Trial Outcomes & Findings for Study Evaluating the Efficacy and Safety of Three Formulations of Ultra-low Dose Estriol Vaginal Gel (0.005%, 0.002%, 0.0008% Estriol Vaginal Gel) for the Treatment of Vaginal Dryness in Postmenopausal Women With Vulvovaginal Atrophy (NCT NCT02967510)

Last Updated: 2019-09-25

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

283 participants

Primary outcome timeframe

From baseline to week 12

Results posted on

2019-09-25

Participant Flow

Participant milestones

Participant milestones
Measure	Estriol 0.005% 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	Estriol 0.002% 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	Estriol 0.0008% 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	Placebo Subjects received 1 gram of 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
Overall Study STARTED	70	70	72	71
Overall Study COMPLETED	66	67	65	63
Overall Study NOT COMPLETED	4	3	7	8

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study Evaluating the Efficacy and Safety of Three Formulations of Ultra-low Dose Estriol Vaginal Gel (0.005%, 0.002%, 0.0008% Estriol Vaginal Gel) for the Treatment of Vaginal Dryness in Postmenopausal Women With Vulvovaginal Atrophy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=70 Participants 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	Estriol 0.0008% n=72 Participants 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	Placebo n=71 Participants Subjects received 1 gram of 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	Total n=283 Participants Total of all reporting groups
Age, Continuous	61.5 years STANDARD_DEVIATION 7.43 • n=5 Participants	61.9 years STANDARD_DEVIATION 6.87 • n=7 Participants	62.2 years STANDARD_DEVIATION 7.05 • n=5 Participants	62.3 years STANDARD_DEVIATION 7.24 • n=4 Participants	62.0 years STANDARD_DEVIATION 7.12 • n=21 Participants
Sex: Female, Male Female	70 Participants n=5 Participants	70 Participants n=7 Participants	72 Participants n=5 Participants	71 Participants n=4 Participants	283 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
Race (NIH/OMB) American Indian or Alaska Native	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
Race (NIH/OMB) Asian	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
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	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
Race (NIH/OMB) Black or African American	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
Race (NIH/OMB) White	70 Participants n=5 Participants	70 Participants n=7 Participants	71 Participants n=5 Participants	71 Participants n=4 Participants	282 Participants n=21 Participants
Race (NIH/OMB) More than one race	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
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants

PRIMARY outcome

Timeframe: From baseline to week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Vaginal Dryness Change from Baseline: -3	15 Participants	13 Participants	13 Participants	9 Participants
Change From Baseline to Week 12 in the Severity of Vaginal Dryness Change from Baseline: -2	23 Participants	33 Participants	26 Participants	26 Participants
Change From Baseline to Week 12 in the Severity of Vaginal Dryness Change from Baseline: -1	26 Participants	16 Participants	20 Participants	19 Participants
Change From Baseline to Week 12 in the Severity of Vaginal Dryness Change from Baseline: 0	4 Participants	6 Participants	11 Participants	13 Participants
Change From Baseline to Week 12 in the Severity of Vaginal Dryness Change from Baseline: 1	2 Participants	0 Participants	0 Participants	1 Participants

PRIMARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Change from Baseline to Week 12 in Vaginal pH was reported. A decrease in pH compare to Baseline represents a positive outcome.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=69 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in Vaginal pH	-1.03 pH Standard Error 0.106	-1.04 pH Standard Error 0.108	-0.95 pH Standard Error 0.107	-0.29 pH Standard Error 0.108

PRIMARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Change from Baseline to week 12 in the proportion of superficial cells of the vaginal epithelium was reported.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=69 Participants 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	Estriol 0.002% n=64 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=66 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Proportion of Superficial Cells of the Vaginal Epithelium.	0.24 ratio Standard Error 0.023	0.17 ratio Standard Error 0.024	0.19 ratio Standard Error 0.023	0.02 ratio Standard Error 0.024

PRIMARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=69 Participants 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	Estriol 0.002% n=64 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=66 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Proportion of Parabasal Cells of the Vaginal Epithelium.	-0.54 ratio Standard Error 0.036	-0.51 ratio Standard Error 0.037	-0.47 ratio Standard Error 0.036	-0.04 ratio Standard Error 0.038

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from baseline to week 12 in the 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=39 Participants 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	Estriol 0.002% n=31 Participants 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	Estriol 0.0008% n=41 Participants 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	Placebo n=32 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Dyspareunia Change from Baseline: -3	7 Participants	5 Participants	4 Participants	3 Participants
Change From Baseline to Week 12 in the Severity of Dyspareunia Change from Baseline: -2	9 Participants	7 Participants	16 Participants	11 Participants
Change From Baseline to Week 12 in the Severity of Dyspareunia Change from Baseline: -1	12 Participants	13 Participants	12 Participants	8 Participants
Change From Baseline to Week 12 in the Severity of Dyspareunia Change from Baseline: 0	10 Participants	5 Participants	5 Participants	9 Participants
Change From Baseline to Week 12 in the Severity of Dyspareunia Change from Baseline: 1	0 Participants	1 Participants	3 Participants	0 Participants
Change From Baseline to Week 12 in the Severity of Dyspareunia Change from Baseline: 2	1 Participants	0 Participants	1 Participants	1 Participants
Change From Baseline to Week 12 in the Severity of Dyspareunia Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with cvhange from Baseline to Week 12 in the 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=69 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Pruritus or Itching Change from Baseline: -3	2 Participants	5 Participants	4 Participants	4 Participants
Change From Baseline to Week 12 in the Severity of Pruritus or Itching Change from Baseline: -2	16 Participants	14 Participants	15 Participants	13 Participants
Change From Baseline to Week 12 in the Severity of Pruritus or Itching Change from Baseline: -1	18 Participants	20 Participants	20 Participants	20 Participants
Change From Baseline to Week 12 in the Severity of Pruritus or Itching Change from Baseline: 0	33 Participants	22 Participants	28 Participants	25 Participants
Change From Baseline to Week 12 in the Severity of Pruritus or Itching Change from Baseline: 1	0 Participants	4 Participants	2 Participants	5 Participants
Change From Baseline to Week 12 in the Severity of Pruritus or Itching Change from Baseline: 2	1 Participants	2 Participants	1 Participants	2 Participants
Change From Baseline to Week 12 in the Severity of Pruritus or Itching Change from Baseline: 3	0 Participants	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 12 in the 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=69 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Burning Change from Baseline: -3	5 Participants	4 Participants	7 Participants	4 Participants
Change From Baseline to Week 12 in the Severity of Burning Change from Baseline: -2	22 Participants	21 Participants	18 Participants	19 Participants
Change From Baseline to Week 12 in the Severity of Burning Change from Baseline: -1	25 Participants	17 Participants	18 Participants	23 Participants
Change From Baseline to Week 12 in the Severity of Burning Change from Baseline: 0	18 Participants	24 Participants	26 Participants	20 Participants
Change From Baseline to Week 12 in the Severity of Burning Change from Baseline: 1	0 Participants	1 Participants	1 Participants	2 Participants
Change From Baseline to Week 12 in the Severity of Burning Change from Baseline: 2	0 Participants	1 Participants	0 Participants	1 Participants
Change From Baseline to Week 12 in the Severity of Burning Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 12 in the 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 putcome.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=69 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Dysuria Change from Baseline: -3	0 Participants	1 Participants	1 Participants	1 Participants
Change From Baseline to Week 12 in the Severity of Dysuria Change from Baseline: -2	8 Participants	8 Participants	5 Participants	5 Participants
Change From Baseline to Week 12 in the Severity of Dysuria Change from Baseline: -1	18 Participants	19 Participants	17 Participants	15 Participants
Change From Baseline to Week 12 in the Severity of Dysuria Change from Baseline: 0	43 Participants	39 Participants	40 Participants	44 Participants
Change From Baseline to Week 12 in the Severity of Dysuria Change from Baseline: 1	1 Participants	1 Participants	7 Participants	0 Participants
Change From Baseline to Week 12 in the Severity of Dysuria Change from Baseline: 2	0 Participants	0 Participants	0 Participants	2 Participants
Change From Baseline to Week 12 in the Severity of Dysuria Change from Baseline: 3	0 Participants	0 Participants	0 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

