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A Comparison of Estradiol Vaginal Cream to Estrace® Cream in 350 Postmenopausal Females With Atrophic Vaginitis

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ClinicalTrials.gov Identifier: NCT02195986
Recruitment Status : Completed
First Posted : July 21, 2014
Results First Posted : September 6, 2017
Last Update Posted : November 29, 2017
Sponsor:
Collaborator:
Mylan Pharmaceuticals
Information provided by (Responsible Party):
Mylan Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Atrophic Vaginitis
Interventions Drug: Estradiol Vaginal Cream, 0.01%
Drug: Estrace® 0.01% cream
Drug: Placebo Vaginal Cream
Enrollment 366
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Estradiol Vaginal Cream Estrace® 0.01% Cream Placebo Vaginal Cream
Hide Arm/Group Description

Estradiol Vaginal Cream, 0.01%, administered once daily for 7 days.

Estradiol Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days)

Estrace® 0.01% vaginal cream, administered once daily for 7 days.

Estrace® 0.01% cream: Estrace® 0.01% vaginal cream (1 x 2 g for 7 days)

Placebo Vaginal Cream, administered once daily for 7 days.

Placebo Vaginal Cream: Placebo Vaginal Cream (1 x 2 g for 7 days)

Period Title: Overall Study
Started 146 147 73
Completed 143 142 71
Not Completed 3 5 2
Reason Not Completed
Adverse Event             3             0             0
Withdrawal by Subject             0             3             0
Family Emergency             0             0             1
Protocol Violation             0             1             1
Non-compliance             0             1             0
Arm/Group Title Estradiol Vaginal Cream Estrace® 0.01% Cream Placebo Vaginal Cream Total
Hide Arm/Group Description

Estradiol Vaginal Cream, 0.01%, administered once daily for 7 days.

Estradiol Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days)

Estrace® 0.01% vaginal cream, administered once daily for 7 days.

Estrace® 0.01% cream: Estrace® 0.01% vaginal cream (1 x 2 g for 7 days)

Placebo Vaginal Cream, administered once daily for 7 days.

Placebo Vaginal Cream: Placebo Vaginal Cream (1 x 2 g for 7 days)

Total of all reporting groups
Overall Number of Baseline Participants 146 147 73 366
Hide Baseline Analysis Population Description
The Baseline Analysis Population includes all randomized subjects.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 146 participants 147 participants 73 participants 366 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
128
  87.7%
124
  84.4%
61
  83.6%
313
  85.5%
>=65 years
18
  12.3%
23
  15.6%
12
  16.4%
53
  14.5%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 146 participants 147 participants 73 participants 366 participants
59.2  (5.25) 59.6  (5.88) 59.4  (5.82) 59.4  (5.61)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 146 participants 147 participants 73 participants 366 participants
Female
146
 100.0%
147
 100.0%
73
 100.0%
366
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 146 participants 147 participants 73 participants 366 participants
Hispanic or Latino
30
  20.5%
23
  15.6%
13
  17.8%
66
  18.0%
Not Hispanic or Latino
116
  79.5%
124
  84.4%
60
  82.2%
300
  82.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 146 participants 147 participants 73 participants 366 participants
American Indian or Alaska Native
0
   0.0%
1
   0.7%
0
   0.0%
1
   0.3%
Asian
1
   0.7%
3
   2.0%
1
   1.4%
5
   1.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
15
  10.3%
18
  12.2%
11
  15.1%
44
  12.0%
White
130
  89.0%
125
  85.0%
61
  83.6%
316
  86.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
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 146 participants 147 participants 73 participants 366 participants
146 147 73 366
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 146 participants 147 participants 73 participants 366 participants
162.1  (6.43) 161.5  (6.18) 162.6  (6.55) 161.9  (6.35)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 146 participants 147 participants 73 participants 366 participants
69.77  (12.74) 69.39  (12.67) 67.61  (11.37) 69.19  (12.44)
BMI  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 146 participants 147 participants 73 participants 366 participants
26.6  (4.41) 26.6  (4.56) 25.6  (4.11) 26.4  (4.42)
1.Primary Outcome
Title Primary Endpoint (Vaginal Cytology + Vaginal pH) Equivalence
Hide Description

Treatment comparison of the proportion of patients in the Per Protocol (PP) population who received either Estradiol Vaginal Cream or Estrace® that were identified as responders at the end of the treatment period on Study Day 8.

