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A Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms (REPLENISH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01942668
Recruitment Status : Completed
First Posted : September 16, 2013
Results First Posted : May 6, 2019
Last Update Posted : May 6, 2019
Sponsor:
Information provided by (Responsible Party):
TherapeuticsMD

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Menopause
Interventions Drug: Estradiol
Drug: Progesterone
Drug: Placebo
Enrollment 1845
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months. Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months. Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months. Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months. Two Placebo softgel capsules taken orally once a day for twelve months.
Period Title: Overall Study
Started [1] 418 426 422 427 152
Completed 284 305 312 281 93
Not Completed 134 121 110 146 59
[1]
Number of subjects started reflects total number of subjects randomized per arm.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo Total
Hide Arm/Group Description Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months. Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months. Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months. Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months. Two Placebo softgel capsules taken orally once a day for twelve months. Total of all reporting groups
Overall Number of Baseline Participants 415 424 421 424 151 1835
Hide Baseline Analysis Population Description
Safety population
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 415 participants 424 participants 421 participants 424 participants 151 participants 1835 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
415
 100.0%
424
 100.0%
421
 100.0%
424
 100.0%
151
 100.0%
1835
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 415 participants 424 participants 421 participants 424 participants 151 participants 1835 participants
54.7  (4.37) 54.5  (4.52) 54.9  (4.27) 54.4  (4.04) 54.5  (4.32) 54.6  (4.31)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 415 participants 424 participants 421 participants 424 participants 151 participants 1835 participants
Female
415
 100.0%
424
 100.0%
421
 100.0%
424
 100.0%
151
 100.0%
1835
 100.0%
Male
0
   0.0%
0
   0.0%
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 415 participants 424 participants 421 participants 424 participants 151 participants 1835 participants
415 424 421 424 151 1835
1.Primary Outcome
Title Co-Primary Efficacy Endpoint: Frequency of Moderate to Severe Vasomotor Symptoms (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 134 144 142 152 126
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-40.6  (30.59) -35.1  (29.14) -33.6  (30.64) -38.9  (31.04) -26.4  (27.05)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -12.81
Confidence Interval (2-Sided) 95%
-19.29 to -6.32
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.30
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.013
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -8.07
Confidence Interval (2-Sided) 95%
-14.46 to -1.68
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.25
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.141
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.81
Confidence Interval (2-Sided) 95%
-11.21 to 1.59
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.26
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -10.40
Confidence Interval (2-Sided) 95%
-16.73 to -4.08
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.22
Estimation Comments Adjusted for baseline using MMRM
2.Primary Outcome
Title Co-Primary Efficacy Endpoint: Frequency of Moderate to Severe Vasomotor Symptoms (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 124 129 124 135 115
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-55.1  (31.36) -53.7  (31.93) -50.2  (31.35) -52.4  (33.90) -40.2  (29.79)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -16.58
Confidence Interval (2-Sided) 95%
-23.33 to -9.82
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.44
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -15.07
Confidence Interval (2-Sided) 95%
-21.72 to -8.42
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.39
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -10.79
Confidence Interval (2-Sided) 95%
-17.48 to -4.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.41
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -11.71
Confidence Interval (2-Sided) 95%
-18.31 to -5.11
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.36
Estimation Comments Adjusted for baseline using MMRM
3.Primary Outcome
Title Co-Primary Efficacy Endpoint: Severity of Moderate to Severe Vasomotor Symptoms (MITT-VMS)
Hide Description Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame Baseline and Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 134 144 142 152 126
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-0.48  (0.547) -0.51  (0.563) -0.40  (0.469) -0.44  (0.514) -0.34  (0.386)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.031
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.13
Confidence Interval (2-Sided) 95%
-0.25 to -0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.061
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.28 to -0.05
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.060
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.401
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.05
Confidence Interval (2-Sided) 95%
-0.17 to 0.07
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.060
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.100
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.10
Confidence Interval (2-Sided) 95%
-0.21 to 0.02
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.059
Estimation Comments Adjusted for baseline using MMRM
4.Primary Outcome
