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Clinical Trial Results:
A Phase 2, Dose-ranging, 12-week, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Evaluating the Efficacy and Safety of Three Formulations of Ultra-low Dose Estriol Vaginal Gel (0.005% Estriol Vaginal Gel, 0.002% Estriol Vaginal Gel, 0.0008% Estriol Vaginal Gel) for the Treatment of Vaginal Dryness in Postmenopausal Women with Vulvovaginal Atrophy.

Summary
EudraCT number	2015-005787-42
Trial protocol	SE CZ HU ES IT
Global end of trial date	10 May 2018

Results information
Results version number	v1(current)
This version publication date	25 May 2019
First version publication date	25 May 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ITFE-2092-C1

ISRCTN number

US NCT number

NCT02967510

WHO universal trial number (UTN)

Sponsor organisation name

ITF Research Pharma SLU

Sponsor organisation address

c/ San Rafael 3, Madrid, Spain, 28108

Public contact

Javier Suárez Almarza, ITF Research Pharma SLU, +34 916572323, jsuarez@itfsp.com

Scientific contact

Javier Suárez Almarza, ITF Research Pharma SLU, +34 916572323, jsuarez@itfsp.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

10 May 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 May 2018

Was the trial ended prematurely?

Main objective of the trial

The primary purpose was to evaluate the efficacy of 0.005%, 0.002%, and 0.0008% estriol vaginal gel and determine the minimal effective dose for the treatment of postmenopausal vaginal atrophy in women who report moderate to severe vaginal dryness as the most bothersome symptom.

Protection of trial subjects

This study was conducted in accordance with the accepted version of the Declaration of Helsinki and all relevant federal regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of the United States (US) Code of Federal Regulations (CFR), in compliance with International Council for Harmonization (ICH) good clinical practice (GCP) guidelines, and according to the appropriate regulatory requirements in the countries where the study was conducted. Safety evaluations included adverse events monitoring, clinical laboratory assessments (hematology, blood chemistry, hormones and urinalysis), transvaginal ultrasound, endometrial biopsy and electrocardiogram (ECG).

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Oct 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 47

Country: Number of subjects enrolled

Sweden: 65

Country: Number of subjects enrolled

Czech Republic: 97

Country: Number of subjects enrolled

Hungary: 41

Country: Number of subjects enrolled

Italy: 33

Worldwide total number of subjects

283

EEA total number of subjects

283

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

183

From 65 to 84 years

100

85 years and over

Subject disposition

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Recruitment details

447 subjects were screened, 164 failed screening and 283 were randomized.

Screening details

A total of 283 subjects were randomized out of which 261 completed the study.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Estriol 0.005%

Arm description

Subjects received 1 gram of Estriol 0.005% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Arm type

Experimental

Investigational medicinal product name

Estriol

Investigational medicinal product code

Other name

Pharmaceutical forms

Vaginal gel

Routes of administration

Vaginal use

Dosage and administration details

Subjects received 1 gram of Estriol 0.005% vaginal gel using the supplied applicator.

Estriol 0.002%

Arm description

Subjects received 1 gram of Estriol 0.002% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Arm type

Experimental

Investigational medicinal product name

Estriol

Investigational medicinal product code

Other name

Pharmaceutical forms

Vaginal gel

Routes of administration

Vaginal use

Dosage and administration details

Subjects received 1 gram of Estriol 0.002% vaginal gel using the supplied applicator.

Estriol 0.0008%

Arm description

Subjects received 1 gram of Estriol 0.0008% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Arm type

Experimental

Investigational medicinal product name

Estriol

Investigational medicinal product code

Other name

Pharmaceutical forms

Vaginal gel

Routes of administration

Vaginal use

Dosage and administration details

Subjects received 1 gram of Estriol 0.0008% vaginal gel using the supplied applicator.

Placebo

Arm description

Subjects received matching placebo vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Vaginal gel

Routes of administration

Vaginal use

Dosage and administration details

Subjects received matching placebo vaginal gel using the supplied applicator.