A responder was defined as a patient with at least a 25% reduction from baseline in the sum of % basal/parabasal + % intermediate cells on vaginal cytology AND vaginal pH ≤ 5.0 with a change from baseline vaginal pH of at least 0.5.

Time Frame Study Day 8
Hide Outcome Measure Data
Hide Analysis Population Description
The Per Protocol population was used for the primary endpoint equivalence comparison which consisted of all randomized subjects that were dosed with 75%-125% of scheduled applications of Test or Reference and completed primary endpoint evaluation on Study Day 8 +/- 2 days with no protocol violations that would affect treatment evaluation
Arm/Group Title Estradiol Vaginal Cream Estrace® 0.01% Cream
Hide Arm/Group Description:

Estradiol Vaginal Cream, 0.01%, administered once daily for 7 days.

Estradiol Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days)

Estrace® 0.01% vaginal cream, administered once daily for 7 days.

Estrace® 0.01% cream: Estrace® 0.01% vaginal cream (1 x 2 g for 7 days)

Overall Number of Participants Analyzed 111 117
Measure Type: Count of Participants
Unit of Measure: Participants
42
  37.8%
45
  38.5%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol Vaginal Cream, Estrace® 0.01% Cream
Comments The compound hypothesis to test was: H0: PT –PR < -.20 or PT –PR > .20 versus HA : -.20 ≤ PT –PR ≤ .20 Where PT = cure rate of test treatment, and PR = cure rate of reference treatment.
Type of Statistical Test Equivalence
Comments Bioequivalence was established for the primary endpoint if the 90% confidence interval for the difference of responder rates (test – reference) from baseline to Day 8 for the primary endpoint is contained within [-0.20, 0.20], using the per-protocol population.
Method of Estimation Estimation Parameter Difference
Estimated Value -0.0062
Confidence Interval (2-Sided) 90%
-0.1209 to 0.1084
Estimation Comments [Not Specified]
2.Primary Outcome
Title Primary Endpoint (Vaginal Cytology + Vaginal pH) Comparison of Active Treatments to Placebo
Hide Description

Treatment comparison of the proportion of patients in the Per Protocol (PP) population who received either Estradiol Vaginal Cream, Estrace®, or Placebo that were identified as responders at the end of the treatment period on Study Day 8.

A responder was defined as a patient with at least a 25% reduction from baseline in the sum of % basal/parabasal + % intermediate cells on vaginal cytology AND vaginal pH ≤ 5.0 with a change from baseline vaginal pH of at least 0.5.

Time Frame Study Day 8
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent-to-treat (ITT) population was used for the comparison of active treatments versus placebo analysis which consisted of all randomized subjects that used at least one dose of Test, Reference or Placebo and returned for at least one post-baseline visit.
Arm/Group Title Estradiol Vaginal Cream Estrace® 0.01% Cream Placebo Vaginal Cream
Hide Arm/Group Description:

Estradiol Vaginal Cream, 0.01%, administered once daily for 7 days.

Estradiol Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days)

Estrace® 0.01% vaginal cream, administered once daily for 7 days.

Estrace® 0.01% cream: Estrace® 0.01% vaginal cream (1 x 2 g for 7 days)

Placebo Vaginal Cream, administered once daily for 7 days.

Placebo Vaginal Cream: Placebo Vaginal Cream (1 x 2 g for 7 days)