Title Co-Primary Efficacy Endpoint: Severity of Moderate to Severe Vasomotor Symptoms (MITT-VMS)
Hide Description Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 124 129 124 135 115
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-1.12  (0.963) -0.90  (0.783) -0.76  (0.744) -0.71  (0.806) -0.56  (0.603)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.57
Confidence Interval (2-Sided) 95%
-0.77 to -0.38
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.100
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.39
Confidence Interval (2-Sided) 95%
-0.59 to -0.20
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.099
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.018
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.24
Confidence Interval (2-Sided) 95%
-0.43 to -0.04
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.100
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.096
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.16
Confidence Interval (2-Sided) 95%
-0.36 to 0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.098
Estimation Comments Adjusted for baseline using MMRM
5.Primary Outcome
Title Primary Safety Endpoint: Endometrial Protection - Hyperplasia
Hide Description Endometrial biopsies centrally evaluated by 2 primary pathologists using criteria from Blaustein's Pathology text. Pathologists classified bx into 1 of following 3 categories: Cat.1: Non-endometrial malignancy/non-hyperplasia; Cat.2: Endometrial hyperplasia; Cat.3: Endometrial malignancy. Consensus reached when 2 primary pathologist agreed on any of above categories; if primary pathologists disagreed on presence of hyperplasia, result of 3rd pathologist was utilized and final decision regarding presence of hyperplasia was based on diagnosis of majority. If all 3 reads disparate, final diagnosis based on most severe dx. Incidence rate calculated as: I=A/B where I=incidence rate at M12 evaluation, A=all new subjects with biopsies positive for endometrial hyperplasia during study but post-Baseline, B=all subjects w/biopsies following M11 meeting criteria specified plus all subjects w/biopsies positive for endometrial hyperplasia by any pathologists before M11.
Time Frame Baseline and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized subjects who had taken at least 1 capsule, had no major protocol violations, acceptable biopsy at baseline (evaluable tissue, no endometrial hyperplasia, polyp or cancer), had a biopsy at month 12 (on or after Study Day 326) or had a diagnosis of endometrial hyperplasia prior to month 12.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation taken orally once a day for twelve months.
Two Placebo capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 280 303 306 274 92
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 1 mg / Progesterone 100 mg.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
1.06
Estimation Comments This calculation is based on a binomial distribution.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.5 mg / Progesterone 100 mg.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
0.98
Estimation Comments This calculation is based on a binomial distribution.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.5 mg / Progesterone 50 mg.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
0.97
Estimation Comments This calculation is based on a binomial distribution.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.25 mg / Progesterone 50 mg.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
1.09
Estimation Comments This calculation is based on a binomial distribution.
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Placebo.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
3.20
Estimation Comments This calculation is based on a binomial distribution.
6.Secondary Outcome
Title Endometrial Protection - Hyperplasia
Hide Description Endometrial biopsies centrally evaluated by 3 primary pathologists using criteria described in Blaustein's Pathology text. Pathologists classified biopsy into 1 of following 3 categories: Cat.1: Non-endometrial malignancy/non-hyperplasia; Cat.2: Endometrial hyperplasia; Cat.3: Endometrial malignancy. Consensus was reached when the 2 of 3 pathologist readers agreed on any of the above categories; if all three reads were disparate, the final diagnosis was based on the most severe diagnosis. Incidence rate calculated as: I=A/B where I=incidence rate at M12 evaluation, A=all new subjects with biopsies positive for endometrial hyperplasia during study but post-Baseline, B=all subjects with biopsies following M11 meeting the criteria specified plus all subjects with biopsies positive for endometrial hyperplasia by any of the pathologists before M11.
Time Frame Baseline and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized subjects who had taken at least 1 capsule, had no major protocol violations, acceptable biopsy at baseline (evaluable tissue, no endometrial hyperplasia, polyp or cancer), had a biopsy at month 12 (on or after Study Day 326) or had a diagnosis of endometrial hyperplasia prior to month 12.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 280 303 306 274 92
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 1 mg / Progesterone 100 mg.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
1.06
Estimation Comments This calculation is based on a binomial distribution.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.5 mg / Progesterone 100 mg.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
0.98
Estimation Comments This calculation is based on a binomial distribution.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.5 mg / Progesterone 50 mg.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
0.97
Estimation Comments This calculation is based on a binomial distribution.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.25 mg / Progesterone 50 mg.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
1.09
Estimation Comments This calculation is based on a binomial distribution.