Number of subjects in period 1	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Started	70	70	72	71
Completed	66	67	65	63
Not completed	4	3	7	8
Consent withdrawn by subject	1	-	5	2
Physician decision	-	-	1	-
Non-Compliance with Study Drug	1	-	-	-
Adverse Event	1	2	1	3
Unspecified	-	1	-	1
Lost to follow-up	-	-	-	1
Protocol deviation	1	-	-	1

Baseline characteristics

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Reporting group title

Estriol 0.005%

Reporting group description

Subjects received 1 gram of Estriol 0.005% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group title

Estriol 0.002%

Reporting group description

Subjects received 1 gram of Estriol 0.002% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group title

Estriol 0.0008%

Reporting group description

Subjects received 1 gram of Estriol 0.0008% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group title

Placebo

Reporting group description

Subjects received matching placebo vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo	Total
Number of subjects	70	70	72	71	283
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	61.5 ± 7.43	61.9 ± 6.87	62.2 ± 7.05	62.3 ± 7.24	-
Gender categorical
Units: Subjects
Female	70	70	72	71	283
Male	0	0	0	0	0

End points

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Reporting group title

Estriol 0.005%

Reporting group description

Subjects received 1 gram of Estriol 0.005% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group title

Estriol 0.002%

Reporting group description

Subjects received 1 gram of Estriol 0.002% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group title

Estriol 0.0008%

Reporting group description

Subjects received 1 gram of Estriol 0.0008% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group title

Placebo

Reporting group description

Subjects received matching placebo vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Primary: Change from Baseline to Week 12 in the Severity of Vaginal Dryness

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End point title

Change from Baseline to Week 12 in the Severity of Vaginal Dryness

End point description

Percentage of Subjects with change from baseline to Week 12 in the severity of vaginal dryness was reported. Severity was defined as: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	68
Units: percentage of subjects
number (not applicable)
Change from Baseline: -3	21.4	19.1	18.6	13.2
Change from Baseline: -2	32.9	48.5	37.1	38.2
Change from Baseline: -1	37.1	23.5	28.6	27.9
Change from Baseline: 0	5.7	8.8	15.7	19.1
Change from Baseline: 1	2.9	0	0	1.5

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.304

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.109

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.119

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Primary: Change from Baseline to Week 12 in Vaginal pH

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End point title

Change from Baseline to Week 12 in Vaginal pH

End point description

Change from Baseline to Week 12 in Vaginal pH was reported. A decrease in pH compared to Baseline represents a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	69
Units: pH
least squares mean (standard error)	-1.03 ± 0.106	-1.04 ± 0.108	-0.95 ± 0.107	-0.29 ± 0.108

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.74

Confidence interval

level

95%

sides

2-sided

lower limit

-1.031

upper limit

-0.444

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.75

Confidence interval

level

95%

sides

2-sided

lower limit

-1.051

upper limit

-0.458

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.66

Confidence interval

level

95%

sides

2-sided

lower limit

-0.951

upper limit

-0.369

Primary: Change from Baseline to Week 12 in the Proportion of Superficial Cells of the Vaginal Epithelium

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End point title

Change from Baseline to Week 12 in the Proportion of Superficial Cells of the Vaginal Epithelium

End point description

Change from Baseline to Week 12 in the proportion of superficial cells of the vaginal epithelium was reported. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	69	64	70	66
Units: ratio
least squares mean (standard error)	0.24 ± 0.023	0.17 ± 0.024	0.19 ± 0.023	0.02 ± 0.024

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.147

upper limit

0.278

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.078

upper limit

0.213

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.097

upper limit

0.226

Primary: Change from Baseline to Week 12 in the Proportion of Parabasal Cells of the Vaginal Epithelium

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End point title

Change from Baseline to Week 12 in the Proportion of Parabasal Cells of the Vaginal Epithelium

End point description

Change from Baseline to Week 12 in the proportion of parabasal cells of the vaginal epithelium was reported. A decrease in proportion of parabasal cells compared to Baseline represents a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	69	64	70	66
Units: ratio
least squares mean (standard error)	-0.54 ± 0.036	-0.51 ± 0.037	-0.47 ± 0.036	-0.04 ± 0.038

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.603

upper limit

-0.4

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.572

upper limit

-0.365

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.43

Confidence interval

level

95%

sides

2-sided

lower limit

-0.531

upper limit

-0.331

Secondary: Change from Baseline to Week 12 in Severity of Dyspareunia

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End point title

Change from Baseline to Week 12 in Severity of Dyspareunia

End point description

Percentage of subjects with change from baseline to Week 12 in severity of Dyspareunia was reported. Dyspareunia was only applicable in subjects who had experienced sexual activity with penetration since the previous study visit. Symptom Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	39	31	41	32
Units: Percentage of subjects
number (not applicable)
Change from Baseline: -3	17.9	16.1	9.8	9.4
Change from Baseline: -2	23.1	22.6	39.0	34.4
Change from Baseline: -1	30.8	41.9	29.3	25.0
Change from Baseline: 0	25.6	16.1	12.2	28.1
Change from Baseline: 1	0	3.2	7.3	0
Change from Baseline: 2	2.6	0	2.4	3.1
Change from Baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.47

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.448

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.451

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Secondary: Change from Baseline to Week 12 in Severity of Pruritus or Itching

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End point title

Change from Baseline to Week 12 in Severity of Pruritus or Itching

End point description

Percentage of subjects with change from baseline to Week 12 in severity of Pruritus or Itching was reported. Symptom Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	69
Units: percentage of subjects
number (not applicable)
Change from Baseline: -3	2.9	7.4	5.7	5.8
Change from Baseline: -2	22.9	20.6	21.4	18.8
Change from Baseline: -1	25.7	29.4	28.6	29.0
Change from Baseline: 0	47.1	32.4	40.0	36.2
Change from Baseline: 1	0	5.9	2.9	7.2
Change from Baseline: 2	1.4	2.9	1.4	2.9
Change from Baseline: 3	0	1.5	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.329

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.348

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.266

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 12 in Severity of Burning

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End point title

Change from Baseline to Week 12 in Severity of Burning

End point description

Percentage of subjects with change from baseline to Week 12 in severity of burning was reported. Symptom Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	69
Units: percentage of subjects
number (not applicable)
Change from Baseline: -3	7.1	5.9	10.0	5.8
Change from Baseline: -2	31.4	30.9	25.7	27.5
Change from Baseline: -1	35.7	25.0	25.7	33.3
Change from Baseline: 0	25.7	35.3	37.1	29.0
Change from Baseline: 1	0	1.5	1.4	2.9
Change from Baseline: 2	0	1.5	0	1.4
Change from Baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.122

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.188

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.222

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 12 in Severity of Dysuria

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End point title

Change from Baseline to Week 12 in Severity of Dysuria

End point description

Percentage of subjects with change from baseline to Week 12 in severity of Dysuria was reported. Symptom Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	69
Units: percentage of subjects
number (not applicable)
Change from Baseline: -3	0	1.5	1.4	1.4
Change from Baseline: -2	11.4	11.8	7.1	7.2
Change from Baseline: -1	25.7	27.9	24.3	21.7
Change from Baseline: 0	61.4	57.4	57.1	63.8
Change from Baseline: 1	1.4	1.5	10.0	0
Change from Baseline: 2	0	0	0	2.9
Change from Baseline: 3	0	0	0	2.9

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.393

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.221

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.432

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 12 in Global Symptom Score 1

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End point title

Change from Baseline to Week 12 in Global Symptom Score 1

End point description

Global Symptom Score 1 was defined as the sum of all 5 individual symptom scores at a given visit, and was calculated only when all 5 symptom scores had a response available. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	39	31	41	31
Units: units on a scale
least squares mean (standard error)	-4.30 ± 0.425	-4.78 ± 0.478	-4.51 ± 0.412	-4.54 ± 0.467

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.65

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

1.487

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.361

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-1.568

upper limit

1.09

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.522

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-1.188

upper limit

1.257

Secondary: Change from Baseline to Week 12 in Global Symptom Score 2

Top of page

End point title

Change from Baseline to Week 12 in Global Symptom Score 2

End point description

Change from baseline to Week 12 in Global Symptom Score 2. Global Symptom Score 2 was defined as the sum of all 4 individual symptom scores (excluding dyspareunia) at a given visit, and was calculated only when all 4 symptom scores had a response available. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	68
Units: units on a scale
least squares mean (standard error)	-3.83 ± 0.231	-3.78 ± 0.234	-3.74 ± 0.233	-3.27 ± 0.237

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.043

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.56

Confidence interval

level

95%

sides

2-sided

lower limit

-1.204

upper limit

0.079

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.061

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.51

Confidence interval

level

95%

sides

2-sided

lower limit

-1.158

upper limit

0.137

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.071

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-1.111

upper limit

0.16

Secondary: Change from Baseline to Week 12 in Severity of Pallor

Top of page

End point title

Change from Baseline to Week 12 in Severity of Pallor

End point description

Percentage of subjects with change from baseline to Week 12 in severity of Pallor was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	69
Units: percentage of subjects
number (not applicable)
Change from Baseline: -3	4.3	7.4	1.4	1.4
Change from Baseline: -2	24.3	23.5	35.7	21.7
Change from Baseline: -1	44.3	45.6	35.7	26.1
Change from Baseline: 0	22.9	23.5	24.3	44.9
Change from Baseline: 1	4.3	0	2.9	5.8
Change from Baseline: 2	0	0	0	0
Change from Baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.012

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Secondary: Change from Baseline to Week 12 in Severity of Friability

Top of page

End point title

Change from Baseline to Week 12 in Severity of Friability

End point description

Percentage of subjects with change from baseline to Week 12 in severity of Friability was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	69
Units: percentage of subjects
number (not applicable)
Change from Baseline: -3	2.9	2.9	2.9	4.3
Change from Baseline: -2	27.1	30.9	25.7	27.5
Change from Baseline: -1	37.1	32.4	44.3	29.0
Change from Baseline: 0	30.0	32.4	22.9	34.8
Change from Baseline: 1	1.4	0	4.3	4.3
Change from Baseline: 2	1.4	1.5	0	0
Change from Baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.438

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.388

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.259

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 12 in Severity of Thinning or Flattening of Folds

Top of page

End point title

Change from Baseline to Week 12 in Severity of Thinning or Flattening of Folds

End point description

Percentage of subjects with change from baseline to Week 12 in severity of thinning or flattening of folds was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	69
Units: percentage of subjects
number (not applicable)
Change from Baseline: -3	5.7	1.5	1.4	1.4
Change from Baseline: -2	25.7	26.5	32.9	8.7
Change from Baseline: -1	41.4	48.5	34.3	44.9
Change from Baseline: 0	24.3	20.6	27.1	37.7
Change from Baseline: 1	2.9	2.9	4.3	7.2
Change from Baseline: 2	0	0	0	0
Change from Baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Secondary: Change from Baseline to Week 12 in Severity of Presence of Petechiae

Top of page

End point title

Change from Baseline to Week 12 in Severity of Presence of Petechiae

End point description

Percentage of subjects with change from baseline to Week 12 in severity of presence of Petechiae was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	69
Units: percentage of subjects
number (not applicable)
Change from Baseline: -3	2.9	1.5	0	2.9
Change from Baseline: -2	14.3	7.4	10.0	2.9
Change from Baseline: -1	37.1	33.8	32.9	18.8
Change from Baseline: 0	41.4	51.5	50.0	71.0
Change from Baseline: 1	4.3	5.9	7.1	4.3
Change from Baseline: 2	0	0	0	0
Change from Baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.331

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.043

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 12 in Severity of Dry Mucosa

Top of page

End point title

Change from Baseline to Week 12 in Severity of Dry Mucosa

End point description

Percentage of subjects with change from baseline to Week 12 in severity of dry mucosa was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	70	68	70	69
Units: percentage of subjects
number (not applicable)
Change from Baseline: -3	11.4	19.1	20.0	13.0
Change from Baseline: -2	55.7	42.6	37.1	27.5
Change from Baseline: -1	24.3	29.4	32.9	27.5
Change from Baseline: 0	7.1	8.8	8.6	27.5
Change from Baseline: 1	1.4	0	1.4	4.3
Change from Baseline: 2	0	0	0	0
Change from Baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.032

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Secondary: Change from Baseline to Week 3 in Severity of Vaginal Dryness

Top of page

End point title

Change from Baseline to Week 3 in Severity of Vaginal Dryness

End point description

Percentage of subjects with change from baseline to Week 3 in severity of vaginal dryness was reported. Severity was defined as: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to Baseline represented a positive outcome.The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	66	68	68
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	8.8	12.1	11.8	4.4
Change from baseline: -2	33.8	19.7	32.4	38.2
Change from baseline: -1	41.2	50.0	38.2	38.2
Change from baseline: 0	11.8	18.2	16.2	16.2
Change from baseline: 1	4.4	0	1.5	2.9

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.176

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.358

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.21

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 3 in Severity of Dyspareunia

Top of page

End point title

Change from Baseline to Week 3 in Severity of Dyspareunia

End point description

Percentage of subjects with change from baseline to Week 3 in severity of Dyspareunia was reported. Dyspareunia was only applicable in subjects who had experienced sexual activity with penetration since the previous study visit. Symptom Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	33	29	37	27
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	3.0	10.3	10.8	7.4
Change from baseline: -2	21.2	13.8	27.0	25.9
Change from baseline: -1	33.3	37.9	37.8	37.0
Change from baseline: 0	39.4	20.7	21.6	25.9
Change from baseline: 1	0	13.8	0	3.7
Change from baseline: 2	3.0	3.4	2.7	0
Change from baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.106

Method

Wilcoxon Rank Sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.229

Method

Wilcoxon Rank Sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.345

Method

Wilcoxon Rank Sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Secondary: Change from Baseline to Week 3 in Severity of Pruritus or Itching

Top of page

End point title

Change from Baseline to Week 3 in Severity of Pruritus or Itching

End point description

Percentage of subjects with change from baseline to Week 3 in severity of Pruritus or Itching was reported. Symptom Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome.The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	67	68	68
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	1.5	6.0	2.9	1.5
Change from baseline: -2	14.7	14.9	10.3	14.7
Change from baseline: -1	22.1	28.4	44.1	35.3
Change from baseline: 0	51.5	40.3	39.7	44.1
Change from baseline: 1	7.4	3.0	2.9	0
Change from baseline: 2	2.9	6.0	0	4.4
Change from baseline: 3	0	1.5	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.424

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.414

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 3 in Severity of Burning

Top of page

End point title

Change from Baseline to Week 3 in Severity of Burning

End point description

Percentage of subjects with change from baseline to Week 3 in severity of Burning was reported. Symptom Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	67	68	68
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	4.4	3.0	5.9	0
Change from baseline: -2	16.2	25.4	20.6	23.5
Change from baseline: -1	39.7	26.9	29.4	30.9
Change from baseline: 0	39.7	41.8	42.6	41.2
Change from baseline: 1	0	1.5	1.5	2.9
Change from baseline: 2	0	1.5	0	1.5
Change from baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.36

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.12

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.266

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 3 in Severity of Dysuria

Top of page

End point title

Change from Baseline to Week 3 in Severity of Dysuria

End point description

Percentage of subjects with change from baseline to Week 3 in severity of Dysuria was reported. Symptom Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome.The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	67	68	68
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	0	0	1.5	0
Change from baseline: -2	7.4	11.9	4.4	8.8
Change from baseline: -1	20.6	23.9	20.6	13.2
Change from baseline: 0	67.6	58.2	70.6	70.6
Change from baseline: 1	4.4	4.5	2.9	4.4
Change from baseline: 2	0	0	0	0
Change from baseline: 3	0	1.5	0	2.9

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.47

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.137

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.133

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 3 in Global Symptom Score 1

Top of page

End point title

Change from Baseline to Week 3 in Global Symptom Score 1

End point description

Change from baseline to Week 3 in Global Symptom Score 1 was reported. Global Symptom Score 1 was defined as the sum of all 5 individual symptom scores at a given visit, and was calculated only when all 5 symptom scores had a response available. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	33	29	37	27
Units: units on a scale
least squares mean (standard error)	-2.99 ± 0.483	-2.86 ± 0.520	-4.37 ± 0.454	-3.73 ± 0.527

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.85

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.74

Confidence interval

level

95%

sides

2-sided

lower limit

-0.669

upper limit

2.153

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.877

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

-0.611

upper limit

2.361

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.178

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.64

Confidence interval

level

95%

sides

2-sided

lower limit

-2.009

upper limit

0.728

Secondary: Change from Baseline to Week 3 in Global Symptom Score 2

Top of page

End point title

Change from Baseline to Week 3 in Global Symptom Score 2

End point description

Change from baseline to Week 3 in Global Symptom Score 2 was reported. Global Symptom Score 2 was defined as the sum of all 4 individual symptom scores (excluding dyspareunia) at a given visit, and was calculated only when all 4 symptom scores had a response available. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	66	68	68
Units: units on a scale
least squares mean (standard error)	-2.76 ± 0.251	-2.82 ± 0.254	-3.20 ± 0.253	-2.60 ± 0.255

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.323

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.854

upper limit

0.531

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.272

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.917

upper limit

0.484

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.043

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.29

upper limit

0.084

Secondary: Change from Baseline to Week 3 in Severity of Pallor

Top of page

End point title

Change from Baseline to Week 3 in Severity of Pallor

End point description

Percentage of subjects with change from baseline to Week 3 in severity of Pallor was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	67	68	68
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	4.4	3.0	1.5	0
Change from baseline: -2	20.6	20.9	20.6	8.8
Change from baseline: -1	27.9	29.9	35.3	27.9
Change from baseline: 0	45.6	44.8	42.6	55.9
Change from baseline: 1	1.5	1.5	0	7.4
Change from baseline: 2	0	0	0	0
Change from baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Secondary: Change from Baseline to Week 3 in Severity of Friability

Top of page

End point title

Change from Baseline to Week 3 in Severity of Friability

End point description

Percentage of subjects with change from baseline to Week 3 in severity of Friability was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome.The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	67	68	68
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	2.9	3.0	1.5	0
Change from baseline: -2	20.6	16.4	19.1	13.2
Change from baseline: -1	42.6	37.3	36.8	35.3
Change from baseline: 0	32.4	37.3	39.7	47.1
Change from baseline: 1	1.5	4.5	2.9	4.4
Change from baseline: 2	0	1.5	0	0
Change from baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.04

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.259

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.104

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 3 in Severity of Thinning or Flattening of Folds

Top of page

End point title

Change from Baseline to Week 3 in Severity of Thinning or Flattening of Folds

End point description

Percentage of subjects with change from baseline to Week 3 in severity of Thinning or Flattening of Folds was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	67	68	68
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	1.5	1.5	0	0
Change from baseline: -2	17.6	13.4	14.7	7.4
Change from baseline: -1	47.1	52.2	45.6	23.5
Change from baseline: 0	29.4	31.3	38.2	63.2
Change from baseline: 1	4.4	1.5	1.5	5.9
Change from baseline: 2	0	0	0	0
Change from baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Secondary: Change from Baseline to Week 3 in Severity of Presence of Petechiae

Top of page

End point title

Change from Baseline to Week 3 in Severity of Presence of Petechiae

End point description

Percentage of subjects with change from baseline to Week 3 in severity of presence of Petechiae was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	67	68	68
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	2.9	0	0	0
Change from baseline: -2	11.8	9.0	8.8	4.4
Change from baseline: -1	33.8	26.9	32.4	10.3
Change from baseline: 0	45.6	61.2	55.9	79.4
Change from baseline: 1	4.4	3.0	1.5	4.4
Change from baseline: 2	1.5	0	1.5	1.5
Change from baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.054

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Change from Baseline to Week 3 in Severity of Dry Mucosa

Top of page

End point title

Change from Baseline to Week 3 in Severity of Dry Mucosa

End point description

Percentage of subjects with change from baseline to Week 3 in severity of dry mucosa was reported. Sign Scores at each visit: 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. A decrease in score compared to Baseline represented a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	67	68	68
Units: percentage of subjects
number (not applicable)
Change from baseline: -3	5.9	11.9	8.8	4.4
Change from baseline: -2	42.6	29.9	38.2	25.0
Change from baseline: -1	32.4	44.8	30.9	29.4
Change from baseline: 0	17.6	13.4	22.1	38.2
Change from baseline: 1	1.5	0	0	2.9
Change from baseline: 2	0	0	0	0
Change from baseline: 3	0	0	0	0

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Secondary: Change from Baseline to Week 3 in Vaginal pH

Top of page

End point title

Change from Baseline to Week 3 in Vaginal pH

End point description

Change from baseline to Week 3 in Vaginal pH was reported. A decrease in pH compared to Baseline represents a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	68	67	68	68
Units: pH
least squares mean (standard error)	-1.03 ± 0.095	-0.97 ± 0.096	-0.88 ± 0.095	-0.22 ± 0.096

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.81

Confidence interval

level

95%

sides

2-sided

lower limit

-1.071

upper limit

-0.548

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.75

Confidence interval

level

95%

sides

2-sided

lower limit

-1.013

upper limit

-0.484

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.66

Confidence interval

level

95%

sides

2-sided

lower limit

-0.916

upper limit

-0.397

Secondary: Change from Baseline to Week 3 in Proportion of Superficial Cells of the Vaginal Epithelium

Top of page

End point title

Change from Baseline to Week 3 in Proportion of Superficial Cells of the Vaginal Epithelium

End point description

Change from baseline to Week 3 in proportion of superficial cells of the vaginal epithelium was reported. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	65	61	68	61
Units: ratio
least squares mean (standard error)	0.48 ± 0.035	0.43 ± 0.036	0.38 ± 0.035	0.04 ± 0.037

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

126

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.44

Confidence interval

level

95%

sides

2-sided

lower limit

0.337

upper limit

0.535

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.39

Confidence interval

level

95%

sides

2-sided

lower limit

0.291

upper limit

0.494

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.245

upper limit

0.439

Secondary: Change from Baseline to Week 3 in Proportion of Parabasal Cells of the Vaginal Epithelium

Top of page

End point title

Change from Baseline to Week 3 in Proportion of Parabasal Cells of the Vaginal Epithelium

End point description

Change from baseline to Week 3 in proportion of parabasal cells of the vaginal epithelium was reported. A decrease in proportion of parabasal cells compared to Baseline represents a positive outcome. The ITT population defined as all randomized subjects. Here, N (number of subjects analyzed) defined as number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 3

End point values	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Number of subjects analysed	65	61	68	61
Units: ratio
least squares mean (standard error)	-0.55 ± 0.037	-0.57 ± 0.037	-0.48 ± 0.036	-0.08 ± 0.038

Statistical analysis 1

Comparison groups

Estriol 0.005% v Placebo

Number of subjects included in analysis

126

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.575

upper limit

-0.371

Statistical analysis 2

Comparison groups

Estriol 0.002% v Placebo

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-0.592

upper limit

-0.383

Statistical analysis 3

Comparison groups

Estriol 0.0008% v Placebo

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

-0.3

Adverse events

Top of page

Timeframe for reporting adverse events

Approximately 20 Weeks

Adverse event reporting additional description

The Safety population included all randomized subjects who received at least 1 dose of study treatment. Data for treatment-emergent adverse events is presented here.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Estriol 0.005%

Reporting group description

Subjects received 1 gram of Estriol 0.005% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group title

Estriol 0.002%

Reporting group description

Subjects received 1 gram of Estriol 0.002% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group title

Estriol 0.0008%

Reporting group description

Subjects received 1 gram of Estriol 0.0008% vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Reporting group title

Placebo

Reporting group description

Subjects received matching placebo vaginal gel administered daily for Weeks 1-3. After 21 days of daily administration, treatment continued with twice-weekly administration up to Week 12.

Serious adverse events	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	3 / 71 (4.23%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-Hodgkin's lymphoma
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Estriol 0.005%	Estriol 0.002%	Estriol 0.0008%	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 70 (20.00%)	11 / 69 (15.94%)	15 / 72 (20.83%)	20 / 71 (28.17%)
Vascular disorders
Flushing
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)	0 / 71 (0.00%)
occurrences all number	0	0	1	0
Hypertension
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Reproductive system and breast disorders
Breast inflammation
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1
Ovarian cyst
subjects affected / exposed	2 / 70 (2.86%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	2	0	0	0
Vulvovaginal burning sensation
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1
Vulvovaginal pruritus
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)	0 / 71 (0.00%)
occurrences all number	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 70 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 70 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 70 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Blood glucose increased
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	4 / 70 (5.71%)	3 / 69 (4.35%)	4 / 72 (5.56%)	3 / 71 (4.23%)
occurrences all number	5	4	4	4
Animal bite
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Fall
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Limb injury
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Neck injury
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Radius fracture
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Road traffic accident
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	1	0	0	1
Flatulence
subjects affected / exposed	0 / 70 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Hyperchlorhydria
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	2 / 71 (2.82%)
occurrences all number	0	0	0	2
Loose tooth
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 70 (1.43%)	0 / 69 (0.00%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	0 / 70 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Pruritus
subjects affected / exposed	0 / 70 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Renal and urinary disorders
Leukocyturia
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)	0 / 71 (0.00%)
occurrences all number	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthritis reactive
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1
Back pain
subjects affected / exposed	0 / 70 (0.00%)	1 / 69 (1.45%)	0 / 72 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Infections and infestations
Bacterial vaginosis
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)	0 / 71 (0.00%)
occurrences all number	0	0	1	0
Bronchitis
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)	0 / 71 (0.00%)
occurrences all number	0	0	1	0
Cystitis
subjects affected / exposed	0 / 70 (0.00%)	1 / 69 (1.45%)	2 / 72 (2.78%)	3 / 71 (4.23%)
occurrences all number	0	1	3	3
Gastroenteritis viral
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1
Influenza
subjects affected / exposed	0 / 70 (0.00%)	1 / 69 (1.45%)	1 / 72 (1.39%)	1 / 71 (1.41%)
occurrences all number	0	1	2	1
Nasopharyngitis
subjects affected / exposed	1 / 70 (1.43%)	2 / 69 (2.90%)	3 / 72 (4.17%)	3 / 71 (4.23%)
occurrences all number	1	2	3	3
Pharyngitis
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)	0 / 71 (0.00%)
occurrences all number	0	0	1	0
Sinusitis
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)	0 / 71 (0.00%)
occurrences all number	0	0	1	0
Tooth abscess
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	1 / 72 (1.39%)	3 / 71 (4.23%)
occurrences all number	0	0	1	3
Viral infection
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	2 / 71 (2.82%)
occurrences all number	0	0	0	2
Vulval abscess
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1
Metabolism and nutrition disorders
Hyperuricaemia
subjects affected / exposed	0 / 70 (0.00%)	0 / 69 (0.00%)	0 / 72 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1

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Were there any global substantial amendments to the protocol? Yes

07 Jun 2017

The major changes to amendment was: to clarify that a negative mammogram at Screening or a documented negative mammogram within 9 months of randomization was required; to clarify that for the subjects being re-screened within 1 month of a previous screen failure, the invasive procedures of biopsy and Factor V Leiden were not to be repeated, and the data from the Screening Visit were to be used again for the re-screened subject; to modify the endometrial biopsy section to clarify to Investigators how bleeding samples were to be analyzed, by adding the text: “If hyperplasia is diagnosed by the single safety reader for the subject who has bled while on study drug, this diagnosis be maintained for the efficacy evaluation and the slides become part of the slide set given to the 2 other pathologists for reading”.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline to Week 12 in the Severity of Vaginal Dryness

Primary: Change from Baseline to Week 12 in the Severity of Vaginal Dryness

Primary: Change from Baseline to Week 12 in Vaginal pH

Primary: Change from Baseline to Week 12 in Vaginal pH

Primary: Change from Baseline to Week 12 in the Proportion of Superficial Cells of the Vaginal Epithelium

Primary: Change from Baseline to Week 12 in the Proportion of Superficial Cells of the Vaginal Epithelium

Primary: Change from Baseline to Week 12 in the Proportion of Parabasal Cells of the Vaginal Epithelium

Primary: Change from Baseline to Week 12 in the Proportion of Parabasal Cells of the Vaginal Epithelium

Secondary: Change from Baseline to Week 12 in Severity of Dyspareunia

Secondary: Change from Baseline to Week 12 in Severity of Dyspareunia

Secondary: Change from Baseline to Week 12 in Severity of Pruritus or Itching

Secondary: Change from Baseline to Week 12 in Severity of Pruritus or Itching

Secondary: Change from Baseline to Week 12 in Severity of Burning

Secondary: Change from Baseline to Week 12 in Severity of Burning

Secondary: Change from Baseline to Week 12 in Severity of Dysuria

Secondary: Change from Baseline to Week 12 in Severity of Dysuria

Secondary: Change from Baseline to Week 12 in Global Symptom Score 1

Secondary: Change from Baseline to Week 12 in Global Symptom Score 1

Secondary: Change from Baseline to Week 12 in Global Symptom Score 2

Secondary: Change from Baseline to Week 12 in Global Symptom Score 2

Secondary: Change from Baseline to Week 12 in Severity of Pallor

Secondary: Change from Baseline to Week 12 in Severity of Pallor

Secondary: Change from Baseline to Week 12 in Severity of Friability

Secondary: Change from Baseline to Week 12 in Severity of Friability

Secondary: Change from Baseline to Week 12 in Severity of Thinning or Flattening of Folds

Secondary: Change from Baseline to Week 12 in Severity of Thinning or Flattening of Folds

Secondary: Change from Baseline to Week 12 in Severity of Presence of Petechiae

Secondary: Change from Baseline to Week 12 in Severity of Presence of Petechiae

Secondary: Change from Baseline to Week 12 in Severity of Dry Mucosa

Secondary: Change from Baseline to Week 12 in Severity of Dry Mucosa

Secondary: Change from Baseline to Week 3 in Severity of Vaginal Dryness

Secondary: Change from Baseline to Week 3 in Severity of Vaginal Dryness

Secondary: Change from Baseline to Week 3 in Severity of Dyspareunia

Secondary: Change from Baseline to Week 3 in Severity of Dyspareunia

Secondary: Change from Baseline to Week 3 in Severity of Pruritus or Itching

Secondary: Change from Baseline to Week 3 in Severity of Pruritus or Itching

Secondary: Change from Baseline to Week 3 in Severity of Burning

Secondary: Change from Baseline to Week 3 in Severity of Burning

Secondary: Change from Baseline to Week 3 in Severity of Dysuria

Secondary: Change from Baseline to Week 3 in Severity of Dysuria

Secondary: Change from Baseline to Week 3 in Global Symptom Score 1

Secondary: Change from Baseline to Week 3 in Global Symptom Score 1

Secondary: Change from Baseline to Week 3 in Global Symptom Score 2

Secondary: Change from Baseline to Week 3 in Global Symptom Score 2

Secondary: Change from Baseline to Week 3 in Severity of Pallor

Secondary: Change from Baseline to Week 3 in Severity of Pallor

Secondary: Change from Baseline to Week 3 in Severity of Friability

Secondary: Change from Baseline to Week 3 in Severity of Friability

Secondary: Change from Baseline to Week 3 in Severity of Thinning or Flattening of Folds

Secondary: Change from Baseline to Week 3 in Severity of Thinning or Flattening of Folds

Secondary: Change from Baseline to Week 3 in Severity of Presence of Petechiae

Secondary: Change from Baseline to Week 3 in Severity of Presence of Petechiae

Secondary: Change from Baseline to Week 3 in Severity of Dry Mucosa

Secondary: Change from Baseline to Week 3 in Severity of Dry Mucosa

Secondary: Change from Baseline to Week 3 in Vaginal pH

Secondary: Change from Baseline to Week 3 in Vaginal pH

Secondary: Change from Baseline to Week 3 in Proportion of Superficial Cells of the Vaginal Epithelium

Secondary: Change from Baseline to Week 3 in Proportion of Superficial Cells of the Vaginal Epithelium

Secondary: Change from Baseline to Week 3 in Proportion of Parabasal Cells of the Vaginal Epithelium

Secondary: Change from Baseline to Week 3 in Proportion of Parabasal Cells of the Vaginal Epithelium

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information