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. the Global Symptom Score 1 ranged at Screening/Baseline between 2 (at least moderate vaginal dryness -per inclusion criteria) to 15 (all 5 studied symptoms severe in intensity). At Week 12/ET visit, the Global Symptom Score ranged between 0 (no symptoms) and 15 (all symptoms severe in intensity). A decrease in score compared to Baseline represented a positive outcome.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=39 Participants 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	Estriol 0.002% n=31 Participants 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	Estriol 0.0008% n=41 Participants 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	Placebo n=31 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Global Symptom Score 1	-4.30 units on a scale Standard Error 0.425	-4.78 units on a scale Standard Error 0.478	-4.51 units on a scale Standard Error 0.412	-4.54 units on a scale Standard Error 0.467

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Change from Baseline to Week 12 in the Global Symptom Score 2 was reported. Global Symptom Score 2 was defined as the sum of all 4 individual symptoms excluding dyspareunia (vaginal dryness, pruritus or itching, burning, and dysuria) for each subject at each time point: Screening/Baseline, Week 3 and Week 12/ET., and was calculated only when all 4 symptom scores had a response available. The maximum score possible to be obtained at a visit with the Global Symptom Score 2 was 12 (all symptoms severe in intensity). A decrease in score compared to baseline represented a positive outcome.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Global Symptom Score 2	-3.83 units on a scale Standard Error 0.231	-3.78 units on a scale Standard Error 0.234	-3.74 units on a scale Standard Error 0.233	-3.27 units on a scale Standard Error 0.237

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 12 in the 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 putcome.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=69 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Pallor. Change from Baseline: -3	3 Participants	5 Participants	1 Participants	1 Participants
Change From Baseline to Week 12 in the Severity of Pallor. Change from Baseline: -2	17 Participants	16 Participants	25 Participants	15 Participants
Change From Baseline to Week 12 in the Severity of Pallor. Change from Baseline: -1	31 Participants	31 Participants	25 Participants	18 Participants
Change From Baseline to Week 12 in the Severity of Pallor. Change from Baseline: 0	16 Participants	16 Participants	17 Participants	31 Participants
Change From Baseline to Week 12 in the Severity of Pallor. Change from Baseline: 1	3 Participants	0 Participants	2 Participants	4 Participants
Change From Baseline to Week 12 in the Severity of Pallor. Change from Baseline: 2	0 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 12 in the Severity of Pallor. Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 12 in the 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=69 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Friability Change from Baseline: -3	2 Participants	2 Participants	2 Participants	3 Participants
Change From Baseline to Week 12 in the Severity of Friability Change from Baseline: -2	19 Participants	21 Participants	18 Participants	19 Participants
Change From Baseline to Week 12 in the Severity of Friability Change from Baseline: -1	26 Participants	22 Participants	31 Participants	20 Participants
Change From Baseline to Week 12 in the Severity of Friability Change from Baseline: 0	21 Participants	22 Participants	16 Participants	24 Participants
Change From Baseline to Week 12 in the Severity of Friability Change from Baseline: 1	1 Participants	0 Participants	3 Participants	3 Participants
Change From Baseline to Week 12 in the Severity of Friability Change from Baseline: 2	1 Participants	1 Participants	0 Participants	0 Participants
Change From Baseline to Week 12 in the Severity of Friability Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 12 in the 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=69 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Thinning or Flattening of Folds Change from Baseline: -3	4 Participants	1 Participants	1 Participants	1 Participants
Change From Baseline to Week 12 in the Severity of Thinning or Flattening of Folds Change from Baseline: -2	18 Participants	18 Participants	23 Participants	6 Participants
Change From Baseline to Week 12 in the Severity of Thinning or Flattening of Folds Change from Baseline: -1	29 Participants	33 Participants	24 Participants	31 Participants
Change From Baseline to Week 12 in the Severity of Thinning or Flattening of Folds Change from Baseline: 0	17 Participants	14 Participants	19 Participants	26 Participants
Change From Baseline to Week 12 in the Severity of Thinning or Flattening of Folds Change from Baseline: 1	2 Participants	2 Participants	3 Participants	5 Participants
Change From Baseline to Week 12 in the Severity of Thinning or Flattening of Folds Change from Baseline: 2	0 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 12 in the Severity of Thinning or Flattening of Folds Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 12 in the 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=69 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Petechiae Change from Baseline: -3	2 Participants	1 Participants	0 Participants	2 Participants
Change From Baseline to Week 12 in the Severity of Petechiae Change from Baseline: -2	10 Participants	5 Participants	7 Participants	2 Participants
Change From Baseline to Week 12 in the Severity of Petechiae Change from Baseline: -1	26 Participants	23 Participants	23 Participants	13 Participants
Change From Baseline to Week 12 in the Severity of Petechiae Change from Baseline: 0	29 Participants	35 Participants	35 Participants	49 Participants
Change From Baseline to Week 12 in the Severity of Petechiae Change from Baseline: 1	3 Participants	4 Participants	5 Participants	3 Participants
Change From Baseline to Week 12 in the Severity of Petechiae Change from Baseline: 2	0 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 12 in the Severity of Petechiae Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 12 in the 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=70 Participants 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	Estriol 0.002% n=68 Participants 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	Estriol 0.0008% n=70 Participants 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	Placebo n=69 Participants Subjects received 1 gram of 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
Change From Baseline to Week 12 in the Severity of Dry Mucosa Change from Baseline: -3	8 Participants	13 Participants	14 Participants	9 Participants
Change From Baseline to Week 12 in the Severity of Dry Mucosa Change from Baseline: -2	39 Participants	29 Participants	26 Participants	19 Participants
Change From Baseline to Week 12 in the Severity of Dry Mucosa Change from Baseline: -1	17 Participants	20 Participants	23 Participants	19 Participants
Change From Baseline to Week 12 in the Severity of Dry Mucosa Change from Baseline: 0	5 Participants	6 Participants	6 Participants	19 Participants
Change From Baseline to Week 12 in the Severity of Dry Mucosa Change from Baseline: 1	1 Participants	0 Participants	1 Participants	3 Participants
Change From Baseline to Week 12 in the Severity of Dry Mucosa Change from Baseline: 2	0 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 12 in the Severity of Dry Mucosa Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 3 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=66 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Vaginal Dryness Change from Baseline: -3	6 Participants	8 Participants	8 Participants	3 Participants
Change From Baseline to Week 3 in the Severity of Vaginal Dryness Change from Baseline: -2	23 Participants	13 Participants	22 Participants	26 Participants
Change From Baseline to Week 3 in the Severity of Vaginal Dryness Change from Baseline: -1	28 Participants	33 Participants	26 Participants	26 Participants
Change From Baseline to Week 3 in the Severity of Vaginal Dryness Change from Baseline: 0	8 Participants	12 Participants	11 Participants	11 Participants
Change From Baseline to Week 3 in the Severity of Vaginal Dryness Change from Baseline: 1	3 Participants	0 Participants	1 Participants	2 Participants

SECONDARY outcome

Timeframe: From baseline to week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint

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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=33 Participants 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	Estriol 0.002% n=29 Participants 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	Estriol 0.0008% n=37 Participants 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	Placebo n=27 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Dyspareunia Change from Baseline: -3	1 Participants	3 Participants	4 Participants	2 Participants
Change From Baseline to Week 3 in the Severity of Dyspareunia Change from Baseline: -2	7 Participants	4 Participants	10 Participants	7 Participants
Change From Baseline to Week 3 in the Severity of Dyspareunia Change from Baseline: -1	11 Participants	11 Participants	14 Participants	10 Participants
Change From Baseline to Week 3 in the Severity of Dyspareunia Change from Baseline: 0	13 Participants	6 Participants	8 Participants	7 Participants
Change From Baseline to Week 3 in the Severity of Dyspareunia Change from Baseline: 1	0 Participants	4 Participants	0 Participants	1 Participants
Change From Baseline to Week 3 in the Severity of Dyspareunia Change from Baseline: 2	1 Participants	1 Participants	1 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Dyspareunia Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 3 in the 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=67 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Pruritus or Itching Change from Baseline: -3	1 Participants	4 Participants	2 Participants	1 Participants
Change From Baseline to Week 3 in the Severity of Pruritus or Itching Change from Baseline: -2	10 Participants	10 Participants	7 Participants	10 Participants
Change From Baseline to Week 3 in the Severity of Pruritus or Itching Change from Baseline: -1	15 Participants	19 Participants	30 Participants	24 Participants
Change From Baseline to Week 3 in the Severity of Pruritus or Itching Change from Baseline: 0	35 Participants	27 Participants	27 Participants	30 Participants
Change From Baseline to Week 3 in the Severity of Pruritus or Itching Change from Baseline: 1	5 Participants	2 Participants	2 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Pruritus or Itching Change from Baseline: 2	2 Participants	4 Participants	0 Participants	3 Participants
Change From Baseline to Week 3 in the Severity of Pruritus or Itching Change from Baseline: 3	0 Participants	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=67 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Burning Change from Baseline: -1	27 Participants	18 Participants	20 Participants	21 Participants
Change From Baseline to Week 3 in the Severity of Burning Change from Baseline: 0	27 Participants	28 Participants	29 Participants	28 Participants
Change From Baseline to Week 3 in the Severity of Burning Change from Baseline: 1	0 Participants	1 Participants	1 Participants	2 Participants
Change From Baseline to Week 3 in the Severity of Burning Change from Baseline: -3	3 Participants	2 Participants	4 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Burning Change from Baseline: -2	11 Participants	17 Participants	14 Participants	16 Participants
Change From Baseline to Week 3 in the Severity of Burning Change from Baseline: 2	0 Participants	1 Participants	0 Participants	1 Participants
Change From Baseline to Week 3 in the Severity of Burning Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=67 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Dysuria Change from Baseline: 1	3 Participants	3 Participants	2 Participants	3 Participants
Change From Baseline to Week 3 in the Severity of Dysuria Change from Baseline: -3	0 Participants	0 Participants	1 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Dysuria Change from Baseline: -2	5 Participants	8 Participants	3 Participants	6 Participants
Change From Baseline to Week 3 in the Severity of Dysuria Change from Baseline: -1	14 Participants	16 Participants	14 Participants	9 Participants
Change From Baseline to Week 3 in the Severity of Dysuria Change from Baseline: 0	46 Participants	39 Participants	48 Participants	48 Participants
Change From Baseline to Week 3 in the Severity of Dysuria Change from Baseline: 2	0 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Dysuria Change from Baseline: 3	0 Participants	1 Participants	0 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

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. the Global Symptom Score 1 ranged at Screening/Baseline between 2 (at least moderate vaginal dryness -per inclusion criteria) to 15 (all 5 studied symptoms severe in intensity). At Week 3 visit, the Global Symptom Score ranged between 0 (no symptoms) and 15 (all symptoms severe in intensity). A decrease in score compared to Baseline represented a positive outcome.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=33 Participants 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	Estriol 0.002% n=29 Participants 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	Estriol 0.0008% n=37 Participants 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	Placebo n=27 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Global Symptom Score 1	-2.99 units on a scale Standard Error 0.483	-2.86 units on a scale Standard Error 0.520	-4.37 units on a scale Standard Error 0.454	-3.73 units on a scale Standard Error 0.527

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Change from Baseline to Week 3 in the Global Symptom Score 2 was reported. Global Symptom Score 2 was defined as the sum of all 4 individual symptoms excluding dyspareunia (vaginal dryness, pruritus or itching, burning, and dysuria) for each subject at each time point: Screening/Baseline, Week 3 and Week 12/ET., and was calculated only when all 4 symptom scores had a response available. The maximum score possible to be obtained at a visit with the Global Symptom Score 2 was 12 (all symptoms severe in intensity). A decrease in score compared to baseline represented a positive outcome.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=66 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Global Symptom Score 2	-2.76 units on a scale Standard Error 0.251	-2.82 units on a scale Standard Error 0.254	-3.20 units on a scale Standard Error 0.253	-2.60 units on a scale Standard Error 0.255

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=67 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Pallor Change from Baseline: -3	3 Participants	2 Participants	1 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Pallor Change from Baseline: -2	14 Participants	14 Participants	14 Participants	6 Participants
Change From Baseline to Week 3 in the Severity of Pallor Change from Baseline: -1	19 Participants	20 Participants	24 Participants	19 Participants
Change From Baseline to Week 3 in the Severity of Pallor Change from Baseline: 0	31 Participants	30 Participants	29 Participants	38 Participants
Change From Baseline to Week 3 in the Severity of Pallor Change from Baseline: 1	1 Participants	1 Participants	0 Participants	5 Participants
Change From Baseline to Week 3 in the Severity of Pallor Change from Baseline: 2	0 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Pallor Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=67 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Friability Change from Baseline: -1	29 Participants	25 Participants	25 Participants	24 Participants
Change From Baseline to Week 3 in the Severity of Friability Change from Baseline: 0	22 Participants	25 Participants	27 Participants	32 Participants
Change From Baseline to Week 3 in the Severity of Friability Change from Baseline: 1	1 Participants	3 Participants	2 Participants	3 Participants
Change From Baseline to Week 3 in the Severity of Friability Change from Baseline: 2	0 Participants	1 Participants	0 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Friability Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Friability Change from Baseline: -3	2 Participants	2 Participants	1 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Friability Change from Baseline: -2	14 Participants	11 Participants	13 Participants	9 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=67 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Thinning or Flattening of Folds Change from Baseline: -3	1 Participants	1 Participants	0 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Thinning or Flattening of Folds Change from Baseline: -2	12 Participants	9 Participants	10 Participants	5 Participants
Change From Baseline to Week 3 in the Severity of Thinning or Flattening of Folds Change from Baseline: -1	32 Participants	35 Participants	31 Participants	16 Participants
Change From Baseline to Week 3 in the Severity of Thinning or Flattening of Folds Change from Baseline: 0	20 Participants	21 Participants	26 Participants	43 Participants
Change From Baseline to Week 3 in the Severity of Thinning or Flattening of Folds Change from Baseline: 1	3 Participants	1 Participants	1 Participants	4 Participants
Change From Baseline to Week 3 in the Severity of Thinning or Flattening of Folds Change from Baseline: 2	0 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Thinning or Flattening of Folds Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Percentage of subjects with change from Baseline to Week 3 in the 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=67 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Presence of Petechiae Change from Baseline: -3	2 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Presence of Petechiae Change from Baseline: -2	8 Participants	6 Participants	6 Participants	3 Participants
Change From Baseline to Week 3 in the Severity of Presence of Petechiae Change from Baseline: -1	23 Participants	18 Participants	22 Participants	7 Participants
Change From Baseline to Week 3 in the Severity of Presence of Petechiae Change from Baseline: 0	31 Participants	41 Participants	38 Participants	54 Participants
Change From Baseline to Week 3 in the Severity of Presence of Petechiae Change from Baseline: 1	3 Participants	2 Participants	1 Participants	3 Participants
Change From Baseline to Week 3 in the Severity of Presence of Petechiae Change from Baseline: 2	1 Participants	0 Participants	1 Participants	1 Participants
Change From Baseline to Week 3 in the Severity of Presence of Petechiae Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=67 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Severity of Dry Mucosa Change from Baseline: -3	4 Participants	8 Participants	6 Participants	3 Participants
Change From Baseline to Week 3 in the Severity of Dry Mucosa Change from Baseline: -2	29 Participants	20 Participants	26 Participants	17 Participants
Change From Baseline to Week 3 in the Severity of Dry Mucosa Change from Baseline: -1	22 Participants	30 Participants	21 Participants	20 Participants
Change From Baseline to Week 3 in the Severity of Dry Mucosa Change from Baseline: 0	12 Participants	9 Participants	15 Participants	26 Participants
Change From Baseline to Week 3 in the Severity of Dry Mucosa Change from Baseline: 1	1 Participants	0 Participants	0 Participants	2 Participants
Change From Baseline to Week 3 in the Severity of Dry Mucosa Change from Baseline: 2	0 Participants	0 Participants	0 Participants	0 Participants
Change From Baseline to Week 3 in the Severity of Dry Mucosa Change from Baseline: 3	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Change from Baseline to Week 3 in vaginal pH was reported. A decrease in pH compared to Baseline represents a positive outcome.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=68 Participants 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	Estriol 0.002% n=67 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=68 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in Vaginal pH	-1.03 pH Standard Error 0.095	-0.97 pH Standard Error 0.096	-0.88 pH Standard Error 0.095	-0.22 pH Standard Error 0.096

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Change from baseline to week 3 in the proportion of superficial cells of the vaginal epithelium was reported.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=65 Participants 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	Estriol 0.002% n=61 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=61 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Proportion of Superficial Cells of the Vaginal Epithelium	0.48 ratio Standard Error 0.035	0.43 ratio Standard Error 0.036	0.38 ratio Standard Error 0.035	0.04 ratio Standard Error 0.037

SECONDARY outcome

Timeframe: Baseline to Week 3

Population: The ITT population defined as all randomized subjects. The number of subjects analyzed defined as number of subjects evaluable for this endpoint.

Change from Baseline to Week 3 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.

Outcome measures

Outcome measures
Measure	Estriol 0.005% n=65 Participants 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	Estriol 0.002% n=61 Participants 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	Estriol 0.0008% n=68 Participants 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	Placebo n=61 Participants Subjects received 1 gram of 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
Change From Baseline to Week 3 in the Proportion of Parabasal Cells of the Vaginal Epithelium	-0.55 ratio Standard Error 0.037	-0.57 ratio Standard Error 0.037	-0.48 ratio Standard Error 0.036	-0.08 ratio Standard Error 0.038

Adverse Events

Estriol 0.005%

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Estriol 0.002%

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Estriol 0.0008%

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Placebo

Serious events: 3 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Estriol 0.005% n=70 participants at risk 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	Estriol 0.002% n=69 participants at risk 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	Estriol 0.0008% n=72 participants at risk 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	Placebo n=71 participants at risk Subjects received 1 gram of 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
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-Hodgkin´s lymphoma	0.00% 0/70 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.	0.00% 0/69 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.	0.00% 0/72 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.	1.4% 1/71 • Number of events 1 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.
Cardiac disorders Atrial fibrillation	0.00% 0/70 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.	0.00% 0/69 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.	0.00% 0/72 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.	1.4% 1/71 • Number of events 1 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.
Infections and infestations Pneumonia	0.00% 0/70 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.	0.00% 0/69 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.	0.00% 0/72 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.	1.4% 1/71 • Number of events 1 • Adverse events were assessed from the time the subject signed the ICF until exit from the study, aproximately 20 weeks 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. Subjects were questioned and observed for evidence of AEs. For any preexisting condition or abnormal laboratory finding that changed in severity after dosing, the change was to be recorded as an AE. New abnormal laboratory findings that were considered clinically significant by the Investigator were considered AEs.

Other adverse events

Additional Information

Javier Suárez Almarza

ITF Research Pharma SLU

Phone: +34 916572323

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place