Trial Outcomes & Findings for Estradiol Vaginal Softgel Capsules in Treating Symptoms of Vulvar and Vaginal Atrophy in Postmenopausal Women (NCT NCT02253173)

Results Overview

• Change from Baseline to Week 12 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

764 participants

Primary outcome timeframe

Baseline and 12 Weeks

Results posted on

2017-05-25

Participant Flow

Participant milestones

Participant milestones
Measure	Estradiol 4mcg Vaginal Softgel Capsule Estradiol 4mcg Vaginal Softgel Capsule Estradiol	Estradiol 10mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol	Estradiol 25mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Estradiol	Placebo Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule Placebo
Overall Study STARTED	191	191	190	192
Overall Study COMPLETED	175	174	177	178
Overall Study NOT COMPLETED	16	17	13	14

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Estradiol Vaginal Softgel Capsules in Treating Symptoms of Vulvar and Vaginal Atrophy in Postmenopausal Women

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=191 Participants Estradiol 4mcg Vaginal Softgel Capsule Estradiol	Estradiol 10mcg Vaginal Softgel Capsule n=191 Participants Estradiol 10mcg Vaginal Softgel Capsule Estradiol	Estradiol 25mcg Vaginal Softgel Capsule n=190 Participants Estradiol 25mcg Vaginal Softgel Capsule Estradiol	Placebo Vaginal Softgel Capsule n=192 Participants Placebo Vaginal Softgel Capsule Placebo	Total n=764 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	148 Participants n=5 Participants	162 Participants n=7 Participants	156 Participants n=5 Participants	151 Participants n=4 Participants	617 Participants n=21 Participants
Age, Categorical >=65 years	43 Participants n=5 Participants	29 Participants n=7 Participants	34 Participants n=5 Participants	41 Participants n=4 Participants	147 Participants n=21 Participants
Age, Continuous	59.8 years STANDARD_DEVIATION 5.90 • n=5 Participants	58.5 years STANDARD_DEVIATION 6.29 • n=7 Participants	58.9 years STANDARD_DEVIATION 6.26 • n=5 Participants	59.3 years STANDARD_DEVIATION 6.07 • n=4 Participants	59.1 years STANDARD_DEVIATION 6.14 • n=21 Participants
Sex: Female, Male Female	191 Participants n=5 Participants	191 Participants n=7 Participants	190 Participants n=5 Participants	192 Participants n=4 Participants	764 Participants n=21 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Region of Enrollment Canada	13 participants n=5 Participants	10 participants n=7 Participants	15 participants n=5 Participants	12 participants n=4 Participants	50 participants n=21 Participants
Region of Enrollment United States	178 participants n=5 Participants	181 participants n=7 Participants	175 participants n=5 Participants	180 participants n=4 Participants	714 participants n=21 Participants
Height	162.7 centimeters STANDARD_DEVIATION 6.86 • n=5 Participants	162.9 centimeters STANDARD_DEVIATION 6.93 • n=7 Participants	162.3 centimeters STANDARD_DEVIATION 6.37 • n=5 Participants	162.2 centimeters STANDARD_DEVIATION 6.30 • n=4 Participants	162.5 centimeters STANDARD_DEVIATION 6.62 • n=21 Participants
Weight	70.4 kilograms STANDARD_DEVIATION 14.26 • n=5 Participants	71.1 kilograms STANDARD_DEVIATION 13.49 • n=7 Participants	70.6 kilograms STANDARD_DEVIATION 13.7 • n=5 Participants	70.4 kilograms STANDARD_DEVIATION 13.6 • n=4 Participants	70.6 kilograms STANDARD_DEVIATION 13.74 • n=21 Participants
BMI	26.5 kg/m^2 STANDARD_DEVIATION 4.87 • n=5 Participants	26.8 kg/m^2 STANDARD_DEVIATION 4.68 • n=7 Participants	26.7 kg/m^2 STANDARD_DEVIATION 4.79 • n=5 Participants	26.7 kg/m^2 STANDARD_DEVIATION 4.59 • n=4 Participants	26.7 kg/m^2 STANDARD_DEVIATION 4.73 • n=21 Participants