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo
Comments Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Placebo.
Type of Statistical Test Other
Comments Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Method of Estimation Estimation Parameter incidence rate
Estimated Value 0
Confidence Interval (1-Sided) 95%
3.20
Estimation Comments This calculation is based on a binomial distribution.
7.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 1 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 1
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 138 149 145 154 134
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-12.2  (20.10) -11.5  (20.19) -11.0  (20.94) -16.3  (22.28) -13.0  (21.25)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.588
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.36
Confidence Interval (2-Sided) 95%
-3.57 to 6.30
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.51
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.601
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.29
Confidence Interval (2-Sided) 95%
-3.56 to 6.15
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.47
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.202
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 3.17
Confidence Interval (2-Sided) 95%
-1.71 to 8.06
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.49
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.431
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.93
Confidence Interval (2-Sided) 95%
-6.76 to 2.89
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.46
Estimation Comments Adjusted for baseline using MMRM
8.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 2 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 2
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 134 146 145 153 133
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-26.6  (27.67) -21.2  (24.79) -19.0  (28.32) -25.4  (26.63) -21.3  (24.75)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.154
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.35
Confidence Interval (2-Sided) 95%
-10.34 to 1.64
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.05
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.956
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-6.06 to 5.73
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.00
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.240
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 3.54
Confidence Interval (2-Sided) 95%
-2.37 to 9.46
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.01
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.353
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.77
Confidence Interval (2-Sided) 95%
-8.62 to 3.08
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.98
Estimation Comments Adjusted for baseline using MMRM
9.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 3 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 3
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 136 144 144 153 131
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-34.3  (29.22) -29.0  (26.73) -28.1  (28.18) -33.6  (27.76) -25.1  (27.26)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -8.56
Confidence Interval (2-Sided) 95%
-14.75 to -2.36
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.16
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.227
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.76
Confidence Interval (2-Sided) 95%
-9.86 to 2.35
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.11
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.597
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.65
Confidence Interval (2-Sided) 95%
-7.77 to 4.47
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.12
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.019
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -7.24
Confidence Interval (2-Sided) 95%
-13.28 to -1.19
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.08
Estimation Comments Adjusted for baseline using MMRM
10.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 4 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 134 144 142 152 126
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-40.6  (30.59) -35.1  (29.14) -33.6  (30.64) -38.9  (31.04) -26.4  (27.05)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -12.81
Confidence Interval (2-Sided) 95%
-19.29 to -6.32
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.30
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.013
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -8.07
Confidence Interval (2-Sided) 95%
-14.46 to -1.68
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.25
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.141
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.81
Confidence Interval (2-Sided) 95%
-11.21 to 1.59
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.26
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -10.40
Confidence Interval (2-Sided) 95%
-16.73 to -4.08
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.22
Estimation Comments Adjusted for baseline using MMRM
11.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 5 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 131 143 139 147 124
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-45.9  (32.31) -39.5  (28.53) -37.1  (30.64) -43.5  (33.31) -31.6  (28.96)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -15.59
Confidence Interval (2-Sided) 95%
-22.16 to -9.02
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.35
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -9.88
Confidence Interval (2-Sided) 95%
-16.34 to -3.41
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.29
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.075
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -5.90
Confidence Interval (2-Sided) 95%
-12.40 to 0.59
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.31
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -12.05
Confidence Interval (2-Sided) 95%
-18.47 to -5.64
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.27
Estimation Comments Adjusted for baseline using MMRM
12.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 6 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 132 143 139 146 123
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-49.4  (32.76) -41.7  (29.97) -40.1  (33.62) -45.5  (33.14) -32.7  (28.53)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 6
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -17.87
Confidence Interval (2-Sided) 95%
-24.57 to -11.05
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.44
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 6
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -11.35
Confidence Interval (2-Sided) 95%
-18.00 to -4.70
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.39
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.022
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 6
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -7.82
Confidence Interval (2-Sided) 95%
-14.50 to -1.14
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.40
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 6
