Skin swelling	1/1066 (0.1%)		0/1052 (0%)
Subcutaneous nodule	1/1066 (0.1%)		1/1052 (0.1%)
Swelling face	2/1066 (0.2%)		2/1052 (0.2%)
Trichorrhexis	0/1066 (0%)		1/1052 (0.1%)
Urticaria	19/1066 (1.8%)		10/1052 (1%)
Yellow skin	1/1066 (0.1%)		0/1052 (0%)
Social circumstances
Ex-tobacco user	0/1066 (0%)		1/1052 (0.1%)
Stress at work	1/1066 (0.1%)		0/1052 (0%)
Surgical and medical procedures
Post procedural drainage	0/1066 (0%)		1/1052 (0.1%)
Vascular disorders
Aortic dilatation	1/1066 (0.1%)		0/1052 (0%)
Flushing	2/1066 (0.2%)		0/1052 (0%)
Haematoma	1/1066 (0.1%)		2/1052 (0.2%)
Hot flush	95/1066 (8.9%)		59/1052 (5.6%)
Hypertension	37/1066 (3.5%)		33/1052 (3.1%)
Hypotension	3/1066 (0.3%)		0/1052 (0%)
Orthostatic hypotension	3/1066 (0.3%)		0/1052 (0%)
Peripheral coldness	1/1066 (0.1%)		0/1052 (0%)
Peripheral embolism	1/1066 (0.1%)		0/1052 (0%)
Raynaud's phenomenon	1/1066 (0.1%)		0/1052 (0%)
Thrombosis	0/1066 (0%)		1/1052 (0.1%)
Varicose vein	0/1066 (0%)		1/1052 (0.1%)

Limitations/Caveats

GCS scales were analyzed only for main study efficacy population.

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Certain Agreements

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

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.