Overall Number of Participants Analyzed 125 138 65
Measure Type: Count of Participants
Unit of Measure: Participants
49
  39.2%
51
  37.0%
1
   1.5%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol Vaginal Cream, Placebo Vaginal Cream
Comments Both the test and reference products should both be statistically superior to placebo (p<0.05, two-sided) using the Chi squared test with Yate's correction for the primary endpoint responder rate, using the ITT study population and last observation carried forward. The compound hypothesis to test was: H0: PT - PP ≤ 0 versus HA: PT - PP > 0; Where PT = cure rate of test treatment, and PP = cure rate of placebo.
Type of Statistical Test Superiority
Comments Superiority test of test product vs placebo
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 0.3766
Confidence Interval (2-Sided) 95%
0.2743 to 0.4790
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estrace® 0.01% Cream, Placebo Vaginal Cream
Comments Both the test and reference products should both be statistically superior to placebo (p<0.05, two-sided) using the Chi squared test with Yate's correction for the primary endpoint responder rate, using the ITT study population and last observation carried forward. The compound hypothesis to test was: H0: PT - PP ≤ 0 versus HA: PT - PP > 0; Where PT = cure rate of test treatment, and PP = cure rate of placebo.
Type of Statistical Test Superiority
Comments Superiority test of reference product vs placebo
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 0.3542
Confidence Interval (2-Sided) 95%
0.2570 to 0.4514
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Equivalence
Hide Description Evaluation and comparison between Estradiol Vaginal Cream and Estrace® treatment groups of the change from baseline in the most bothersome vulvar and/or vaginal atrophy symptom including vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, or vaginal bleeding associated with sexual activity as identified by each subject. A score ≤ 1 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment success. A score ≥ 2 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment failure.
Time Frame Day 8
Hide Outcome Measure Data
Hide Analysis Population Description
The Per Protocol population was used for the secondary endpoint equivalence comparison which consisted of all randomized subjects that were dosed with 75%-125% of scheduled applications of Test or Reference and completed secondary endpoint evaluation on Study Day 8 +/- 2 days with no protocol violations that would affect treatment evaluation
Arm/Group Title Estradiol Vaginal Cream Estrace® 0.01% Cream
Hide Arm/Group Description:

Estradiol Vaginal Cream, 0.01%, administered once daily for 7 days.

Estradiol Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days)

Estrace® 0.01% vaginal cream, administered once daily for 7 days.

Estrace® 0.01% cream: Estrace® 0.01% vaginal cream (1 x 2 g for 7 days)

Overall Number of Participants Analyzed 97 91
Measure Type: Count of Participants
Unit of Measure: Participants
72
  74.2%
63
  69.2%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol Vaginal Cream, Estrace® 0.01% Cream
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments Bioequivalence was established for the secondary endpoint if the 90% confidence interval for the difference of responder rates (test - reference) from baseline to Day 8 for the secondary endpoint is contained within [-0.20, 0.20], using the per-protocol population.
Method of Estimation Estimation Parameter Difference
Estimated Value 0.0500
Confidence Interval (2-Sided) 90%
-0.0687 to 0.1686
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Comparison to Placebo
Hide Description Evaluation and comparison between Estradiol Vaginal Cream, Estrace®, and Placebo treatment groups of the change from baseline in the most bothersome vulvar and/or vaginal atrophy symptom including vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, or vaginal bleeding associated with sexual activity as identified by each subject. A score ≤ 1 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment success. A score ≥ 2 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment failure.
Time Frame Day 8
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent-to-treat (ITT) population was used for the Superiority Analysis which consisted of all randomized subjects that used at least one dose of Estradiol Vaginal Cream, Estrace®, or Placebo and returned for at least one post-baseline visit
Arm/Group Title Estradiol Vaginal Cream Estrace® 0.01% Cream Placebo Vaginal Cream
Hide Arm/Group Description:

Estradiol Vaginal Cream, 0.01%, administered once daily for 7 days.

Estradiol Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days)

Estrace® 0.01% vaginal cream, administered once daily for 7 days.

Estrace® 0.01% cream: Estrace® 0.01% vaginal cream (1 x 2 g for 7 days)

Placebo Vaginal Cream, administered once daily for 7 days.

Placebo Vaginal Cream: Placebo Vaginal Cream (1 x 2 g for 7 days)

Overall Number of Participants Analyzed 111 107 55
Measure Type: Count of Participants
Unit of Measure: Participants
82
  73.9%
77
  72.0%
33
  60.0%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol Vaginal Cream, Placebo Vaginal Cream
Comments Both the test and reference products should both be statistically superior to placebo (p<0.05, two-sided) using the Chi squared test with Yate's correction for the secondary endpoint responder rate, using the ITT study population and last observation carried forward. The compound hypothesis to test was: H0: PT - PP ≤ 0 versus HA: PT - PP > 0; Where PT = cure rate of test treatment, and PP = cure rate of placebo.
Type of Statistical Test Superiority
Comments Superiority test of test product vs placebo
Statistical Test of Hypothesis P-Value 0.1092
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 0.1387
Confidence Interval (2-Sided) 95%
-0.0280 to 0.3054
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estrace® 0.01% Cream, Placebo Vaginal Cream
Comments Both the test and reference products should both be statistically superior to placebo (p<0.05, two-sided) using the Chi squared test with Yate's correction for the secondary endpoint responder rate, using the ITT study population and last observation carried forward. The compound hypothesis to test was: H0: PT - PP ≤ 0 versus HA: PT - PP > 0; Where PT = cure rate of test treatment, and PP = cure rate of placebo.
Type of Statistical Test Superiority
Comments Superiority test of reference product vs placebo
Statistical Test of Hypothesis P-Value 0.1805
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 0.1196
Confidence Interval (2-Sided) 95%
-0.0491 to 0.2883
Estimation Comments [Not Specified]
Time Frame Adverse event data was collected from signing of the ICF until 30 days post study exit on Study Day 8.
Adverse Event Reporting Description Adverse events were collected via subject self-reporting in a diary and queries at clinic visits. Only subjects that were confirmed to have received at least 1 dose of study medication were included in the Safety Population (i.e., At risk) for adverse event reporting. The Safety Population consisted of 146 subjects for the Estradiol Vaginal Cream arm, 144 subjects for the Estrace® arm, and 72 subjects for the Placebo arm.
 
Arm/Group Title Estradiol Vaginal Cream Estrace® 0.01% Cream Placebo Vaginal Cream
Hide Arm/Group Description

Estradiol Vaginal Cream, 0.01%, administered once daily for 7 days.

Estradiol Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days)

Estrace® 0.01% vaginal cream, administered once daily for 7 days.

Estrace® 0.01% cream: Estrace® 0.01% vaginal cream (1 x 2 g for 7 days)

Placebo Vaginal Cream, administered once daily for 7 days.

Placebo Vaginal Cream: Placebo Vaginal Cream (1 x 2 g for 7 days)

All-Cause Mortality
Estradiol Vaginal Cream Estrace® 0.01% Cream Placebo Vaginal Cream
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/146 (0.00%)      0/144 (0.00%)      0/72 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Estradiol Vaginal Cream Estrace® 0.01% Cream Placebo Vaginal Cream
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/146 (0.68%)      0/144 (0.00%)      0/72 (0.00%)    
Cardiac disorders       
Sick Sinus Syndrome  1  1/146 (0.68%)  1 0/144 (0.00%)  0 0/72 (0.00%)  0
Cardiac Arrest  1  1/146 (0.68%)  1 0/144 (0.00%)  0 0/72 (0.00%)  0
Pericardial Haemorrhage  1  1/146 (0.68%)  1 0/144 (0.00%)  0 0/72 (0.00%)  0
Cardiac Tamponade  1  1/146 (0.68%)  1 0/144 (0.00%)  0 0/72 (0.00%)  0
1
Term from vocabulary, MedDRA (17.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Estradiol Vaginal Cream Estrace® 0.01% Cream Placebo Vaginal Cream
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   31/146 (21.23%)      27/144 (18.75%)      8/72 (11.11%)    
Gastrointestinal disorders       
Abdominal Pain  1  12/146 (8.22%)  13 17/144 (11.81%)  22 0/72 (0.00%)  0
Nervous system disorders       
Headache  1  9/146 (6.16%)  11 4/144 (2.78%)  4 4/72 (5.56%)  4
Reproductive system and breast disorders       
Vulvovaginal Pruritus  1  9/146 (6.16%)  10 2/144 (1.39%)  2 2/72 (2.78%)  2
Breast Tenderness  1  2/146 (1.37%)  2 8/144 (5.56%)  8 0/72 (0.00%)  0
Vaginal Discharge  1  0/146 (0.00%)  0 1/144 (0.69%)  1 4/72 (5.56%)  4
1
Term from vocabulary, MedDRA (17.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Abhijit Barve, Head of Global Clinical Research
Organization: Mylan Inc.
EMail: abhijit.barve@mylan.com
Layout table for additonal information
Responsible Party: Mylan Inc.
ClinicalTrials.gov Identifier: NCT02195986     History of Changes
Other Study ID Numbers: EVCR-11196
First Submitted: July 16, 2014
First Posted: July 21, 2014
Results First Submitted: August 4, 2017
Results First Posted: September 6, 2017
Last Update Posted: November 29, 2017