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -12.51
Confidence Interval (2-Sided) 95%
-19.11 to -5.91
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.36
Estimation Comments Adjusted for baseline using MMRM
13.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 7 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 7. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 7
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 130 142 139 147 120
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-51.5  (31.51) -45.0  (30.73) -43.8  (33.20) -47.7  (32.18) -33.4  (29.37)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 7
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -17.75
Confidence Interval (2-Sided) 95%
-24.45 to -11.06
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.41
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 7
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -13.29
Confidence Interval (2-Sided) 95%
-19.88 to -6.70
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.36
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 7
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -10.22
Confidence Interval (2-Sided) 95%
-16.83 to -3.60
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.37
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 7
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -13.61
Confidence Interval (2-Sided) 95%
-20.15 to -7.07
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.33
Estimation Comments Adjusted for baseline using MMRM
14.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 8 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 8. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 129 140 137 147 120
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-52.3  (31.63) -46.8  (30.64) -45.4  (32.55) -48.4  (32.82) -36.0  (30.66)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -16.63
Confidence Interval (2-Sided) 95%
-23.35 to -9.91
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.42
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -12.97
Confidence Interval (2-Sided) 95%
-19.58 to -6.36
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.37
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -9.63
Confidence Interval (2-Sided) 95%
-16.27 to -2.99
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.38
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -11.97
Confidence Interval (2-Sided) 95%
-18.53 to -5.41
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.34
Estimation Comments Adjusted for baseline using MMRM
15.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 9 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 9. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 9
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 124 137 132 141 119
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-52.6  (32.57) -50.5  (31.01) -47.4  (30.13) -50.1  (33.92) -36.4  (29.09)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 9
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -17.12
Confidence Interval (2-Sided) 95%
-23.79 to -10.44
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.40
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 9
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -15.58
Confidence Interval (2-Sided) 95%
-22.15 to -9.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.34
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 9
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -11.05
Confidence Interval (2-Sided) 95%
-17.65 to -4.44
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.36
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 9
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -13.02
Confidence Interval (2-Sided) 95%
-19.54 to -6.50
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.32
Estimation Comments Adjusted for baseline using MMRM
16.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 10 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 10. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 126 133 129 140 118
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-53.2  (32.58) -51.9  (32.79) -49.0  (30.24) -50.6  (33.36) -37.1  (29.74)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 10
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -16.80
Confidence Interval (2-Sided) 95%
-23.58 to -10.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.45
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 10
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -15.66
Confidence Interval (2-Sided) 95%
-22.32 to -8.99
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.40
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 10
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -11.20
Confidence Interval (2-Sided) 95%
-17.90 to -4.49
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.41
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 10
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -12.16
Confidence Interval (2-Sided) 95%
-18.78 to -5.55
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.37
Estimation Comments Adjusted for baseline using MMRM
17.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 11 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 11. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 11
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 126 134 129 137 118
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-53.7  (32.21) -52.0  (31.24) -49.4  (30.71) -50.9  (34.33) -36.7  (30.32)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 11
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -18.11
Confidence Interval (2-Sided) 95%
-24.92 to -11.29
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.47
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 11
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -16.45
Confidence Interval (2-Sided) 95%
-23.17 to -9.74
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.42
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 11
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -12.41
Confidence Interval (2-Sided) 95%
-19.15 to -5.66
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.44
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 11
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -13.60
Confidence Interval (2-Sided) 95%
-20.26 to -6.93
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.39
Estimation Comments Adjusted for baseline using MMRM
18.Secondary Outcome
Title Frequency of Moderate to Severe Vasomotor Symptoms - Week 12 (MITT-VMS)
Hide Description Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 124 129 124 135 115
Mean (Standard Deviation)
Unit of Measure: weekly hot flushes
-55.1  (31.36) -53.7  (31.93) -50.2  (31.35) -52.4  (33.90) -40.2  (29.79)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -16.58
Confidence Interval (2-Sided) 95%
-23.33 to -9.82
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.44
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -15.07
Confidence Interval (2-Sided) 95%
-21.72 to -8.42
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.39
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -10.79
Confidence Interval (2-Sided) 95%
-17.48 to -4.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.41
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -11.71
Confidence Interval (2-Sided) 95%
-18.31 to -5.11
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.36
Estimation Comments Adjusted for baseline using MMRM
19.Secondary Outcome
Title Severity of Moderate to Severe Vasomotor Symptoms - Week 1 (MITT-VMS)
Hide Description Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame Baseline and Week 1
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 138 149 145 154 134
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-0.24  (0.305) -0.25  (0.270) -0.23  (0.264) -0.25  (0.327) -0.25  (0.257)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.801
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.01
Confidence Interval (2-Sided) 95%
-0.06 to 0.08
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.034
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.991
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.07 to 0.07
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.034
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.642
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.05 to 0.08
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.034
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.928
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.00
Confidence Interval (2-Sided) 95%
-0.07 to 0.06
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.034
Estimation Comments Adjusted for baseline using MMRM
20.Secondary Outcome
Title Severity of Moderate to Severe Vasomotor Symptoms - Week 2 (MITT-VMS)
Hide Description Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame Baseline and Week 2
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 134 146 145 153 133
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-0.34  (0.411) -0.34  (0.390) -0.27  (0.354) -0.29  (0.314) -0.28  (0.310)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.231
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.05
Confidence Interval (2-Sided) 95%
-0.14 to 0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.043
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.173
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.06
Confidence Interval (2-Sided) 95%
-0.14 to 0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.042
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.717
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.07 to 0.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.042
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.849
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.09 to 0.07
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.042
Estimation Comments Adjusted for baseline using MMRM
21.Secondary Outcome
Title Severity of Moderate to Severe Vasomotor Symptoms - Week 3 (MITT-VMS)
Hide Description Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame Baseline and Week 3
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 136 144 144 153 131
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-0.43  (0.514) -0.44  (0.437) -0.32  (0.410) -0.37  (0.424) -0.32  (0.372)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.039
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.11
Confidence Interval (2-Sided) 95%
-0.21 to -0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.052
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.030
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.11
Confidence Interval (2-Sided) 95%
-0.21 to -0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.052
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.946
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.10 to 0.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.052
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.309
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.05
Confidence Interval (2-Sided) 95%
-0.15 to 0.05
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.051
Estimation Comments Adjusted for baseline using MMRM
22.Secondary Outcome
Title Severity of Moderate to Severe Vasomotor Symptoms - Week 4 (MITT-VMS)
Hide Description Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame Baseline and Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 134 144 142 152 126
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-0.48  (0.547) -0.51  (0.563) -0.40  (0.469) -0.44  (0.514) -0.34  (0.386)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.031
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.13
Confidence Interval (2-Sided) 95%
-0.25 to -0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.061
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.28 to -0.05
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.060
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.401
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.05
Confidence Interval (2-Sided) 95%
-0.17 to 0.07
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.060
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.100
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.10
Confidence Interval (2-Sided) 95%
-0.21 to 0.02
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.059
Estimation Comments Adjusted for baseline using MMRM
23.Secondary Outcome
Title Severity of Moderate to Severe Vasomotor Symptoms - Week 5 (MITT-VMS)
Hide Description Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame Baseline and Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.
Arm/Group Title Combined Estradiol 1 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 100 mg Combined Estradiol 0.5 mg / Progesterone 50 mg Combined Estradiol 0.25 mg / Progesterone 50 mg Placebo
Hide Arm/Group Description:
Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.
Two Placebo softgel capsules taken orally once a day for twelve months.
Overall Number of Participants Analyzed 131 143 139 147 124
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-0.64  (0.702) -0.56  (0.558) -0.44  (0.463) -0.53  (0.610) -0.42  (0.551)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.23
Confidence Interval (2-Sided) 95%
-0.37 to -0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.071
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.034
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.15
Confidence Interval (2-Sided) 95%
-0.28 to -0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.070
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.790
Comments p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.02
Confidence Interval (2-Sided) 95%
-0.16 to 0.12
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.070
Estimation Comments Adjusted for baseline using MMRM
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.086
Comments p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.12
Confidence Interval (2-Sided) 95%
-0.25 to 0.02
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.069
Estimation Comments Adjusted for baseline using MMRM
24.Secondary Outcome
Title Severity of Moderate to Severe Vasomotor Symptoms - Week 6 (MITT-VMS)
Hide Description Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame Baseline and Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes