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MsFLASH-03: Comparative Efficacy of Low-Dose Estradiol and Venlafaxine XR for Treatment of Menopausal Symptoms

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ClinicalTrials.gov Identifier: NCT01418209
Recruitment Status : Completed
First Posted : August 17, 2011
Results First Posted : August 20, 2014
Last Update Posted : August 27, 2014
Sponsor:
Collaborators:
National Institute on Aging (NIA)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Center for Complementary and Integrative Health (NCCIH)
Office of Research on Women's Health (ORWH)
Information provided by (Responsible Party):
Katherine Guthrie, Fred Hutchinson Cancer Research Center

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Hot Flashes
Menopause
Vasomotor Disturbance
Interventions Drug: Low-dose 17-ß-estradiol with progesterone taper
Drug: Venlafaxine XR
Drug: Placebo
Enrollment 339
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Low-dose 17-ß-Estradiol With Progesterone Taper Venlafaxine XR Placebo
Hide Arm/Group Description Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably. The 8 week estradiol treatment is followed 14 days (2 weeks) of progesterone taper (as medroxy-progesterone 10 mg/day). Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks). Placebo: The placebo is an inactive pill that looks like the active medication.
Period Title: Overall Study
Started 97 96 146
Completed 95 93 142
Not Completed 2 3 4
Reason Not Completed
Withdrawal by Subject             1             0             1
Did not provide hot flash diary data             1             3             3
Arm/Group Title Low-dose 17-ß-estradiol With Progesterone Taper Venlafaxine XR Placebo Total
Hide Arm/Group Description Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably. Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks). Placebo: The placebo is an inactive pill that looks like the active medication. Total of all reporting groups
Overall Number of Baseline Participants 97 96 146 339
Hide Baseline Analysis Population Description
Randomized participants per trial arm
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 97 participants 96 participants 146 participants 339 participants
54.9  (4.1) 54.8  (3.7) 54.3  (3.8) 54.6  (3.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
Female
97
 100.0%
96
 100.0%
146
 100.0%
339
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 97 participants 96 participants 146 participants 339 participants
97 96 146 339
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 97 participants 96 participants 146 participants 339 participants
28.5  (6.5) 29.3  (6.9) 27.6  (6.8) 28.3  (6.8)
Smoking  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
Never 50 54 70 174
Past 30 27 50 107
Current 17 14 24 55
Missing 0 1 2 3
Alcohol use (drinks/week)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
<7 71 77 117 265
>=7 21 13 27 61
Missing 5 6 2 13
Marital status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
Never married / Divorced / Widowed 38 40 49 127
Married / living with partner 58 56 96 210
Missing 1 0 1 2
Education  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
<College graduate 48 48 70 166
College graduate 49 48 75 172
Missing 0 0 1 1
Menopause status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
Perimenopausal 14 16 22 52
Postmenopausal 74 72 110 256
Indeterminate 9 8 14 31
Years since final menstrual period (postmenopausal only)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
0 - 5 35 39 68 142
6 - 10 23 20 29 72
> 10 16 13 13 42
Not postmenopausal 23 24 36 83
Vasomotor symptom (VMS) number of participants with number of hot flashes / day  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
< 6 36 36 67 139
6 - < 9 32 31 39 102
9 - < 12 11 15 19 45
>= 12 18 14 21 53
Age at starting vasomotor symptoms (VMS), years of age  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
< 50 47 51 73 171
>= 50 48 44 71 163
Missing 2 1 2 5
Insomnia Severity Index (ISI) Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 97 participants 96 participants 146 participants 339 participants
11.0  (6.3) 11.7  (6.0) 10.4  (5.8) 11.0  (6.0)
[1]
Measure Description: The Insomnia Severity Index (ISI) assesses level of insomnia, an inability to sleep. There are 7 questions, each ranging in a numerical rating from 0 (zero) to 4 with 0 indicating less insomnia and 4 indicating more insomnia. The numbers from each question are summed for a total score ranging from 0 to 28 with 0 indicating less insomnia and 28 indicating more insomnia.
Insomnia Severity Index (ISI) Score  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
No clinically significant insomnia (<= 7) 28 26 52 106
Subthreshold insomnia (8 - 14) 40 39 54 133
Clinical insomnia (moderate, 15 - 21) 21 25 32 78
Clinical insomnia (severe, >= 22) 5 5 4 14
Missing 3 1 4 8
Pittsburgh Sleep Quality Index (PSQI) Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 97 participants 96 participants 146 participants 339 participants
7.6  (3.6) 7.6  (3.2) 7.3  (3.5) 7.5  (3.4)
[1]
Measure Description: The Pittsburgh Sleep Quality Index (PSQI) assesses quality of sleep. There are 7 questions. Each question is scored 0 (better quality sleep) to 3 (worse quality sleep). The scores from each question are summed to a total score, ranging from 0 (better quality sleep) to 21 (worse quality sleep).
Pittsburgh Sleep Quality Index (PSQI) Score  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
Good quality sleep (< 5) 23 14 30 67
Moderate sleep quality (5 - < 8) 21 35 46 102
Poor sleep quality (>= 8) 46 40 65 151
Missing 7 7 5 19
Patient Health Questionnaire (PHQ-9) Depression Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 97 participants 96 participants 146 participants 339 participants
3.9  (4.4) 3.0  (2.9) 3.4  (3.7) 3.4  (3.7)
[1]
Measure Description: The Patient Health Questionnaire (PHQ-9) assesses severity of depression. There are 10 questions with the first nine questions each scored from 0 to 3. The individual scores are summed to create a total score ranging from 0 to 45. Scores from 5 to >20 provisionally indicate, from lower to higher numbers, minimal symptoms to severe depression.
PHQ-9 Depression Score  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
No depression (0 - 4) 68 70 108 246
Mild depression (5 - 9) 18 23 23 64
Moderate depression (>= 10) 11 3 15 29
Generalized Anxiety Disorder 7 (GAD-7) Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 97 participants 96 participants 146 participants 339 participants
3.0  (4.3) 2.2  (3.0) 2.4  (3.4) 2.5  (3.6)
[1]
Measure Description: Generalized Anxiety Disorder 7 (GAD-7) assesses generalized anxiety. There are 7 questions with each scored from 0 to 3. The scores from each question are summed to a total score ranging from 0 to 21. Lower scores are better.
Generalized Anxiety Disorder 7 (GAD-7) Score  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants 96 participants 146 participants 339 participants
No anxiety (0 - 4) 73 76 116 265
Mild anxiety (5 - 9) 15 17 19 51
Moderate anxiety (>= 10) 9 3 11 23
Vasomotor Symptoms (VMS) as number of hot flashes   [1] 
Mean (Standard Deviation)
Unit of measure:  Number of hot flashes per day
Number Analyzed 97 participants 96 participants 146 participants 339 participants
8.5  (5.7) 8.2  (5.5) 7.7  (4.8) 8.1  (5.3)
[1]
Measure Description: Vasomotor Symptoms (VMS) frequency measures the number of hot flashes during the day and during the night. The day and night frequencies are summed for a 24-hour score.
Severity of Hot Flashes   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 97 participants 96 participants 146 participants 339 participants
1.1  (0.5) 1.0  (0.5) 1.0  (0.4) 1.0  (0.5)
[1]
Measure Description: Severity of hot flashes is measured as a scale from 0 to 3. Lower numbers indicate less severity and higher numbers indicate more severity.
Bothersomeness of Hot Flashes   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 97 participants 96 participants 146 participants 339 participants
2.1  (0.5) 2.0  (0.5) 2.0  (0.5) 2.0  (0.5)
[1]
Measure Description: Bothersomeness of hot flashes is measured on a scale from 0 to 3. Lower numbers indicate less bother and higher numbers indicate more bother.
Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 97 participants 96 participants 146 participants 339 participants
36.9  (23.8) 36.8  (23.4) 32.8  (21.3) 35.1  (22.6)
[1]
Measure Description: The perceived hot flash related daily interference scale (HFRDIS) is a tool for assessing the impact of hot flashes on quality of life. There are 10 questions with each having a score ranging from 0 to 10. The scores from each question are summed for a total score ranging from 0 to 100. Lower numbers indicate less interference and higher numbers indicate more interference.
1.Primary Outcome
Title Frequency of Hot Flashes (Vasomotor Symptom [VMS] Frequency) -- Week 4
Hide Description Measured by self-report diary twice daily (day and night). The day and night frequencies were summed to produce a single number of hot flashes per day. The single number of hot flashes per day were summed and averaged for one week prior to the week 4 study assessment to produce a mean daily frequency for week 4.
Time Frame Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Intention-to-treat, i.e., all participants with follow-up data were included.
Arm/Group Title Low-dose 17-ß-estradiol With Progesterone Taper Venlafaxine XR Placebo
Hide Arm/Group Description:
Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.
Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).
Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Number of Participants Analyzed 91 93 139
Mean (95% Confidence Interval)
Unit of Measure: number of hot flashes per day
5.3
(4.2 to 6.5)
5.1
(4.1 to 6.0)
5.8
(4.9 to 6.7)
2.Primary Outcome
Title Frequency of Hot Flashes (Daily Vasomotor Symptom [VMS] Frequency) -- Week 8
Hide Description Measured by self-report diary twice daily (day and night). The day and night frequencies were summed to produce a single number of hot flashes per day. The single number of hot flashes per day were summed and averaged for one week prior to the week 8 study assessment to produce a mean daily frequency for week 8.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Intention-to-treat, i.e., all participants with follow-up data were included.
Arm/Group Title Low-dose 17-ß-estradiol With Progesterone Taper Venlafaxine XR Placebo
Hide Arm/Group Description:
Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.
Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).
Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Number of Participants Analyzed 92 89 137
Mean (95% Confidence Interval)
Unit of Measure: number of hot flashes per day
3.9
(2.9 to 4.9)
4.4
(3.5 to 5.3)
5.5
(4.7 to 6.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose 17-ß-estradiol With Progesterone Taper, Placebo
Comments VMS frequency values were log transformed for modeling.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
Method repeated measures linear model
Comments Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Venlafaxine XR, Placebo
Comments VMS frequency values were log transformed for modeling.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
Method repeated measures linear model
Comments Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures
3.Secondary Outcome
Title Severity of Hot Flashes -- Week 4
Hide Description Measured by self-report diary twice daily (day and night) for 7 days. Severity ratings ranged from 0 to 3 with lower numbers being less severe and higher numbers being more severe. Data from the day and night severity ratings were averaged for a single daily score. The single daily scores for the week prior to the week 4 study assessment were summed and averaged to produce a mean daily VMS severity for week 4.
Time Frame Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Intention-to-treat, i.e., all participants with follow-up data were included.
Arm/Group Title Low-dose 17-ß-estradiol With Progesterone Taper Venlafaxine XR Placebo
Hide Arm/Group Description:
Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.
Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).
Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Number of Participants Analyzed 81 86 134
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.7
(0.6 to 0.9)
0.7
(0.5 to 0.8)
0.8
(0.7 to 0.9)
4.Secondary Outcome
Title Severity of Hot Flashes -- Week 8
Hide Description Measured by self-report diary twice daily (day and night) for 7 days. Severity ratings ranged from 0 to 3 with lower numbers being less severe and higher numbers being more severe. Data from the day and night severity ratings were averaged for a single daily score. The single daily scores for the week prior to the week 8 study assessment were summed and averaged to produce a mean daily VMS severity for week 8.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Intention-to-treat, i.e., all participants with follow-up data were included.
Arm/Group Title Low-dose 17-ß-estradiol With Progesterone Taper Venlafaxine XR Placebo
Hide Arm/Group Description:
Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.
Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).
Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Number of Participants Analyzed 73 86 133
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.6
(0.4 to 0.7)
0.6
(0.4 to 0.7)
0.7
(0.6 to 0.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose 17-ß-estradiol With Progesterone Taper, Placebo
Comments Outcome differences between active treatment and placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
Method repeated measures linear model
Comments Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Venlafaxine XR, Placebo
Comments Outcome differences between active treatment and placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments p-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold of statistical significance was 0.025.
Method repeated measures linear model
Comments Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures.
5.Secondary Outcome
Title Bothersomeness of Hot Flashes -- Week 4
Hide Description Measured by self-report diary twice daily (day and night) for 7 days. Bothersomeness ratings ranged from 0 to 3 with lower numbers being less bothersome and higher numbers being more bothersome. Data from the day and night bothersomeness ratings were averaged for a single daily score. The single daily scores for the week prior to the week 4 study assessment were summed and averaged to produce a mean daily VMS bothersomeness for week 4.
Time Frame Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Intention-to-treat, i.e., all participants with follow-up data were included.
Arm/Group Title Low-dose 17-ß-estradiol With Progesterone Taper Venlafaxine XR Placebo
Hide Arm/Group Description:
Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.
Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).
Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Number of Participants Analyzed 82 88 135
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
1.6
(1.4 to 1.7)
1.6
(1.4 to 1.7)
1.7
(1.6 to 1.8)
6.Secondary Outcome
Title Bothersomeness of Hot Flashes -- Week 8
Hide Description Measured by self-report diary twice daily (day and night) for 7 days. Bothersomeness ratings ranged from 0 to 3 with lower numbers being less bothersome and higher numbers being more bothersome. Data from the day and night bothersomeness ratings were averaged for a single daily score. The single daily scores for the week prior to the week 8 study assessment were summed and averaged to produce a mean daily VMS bothersomeness for week 8.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Intention-to-treat, i.e., all participants with follow-up data were included.
Arm/Group Title Low-dose 17-ß-estradiol With Progesterone Taper Venlafaxine XR Placebo
Hide Arm/Group Description:
Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.
Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).
Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Number of Participants Analyzed 73 86 133
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
1.4
(1.2 to 1.6)
1.4
(1.3 to 1.6)
1.6
(1.5 to 1.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose 17-ß-estradiol With Progesterone Taper, Placebo
Comments Outcome differences between active treatment and placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01
Comments P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
Method repeated measures linear model
Comments Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Venlafaxine XR, Placebo
Comments Outcome differences between active treatment and placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.07
Comments P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
Method repeated measures linear model
Comments Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures.
7.Secondary Outcome
Title Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 4
Hide Description The perceived hot flash related daily interference scale (HFRDIS) is a tool for assessing the impact of hot flashes on quality of life. There are 10 questions with each having a score ranging from 0 to 10. The scores from each question are summed for a total score ranging from 0 to 100. Lower numbers indicate less interference and higher numbers indicate more interference.
Time Frame Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Intention-to-treat, i.e., all participants with follow-up data were included.
Arm/Group Title Low-dose 17-ß-estradiol With Progesterone Taper Venlafaxine XR Placebo
Hide Arm/Group Description:
Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.
Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).
Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Number of Participants Analyzed 84 83 128
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
18.3
(13.8 to 22.8)
19.8
(15.6 to 23.9)
24.2
(20.7 to 27.7)
8.Secondary Outcome
Title Perceived Hot Flash Interference (Hot Flash Related Daily Interference Scale; HFRDIS) -- Week 8
Hide Description The perceived hot flash related daily interference scale (HFRDIS) is a tool for assessing the impact of hot flashes on quality of life. There are 10 questions with each having a score ranging from 0 to 10. The scores from each question are summed for a total score ranging from 0 to 100. Lower numbers indicate less interference and higher numbers indicate more interference.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Intention-to-treat, i.e., all participants with follow-up data were included.
Arm/Group Title Low-dose 17-ß-estradiol With Progesterone Taper Venlafaxine XR Placebo
Hide Arm/Group Description:
Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably.
Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks).
Placebo: The placebo is an inactive pill that looks like the active medication.
Overall Number of Participants Analyzed 92 86 137
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
14.6
(10.6 to 18.7)
18.3
(13.8 to 22.7)
21.5
(18.1 to 24.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose 17-ß-estradiol With Progesterone Taper, Placebo
Comments Outcome differences between active treatment and placebo.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
Method repeated measures linear model
Comments Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Venlafaxine XR, Placebo
Comments Outcome differences between active treatment and placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.03
Comments P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
Method repeated measures linear model
Comments Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures.
Time Frame 8 weeks
Adverse Event Reporting Description At 1-, 4, and 8-weeks, potential adverse events were assessed by a Management and Safety Interview. Symptoms data were collected at screening and weeks 4 and 8. Data are reported as newly emergent adverse events.
 
Arm/Group Title Low-dose 17-ß-estradiol Venlafaxine XR Placebo
Hide Arm/Group Description Low-dose 17-ß-estradiol: Low-dose 17-ß-estradiol oral (by mouth), 0.5 mg once per day for 8 (eight) weeks. After the 8-week treatment, women with a uterus will receive medroxyprogesterone 10 mg once per day for 2 weeks (14 days). 17-ß-estradiol is approved by the US Food and Drug Administration (FDA) and is indicated for the treatment of menopausal symptoms. ß is the Greek symbol for beta; the symbol and the word are used interchangeably. Venlafaxine XR: Venlafaxine oral (by mouth) 37.5 mg once per day for 1 (one) week, then 75 mg once per day for 7 (seven) weeks. Venlafaxine XR should not be taken while also taking monoamine oxidase inhibitors (MAOIs). Venlafaxine XR is approved by the US Food and Drug Administration (FDA) for treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder, and is available by prescription. Venlafaxine XR is not FDA-approved for the treatment of hot flashes, although prior studies have indicated that it is useful for treating hot flashes and vasomotor symptoms. After the 8-week venlafaxine XR study treatment period, women will receive a tapering dose of venlafaxine XR 37.5 mg once per day for 14 days (2 weeks). Placebo: The placebo is an inactive pill that looks like the active medication.
All-Cause Mortality
Low-dose 17-ß-estradiol Venlafaxine XR Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Low-dose 17-ß-estradiol Venlafaxine XR Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/97 (0.00%)   0/96 (0.00%)   0/146 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Low-dose 17-ß-estradiol Venlafaxine XR Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   53/97 (54.64%)   65/96 (67.71%)   88/146 (60.27%) 
Gastrointestinal disorders       
Any GI symptom   23/94 (24.47%)  25/93 (26.88%)  44/142 (30.99%) 
General disorders       
Any fatigue/arousal symptom   20/85 (23.53%)  26/81 (32.10%)  33/127 (25.98%) 
Any miscellaneous symptom   28/94 (29.79%)  36/94 (38.30%)  43/142 (30.28%) 
Musculoskeletal and connective tissue disorders       
Any musculoskeletal symptom   9/92 (9.78%)  5/94 (5.32%)  13/141 (9.22%) 
Nervous system disorders       
Any central nervous system symptom   22/92 (23.91%)  30/94 (31.91%)  36/142 (25.35%) 
Reproductive system and breast disorders       
Breast tenderness   5/90 (5.56%)  0/93 (0.00%)  8/142 (5.63%) 
Vaginal secretions   2/90 (2.22%)  3/90 (3.33%)  3/139 (2.16%) 
Indicates events were collected by systematic assessment
Findings may be specific to the particular dose of each agent used, treatment period, as well as the preparation and oral administration of estrogen therapy.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Hadine Joffe, MD, MSc
Organization: Brigham and Women's Hospital
Phone: 617-732-4906
EMail: hjoffe@partners.org
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Katherine Guthrie, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01418209     History of Changes
Other Study ID Numbers: MsFLASH-03
1U01AG032700-01 ( U.S. NIH Grant/Contract )
1U01AG032699-01 ( U.S. NIH Grant/Contract )
First Submitted: August 15, 2011
First Posted: August 17, 2011
Results First Submitted: June 18, 2014
Results First Posted: August 20, 2014
Last Update Posted: August 27, 2014