PRIMARY outcome

Timeframe: Baseline and 12 Weeks

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

• Change from Baseline to Week 12 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=171 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=174 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Co-Primary Efficacy Endpoint - Vaginal Superficial Cells	17.50 percentage of vaginal superficial cells Standard Error 1.542	16.72 percentage of vaginal superficial cells Standard Error 1.540	23.20 percentage of vaginal superficial cells Standard Error 1.529	5.63 percentage of vaginal superficial cells Standard Error 1.537

PRIMARY outcome

Timeframe: Baseline and 12 Weeks

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

• Change from Baseline to Week 12 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=171 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=174 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Co-Primary Efficacy Endpoint - Vaginal Parabasal Cells	-40.63 percentage of vaginal parabasal cells Standard Error 1.755	-44.07 percentage of vaginal parabasal cells Standard Error 1.751	-45.55 percentage of vaginal parabasal cells Standard Error 1.745	-6.73 percentage of vaginal parabasal cells Standard Error 1.750

PRIMARY outcome

Timeframe: Baseline and 12 Weeks

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

• Change from Baseline to Week 12 in vaginal pH as compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=171 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=174 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=174 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Co-Primary Efficacy Endpoint - Vaginal pH	-1.32 pH units Standard Error 0.066	-1.42 pH units Standard Error 0.066	-1.34 pH units Standard Error 0.066	-0.28 pH units Standard Error 0.066

PRIMARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

• Change from Baseline to Week 12 on the severity of the MBS of dyspareunia (vaginal pain associated with sexual activity) associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 12

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=151 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=154 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=159 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=163 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Co-Primary Efficacy Endpoint - Severity of Most Bothersome Symptom (Dyspareunia)	-1.52 units on a scale Standard Error 0.071	-1.69 units on a scale Standard Error 0.071	-1.69 units on a scale Standard Error 0.071	-1.28 units on a scale Standard Error 0.070

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

• Change from Baseline to Week 2 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=186 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=188 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=184 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=185 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Superficial Cells	31.35 percentage of vaginal superficial cells Standard Error 1.496	31.93 percentage of vaginal superficial cells Standard Error 1.488	38.85 percentage of vaginal superficial cells Standard Error 1.500	6.05 percentage of vaginal superficial cells Standard Error 1.498

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 6 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints- Vaginal Superficial Cells	18.41 percentage of vaginal superficial cells Standard Error 1.536	16.88 percentage of vaginal superficial cells Standard Error 1.543	22.65 percentage of vaginal superficial cells Standard Error 1.532	5.43 percentage of vaginal superficial cells Standard Error 1.525

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=164 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=166 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=167 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Superficial Cells	19.04 percentage of vaginal superficial cells Standard Error 1.561	17.41 percentage of vaginal superficial cells Standard Error 1.558	23.88 percentage of vaginal superficial cells Standard Error 1.554	5.98 percentage of vaginal superficial cells Standard Error 1.551

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 2 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=186 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=188 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=184 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=185 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Parabasal Cells	-40.23 percentage of vaginal parabasal cells Standard Error 1.720	-44.42 percentage of vaginal parabasal cells Standard Error 1.710	-45.60 percentage of vaginal parabasal cells Standard Error 1.723	-7.00 percentage of vaginal parabasal cells Standard Error 1.720

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 6 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Parabasal Cells	-39.36 percentage of vaginal parabasal cells Standard Error 1.750	-43.55 percentage of vaginal parabasal cells Standard Error 1.752	-45.61 percentage of vaginal parabasal cells Standard Error 1.746	-9.23 percentage of vaginal parabasal cells Standard Error 1.741

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=164 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=166 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=167 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Parabasal Cells	-41.87 percentage of vaginal parabasal cells Standard Error 1.768	-43.78 percentage of vaginal parabasal cells Standard Error 1.764	-45.08 percentage of vaginal parabasal cells Standard Error 1.762	-7.86 percentage of vaginal parabasal cells Standard Error 1.760

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 2 in vaginal pH as compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=186 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=188 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=184 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=186 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal pH	-1.23 pH units Standard Error 0.064	-1.37 pH units Standard Error 0.064	-1.30 pH units Standard Error 0.065	-0.28 pH units Standard Error 0.064

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 6 in vaginal pH as compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal pH	-1.32 pH units Standard Error 0.066	-1.40 pH units Standard Error 0.066	-1.48 pH units Standard Error 0.066	-0.30 pH units Standard Error 0.065

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 in vaginal pH as compared to placebo

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=164 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=166 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=167 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal pH	-1.35 pH units Standard Error 0.067	-1.46 pH units Standard Error 0.067	-1.45 pH units Standard Error 0.066	-0.38 pH units Standard Error 0.066

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 2 on the severity of the MBS of dyspareunia (vaginal pain associated with sexual activity) associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 2

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=145 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=147 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=140 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=141 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)	-0.99 units on a scale Standard Error 0.072	-1.08 units on a scale Standard Error 0.072	-1.02 units on a scale Standard Error 0.073	-0.76 units on a scale Standard Error 0.072

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 6 on the severity of the MBS of dyspareunia (vaginal pain associated with sexual activity) associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 6

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=148 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=150 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=150 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=159 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)	-1.30 units on a scale Standard Error 0.072	-1.37 units on a scale Standard Error 0.072	-1.48 units on a scale Standard Error 0.072	-1.03 units on a scale Standard Error 0.070

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 on the severity of the MBS of dyspareunia (vaginal pain associated with sexual activity) associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 8

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=140 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=136 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=129 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=143 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)	-1.52 units on a scale Standard Error 0.073	-1.64 units on a scale Standard Error 0.074	-1.62 units on a scale Standard Error 0.075	-1.15 units on a scale Standard Error 0.072

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 2 on the severity of vaginal dryness associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 2

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=186 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=188 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=184 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=185 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)	-0.86 units on a scale Standard Error 0.066	-1.01 units on a scale Standard Error 0.065	-0.96 units on a scale Standard Error 0.066	-0.72 units on a scale Standard Error 0.066

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 6 on the severity of vaginal dryness associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 6

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)	-1.14 units on a scale Standard Error 0.067	-1.27 units on a scale Standard Error 0.068	-1.23 units on a scale Standard Error 0.067	-0.90 units on a scale Standard Error 0.067

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 on the severity of vaginal dryness associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 8

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=163 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=167 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)	-1.25 units on a scale Standard Error 0.069	-1.44 units on a scale Standard Error 0.068	-1.34 units on a scale Standard Error 0.068	-1.01 units on a scale Standard Error 0.068

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 on the severity of vaginal dryness associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 12

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=171 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=174 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)	-1.27 units on a scale Standard Error 0.068	-1.47 units on a scale Standard Error 0.067	-1.47 units on a scale Standard Error 0.067	-0.97 units on a scale Standard Error 0.067

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 2 on the severity of vulvar and/or vaginal itching or irritation associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 2

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=186 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=188 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=184 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=185 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)	-0.47 units on a scale Standard Error 0.054	-0.56 units on a scale Standard Error 0.053	-0.51 units on a scale Standard Error 0.054	-0.47 units on a scale Standard Error 0.054

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 6 on the severity of vulvar and/or vaginal itching or irritation associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 6

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)	-0.57 units on a scale Standard Error 0.055	-0.64 units on a scale Standard Error 0.055	-0.61 units on a scale Standard Error 0.055	-0.55 units on a scale Standard Error 0.055

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 on the severity of vulvar and/or vaginal itching or irritation associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 8

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=163 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=167 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)	-0.74 units on a scale Standard Error 0.056	-0.76 units on a scale Standard Error 0.056	-0.73 units on a scale Standard Error 0.056	-0.59 units on a scale Standard Error 0.056

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 on the severity of vulvar and/or vaginal itching or irritation associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 12

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=171 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=174 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)	-0.75 units on a scale Standard Error 0.055	-0.81 units on a scale Standard Error 0.055	-0.77 units on a scale Standard Error 0.055	-0.60 units on a scale Standard Error 0.055

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 2 in Vaginal Color as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Color: No atrophy (pink) = 0; Mild (lighter in color) = 1; Moderate(pale in color) = 2; Severe (transparent/no color or inflamed) = 3 Severity was assessed by the Investigator at Baseline and Week 2

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=185 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=187 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=184 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=187 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)	-0.69 units on a scale Standard Error 0.048	-0.77 units on a scale Standard Error 0.047	-0.78 units on a scale Standard Error 0.048	-0.40 units on a scale Standard Error 0.047

SECONDARY outcome

Timeframe: Baseline to Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 6 in Vaginal Color as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Color: No atrophy (pink) = 0; Mild (lighter in color) = 1; Moderate(pale in color) = 2; Severe (transparent/no color or inflamed) = 3 Severity was assessed by the Investigator at Baseline and Week 6

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)	-0.82 units on a scale Standard Error 0.049	-0.93 units on a scale Standard Error 0.049	-0.89 units on a scale Standard Error 0.049	-0.50 units on a scale Standard Error 0.048

SECONDARY outcome

Timeframe: Baseline to Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 in Vaginal Color as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Color: No atrophy (pink) = 0; Mild (lighter in color) = 1; Moderate(pale in color) = 2; Severe (transparent/no color or inflamed) = 3 Severity was assessed by the Investigator at Baseline and Week 8

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=164 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=166 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=167 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)	-0.98 units on a scale Standard Error 0.050	-1.04 units on a scale Standard Error 0.050	-0.99 units on a scale Standard Error 0.049	-0.50 units on a scale Standard Error 0.049

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 in Vaginal Color as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Color: No atrophy (pink) = 0; Mild (lighter in color) = 1; Moderate(pale in color) = 2; Severe (transparent/no color or inflamed) = 3 Severity was assessed by the Investigator at Baseline and Week 12

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=171 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=175 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=175 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)	-0.97 units on a scale Standard Error 0.049	-1.06 units on a scale Standard Error 0.049	-0.96 units on a scale Standard Error 0.049	-0.60 units on a scale Standard Error 0.049

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 2 in Vaginal Epithelial Integrity as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Integrity: No atrophy (normal) = 0; Mild (vaginal surface bleeds with scraping) = 1; Moderate (vaginal surface bleeds with light contact) = 2; Severe (vaginal surface has petechiae before contact and bleeds with light contact) = 3 Severity was assessed by the Investigator at Baseline and Week 2

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=185 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=187 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=184 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=186 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)	-0.85 units on a scale Standard Error 0.049	-0.87 units on a scale Standard Error 0.049	-0.93 units on a scale Standard Error 0.049	-0.53 units on a scale Standard Error 0.049

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 6 in Vaginal Epithelial Integrity as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Integrity: No atrophy (normal) = 0; Mild (vaginal surface bleeds with scraping) = 1; Moderate (vaginal surface bleeds with light contact) = 2; Severe (vaginal surface has petechiae before contact and bleeds with light contact) = 3 Severity was assessed by the Investigator at Baseline and Week 6

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)	-0.97 units on a scale Standard Error 0.051	-1.02 units on a scale Standard Error 0.051	-1.01 units on a scale Standard Error 0.051	-0.61 units on a scale Standard Error 0.050

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 in Vaginal Epithelial Integrity as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Integrity: No atrophy (normal) = 0; Mild (vaginal surface bleeds with scraping) = 1; Moderate (vaginal surface bleeds with light contact) = 2; Severe (vaginal surface has petechiae before contact and bleeds with light contact) = 3 Severity was assessed by the Investigator at Baseline and Week 8

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=164 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=166 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=167 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)	-1.03 units on a scale Standard Error 0.052	-1.08 units on a scale Standard Error 0.051	-1.08 units on a scale Standard Error 0.051	-0.66 units on a scale Standard Error 0.051

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline

Change from Baseline to Week 12 in Vaginal Epithelial Integrity as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Integrity: No atrophy (normal) = 0; Mild (vaginal surface bleeds with scraping) = 1; Moderate (vaginal surface bleeds with light contact) = 2; Severe (vaginal surface has petechiae before contact and bleeds with light contact) = 3 Severity was assessed by the Investigator at Baseline and Week 12

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=171 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=175 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=175 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)	-0.97 units on a scale Standard Error 0.051	-1.07 units on a scale Standard Error 0.051	-1.01 units on a scale Standard Error 0.050	-0.60 units on a scale Standard Error 0.050

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 2 in Vaginal Epithelial Surface Thickness as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Surface Thickness: No atrophy (rogation and elasticity of vault) = 0; Mild (poor rogation with some elasticity noted of vaginal vault) = 1; Moderate (smooth, some elasticity of vaginal vault) = 2; Severe \[smooth, no elasticity, constriction of the upper one third of vagina or loss of vaginal tone (cystocele and rectocele)\] = 3 Severity was assessed by the Investigator at Baseline and Week 2

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=185 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=187 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=184 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=186 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)	-0.76 units on a scale Standard Error 0.049	-0.76 units on a scale Standard Error 0.049	-0.76 units on a scale Standard Error 0.049	-0.40 units on a scale Standard Error 0.049

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline

Change from Baseline to Week 6 in Vaginal Epithelial Surface Thickness as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Surface Thickness: No atrophy (rogation and elasticity of vault) = 0; Mild (poor rogation with some elasticity noted of vaginal vault) = 1; Moderate (smooth, some elasticity of vaginal vault) = 2; Severe \[smooth, no elasticity, constriction of the upper one third of vagina or loss of vaginal tone (cystocele and rectocele)\] = 3 Severity was assessed by the Investigator at Baseline and Week 6

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)	-0.85 units on a scale Standard Error 0.051	-0.93 units on a scale Standard Error 0.051	-0.90 units on a scale Standard Error 0.050	-0.53 units on a scale Standard Error 0.050

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 in Vaginal Epithelial Surface Thickness as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Surface Thickness: No atrophy (rogation and elasticity of vault) = 0; Mild (poor rogation with some elasticity noted of vaginal vault) = 1; Moderate (smooth, some elasticity of vaginal vault) = 2; Severe \[smooth, no elasticity, constriction of the upper one third of vagina or loss of vaginal tone (cystocele and rectocele)\] = 3 Severity was assessed by the Investigator at Baseline and Week 8

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=164 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=166 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=167 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)	-0.96 units on a scale Standard Error 0.051	-1.04 units on a scale Standard Error 0.051	-0.99 units on a scale Standard Error 0.051	-0.59 units on a scale Standard Error 0.051

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline

Change from Baseline to Week 12 in Vaginal Epithelial Surface Thickness as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Surface Thickness: No atrophy (rogation and elasticity of vault) = 0; Mild (poor rogation with some elasticity noted of vaginal vault) = 1; Moderate (smooth, some elasticity of vaginal vault) = 2; Severe \[smooth, no elasticity, constriction of the upper one third of vagina or loss of vaginal tone (cystocele and rectocele)\] = 3 Severity was assessed by the Investigator at Baseline and Week 12

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=171 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=175 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=175 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)	-0.98 units on a scale Standard Error 0.051	-1.03 units on a scale Standard Error 0.051	-0.94 units on a scale Standard Error 0.050	-0.61 units on a scale Standard Error 0.050

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 2 in Vaginal Secretions as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Secretions: No atrophy (normal clear secretions noted on vaginal walls) = 0; Mild (superficial coating of secretions, difficulty with speculum insertion) = 1; Moderate (scant not covering the entire vaginal vault, may need lubrication with speculum insertion to prevent pain) = 2; Severe (none, inflamed, ulceration noted, need lubrication with speculum insertion to prevent pain) = 3 Severity was assessed by the Investigator at Baseline and Week 2

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=185 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=187 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=184 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=186 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)	-0.79 units on a scale Standard Error 0.050	-0.83 units on a scale Standard Error 0.050	-0.86 units on a scale Standard Error 0.050	-0.54 units on a scale Standard Error 0.050

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 6 in Vaginal Secretions as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Secretions: No atrophy (normal clear secretions noted on vaginal walls) = 0; Mild (superficial coating of secretions, difficulty with speculum insertion) = 1; Moderate (scant not covering the entire vaginal vault, may need lubrication with speculum insertion to prevent pain) = 2; Severe (none, inflamed, ulceration noted, need lubrication with speculum insertion to prevent pain\] = 3 Severity was assessed by the Investigator at Baseline and Week 6

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=172 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=170 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=176 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)	-0.90 units on a scale Standard Error 0.051	-0.95 units on a scale Standard Error 0.051	-0.97 units on a scale Standard Error 0.051	-0.60 units on a scale Standard Error 0.051

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 8 in Vaginal Secretions as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Secretions: No atrophy (normal clear secretions noted on vaginal walls) = 0; Mild (superficial coating of secretions, difficulty with speculum insertion) = 1; Moderate (scant not covering the entire vaginal vault, may need lubrication with speculum insertion to prevent pain) = 2; Severe (none, inflamed, ulceration noted, need lubrication with speculum insertion to prevent pain\] = 3 Severity was assessed by the Investigator at Baseline and Week 8

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=164 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=165 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=166 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=167 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)	-1.00 units on a scale Standard Error 0.052	-1.04 units on a scale Standard Error 0.052	-1.06 units on a scale Standard Error 0.052	-0.63 units on a scale Standard Error 0.052

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 in Vaginal Secretions as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Secretions: No atrophy (normal clear secretions noted on vaginal walls) = 0; Mild (superficial coating of secretions, difficulty with speculum insertion) = 1; Moderate (scant not covering the entire vaginal vault, may need lubrication with speculum insertion to prevent pain) = 2; Severe (none, inflamed, ulceration noted, need lubrication with speculum insertion to prevent pain\] = 3 Severity was assessed by the Investigator at Baseline and Week 12

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=171 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=173 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=175 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=175 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)	-1.01 units on a scale Standard Error 0.051	-1.06 units on a scale Standard Error 0.051	-1.04 units on a scale Standard Error 0.051	-0.64 units on a scale Standard Error 0.051

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 in FSFI Total Score as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=153 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=152 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=156 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=158 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) - Total Score	7.909 units on a scale Interval 6.748 to 9.07	9.431 units on a scale Interval 8.261 to 10.601	10.283 units on a scale Interval 9.133 to 11.434	7.458 units on a scale Interval 6.315 to 8.602

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 in FSFI Domain Score (Arousal) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=154 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=152 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=157 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=159 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Arousal	0.875 units on a scale Interval 0.657 to 1.093	1.287 units on a scale Interval 1.066 to 1.507	1.392 units on a scale Interval 1.176 to 1.608	0.93 units on a scale Interval 0.715 to 1.145

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 in FSFI Domain Score (Desire) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=154 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=152 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=157 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=159 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Desire	0.625 units on a scale Interval 0.471 to 0.779	0.800 units on a scale Interval 0.646 to 0.955	0.848 units on a scale Interval 0.695 to 1.0	0.630 units on a scale Interval 0.479 to 0.782

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 in FSFI Domain Score (Lubrication) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=153 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=152 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=156 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=159 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Lubrication	1.834 units on a scale Interval 1.578 to 2.09	2.242 units on a scale Interval 1.984 to 2.5	2.299 units on a scale Interval 2.045 to 2.553	1.595 units on a scale Interval 1.343 to 1.846

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 in FSFI Domain Score (Orgasm) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=153 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=152 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=156 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=159 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Orgasm	1.162 units on a scale Interval 0.903 to 1.421	1.274 units on a scale Interval 1.013 to 1.535	1.591 units on a scale Interval 1.334 to 1.847	1.202 units on a scale Interval 0.948 to 1.457

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 in FSFI Domain Score (Pain) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=154 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=152 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=156 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=159 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Pain	2.173 units on a scale Interval 1.879 to 2.467	2.548 units on a scale Interval 2.251 to 2.844	2.514 units on a scale Interval 2.222 to 2.805	1.930 units on a scale Interval 1.641 to 2.219

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.

Change from Baseline to Week 12 in FSFI Domain Score (Satisfaction) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.

Outcome measures

Outcome measures
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=154 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=152 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=157 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=158 Participants Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Satisfaction	1.257 units on a scale Interval 1.046 to 1.469	1.384 units on a scale Interval 1.17 to 1.597	1.629 units on a scale Interval 1.42 to 1.839	1.174 units on a scale Interval 0.965 to 1.383

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-treatment, Day 2, Weeks 2 and 12

Blood samples will be obtained from a subset of subjects at pre-selected sites to characterize PK parameters (AUC, tmax, Cmin, Cmax, Cavg) and to measure SHBG

Outcome measures

Outcome data not reported

Adverse Events

Estradiol 4mcg Vaginal Softgel Capsule

Serious events: 0 serious events

Other events: 46 other events

Deaths: 0 deaths

Estradiol 10mcg Vaginal Softgel Capsule

Serious events: 3 serious events

Other events: 41 other events

Deaths: 0 deaths

Estradiol 25mcg Vaginal Softgel Capsule

Serious events: 4 serious events

Other events: 45 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 66 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=191 participants at risk Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=191 participants at risk Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=190 participants at risk Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=192 participants at risk Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Cardiac disorders Atrial fibrillation	0.00% 0/191	0.00% 0/191	0.53% 1/190	0.00% 0/192
Cardiac disorders Sinus node dysfunction	0.00% 0/191	0.52% 1/191	0.00% 0/190	0.00% 0/192
Gastrointestinal disorders Appendicitis	0.00% 0/191	0.00% 0/191	0.53% 1/190	0.00% 0/192
Infections and infestations Endophthalmitis	0.00% 0/191	0.00% 0/191	0.53% 1/190	0.00% 0/192
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/191	0.52% 1/191	0.00% 0/190	0.00% 0/192
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/191	0.52% 1/191	0.00% 0/190	0.00% 0/192
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.00% 0/191	0.52% 1/191	0.00% 0/190	0.00% 0/192
Nervous system disorders Cervical myelopathy	0.00% 0/191	0.00% 0/191	0.00% 0/190	0.52% 1/192
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/191	0.00% 0/191	0.53% 1/190	0.00% 0/192

Other adverse events

Other adverse events
Measure	Estradiol 4mcg Vaginal Softgel Capsule n=191 participants at risk Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 10mcg Vaginal Softgel Capsule n=191 participants at risk Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Estradiol 25mcg Vaginal Softgel Capsule n=190 participants at risk Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.	Placebo n=192 participants at risk Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Infections and infestations Nasopharyngitis	2.6% 5/191	3.1% 6/191	3.7% 7/190	5.2% 10/192
Infections and infestations Upper respiratory infection	2.6% 5/191	3.1% 6/191	1.6% 3/190	2.6% 5/192
Infections and infestations Urinary tract infection	2.6% 5/191	2.6% 5/191	4.2% 8/190	2.1% 4/192
Musculoskeletal and connective tissue disorders Back pain	4.7% 9/191	0.52% 1/191	2.1% 4/190	4.2% 8/192
Nervous system disorders Headache	6.3% 12/191	7.3% 14/191	3.2% 6/190	7.8% 15/192
Reproductive system and breast disorders Vaginal discharge	2.6% 5/191	3.1% 6/191	2.1% 4/190	6.8% 13/192
Reproductive system and breast disorders Vulvovaginal pruritus	2.1% 4/191	1.6% 3/191	3.7% 7/190	5.2% 10/192
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.52% 1/191	0.00% 0/191	3.2% 6/190	0.52% 1/192

Additional Information

Sebastian Mirkin, MD, Chief Medical Officer

TherapeuticsMD

Phone: 561-961-1900

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER