Trial Outcomes & Findings for Evaluate Long-Term Safety and Efficacy WC3011 (Estradiol Vaginal Cream) (NCT NCT01455597)

NCT ID: NCT01455597

Last Updated: 2022-05-09

Results Overview

The endometrial biopsy results was categorized as: normal results categorized as atrophic/inactive or proliferative, unsatisfactory with endometrial thickness ≤4 mm and missing biopsy with endometrial thickness ≤4 mm; abnormal results categorized as polyp, hyperplasia, and carcinoma; unknown result categorized as unsatisfactory with endometrial thickness \>4 mm, missing biopsy with endometrial thickness \>4 mm, unsatisfactory without transvaginal ultrasonography (TVU) result and missing biopsy without TVU result. The duration of estradiol exposure was combination of studies PR-04409.3 and PR-04509.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 309 participants
• Primary outcome timeframe: Final Visit (Day closest to Day 281)
• Results posted on: 2022-05-09

Participant Flow

Participants who completed study PR-04409.3 (NCT01400776) were enrolled to receive W13011 estradiol vaginal cream three times a week in this study. Participant flow and outcome measures data were summarized as per treatment received in previous study.

Participant milestones

Measure	Previous WC3011 Estradiol Vaginal Cream (2 Times/Week) WC3011 estradiol vaginal cream. applied vaginally 3 times a week for up to 40 weeks in this study (Participants who received WC3011 estradiol vaginal cream 2 times a week in the previous study were included in this arm group).	Previous Vehicle (2 Times/Week) WC3011 estradiol vaginal cream applied vaginally 3 times a week for up to 40 weeks in this study (Participants who received vehicle 2 times a week in the previous study were included in this arm group).	Previous WC3011 Estradiol Vaginal Cream (3 Times/Week) WC3011 estradiol vaginal cream applied vaginally 3 times a week for up to 40 weeks in this study (Participants who received WC13011 estradiol vaginal cream 3 times a week in the previous study were included in this arm group).	Previous Vehicle (3 Times/Week) WC3011 estradiol vaginal cream applied vaginally 3 times a week for up to 40 weeks in this study (Participants who received vehicle 3 times a week in the previous study were included in this arm group).
Overall Study STARTED	101	56	100	52
Overall Study All-Participants-Treated Population	101	56	99	52
Overall Study COMPLETED	84	48	80	42
Overall Study NOT COMPLETED	17	8	20	10

Reasons for withdrawal

Measure	Previous WC3011 Estradiol Vaginal Cream (2 Times/Week) WC3011 estradiol vaginal cream. applied vaginally 3 times a week for up to 40 weeks in this study (Participants who received WC3011 estradiol vaginal cream 2 times a week in the previous study were included in this arm group).	Previous Vehicle (2 Times/Week) WC3011 estradiol vaginal cream applied vaginally 3 times a week for up to 40 weeks in this study (Participants who received vehicle 2 times a week in the previous study were included in this arm group).	Previous WC3011 Estradiol Vaginal Cream (3 Times/Week) WC3011 estradiol vaginal cream applied vaginally 3 times a week for up to 40 weeks in this study (Participants who received WC13011 estradiol vaginal cream 3 times a week in the previous study were included in this arm group).	Previous Vehicle (3 Times/Week) WC3011 estradiol vaginal cream applied vaginally 3 times a week for up to 40 weeks in this study (Participants who received vehicle 3 times a week in the previous study were included in this arm group).
Overall Study Adverse Event	7	0	5	1
Overall Study Lack of Efficacy	0	1	2	0
Overall Study Lost to Follow-up	3	0	2	1
Overall Study Withdrew Consent	6	5	8	5
Overall Study Reason not Specified	1	2	3	3

Baseline Characteristics

Evaluate Long-Term Safety and Efficacy WC3011 (Estradiol Vaginal Cream)

Baseline characteristics by cohort

Measure	WC3011 Estradiol Vaginal Cream n=308 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for up to 40 weeks.
Age, Continuous	59.0 years STANDARD_DEVIATION 5.54 • n=5 Participants
Sex: Female, Male Female	308 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Final Visit (Day closest to Day 281)

Population: All participants who received at least 1 dose of study drug in Study PR-04509. Data is reported as per the duration of exposure of participants receiving study treatment. Overall number analyzed is the number of participants with available data at the given timepoint. Only categories for which there was at least 1 participant are reported.

The endometrial biopsy results was categorized as: normal results categorized as atrophic/inactive or proliferative, unsatisfactory with endometrial thickness ≤4 mm and missing biopsy with endometrial thickness ≤4 mm; abnormal results categorized as polyp, hyperplasia, and carcinoma; unknown result categorized as unsatisfactory with endometrial thickness >4 mm, missing biopsy with endometrial thickness >4 mm, unsatisfactory without transvaginal ultrasonography (TVU) result and missing biopsy without TVU result. The duration of estradiol exposure was combination of studies PR-04409.3 and PR-04509.

Outcome measures

Measure	WC3011 Estradiol Vaginal Cream: Less Than 92 Days n=7 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for a median exposure of less than 92 days.	WC3011 Estradiol Vaginal Cream: 92-182 Days n=27 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 92 to 182 days.	WC3011 Estradiol Vaginal Cream: 183-273 Days n=19 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 183 to 273 days.	WC3011 Estradiol Vaginal Cream: More Than 273 Days n=255 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of more than 273 days.
Number of Participants With Endometrial Biopsy Results at Final Visit Unknown: Missing Biopsy Without TVU Result	3 Participants	9 Participants	6 Participants	6 Participants
Number of Participants With Endometrial Biopsy Results at Final Visit Normal Biopsy: Atrophic	3 Participants	10 Participants	7 Participants	166 Participants
Number of Participants With Endometrial Biopsy Results at Final Visit Normal Biopsy: Proliferative	0 Participants	1 Participants	1 Participants	3 Participants
Number of Participants With Endometrial Biopsy Results at Final Visit Normal Biopsy: Unsatisfactory With Endometrial Thickness ≤4 mm	0 Participants	3 Participants	4 Participants	48 Participants
Number of Participants With Endometrial Biopsy Results at Final Visit Normal Biopsy: Missing Biopsy With Endometrial Thickness ≤4 mm	1 Participants	1 Participants	1 Participants	21 Participants
Number of Participants With Endometrial Biopsy Results at Final Visit Abnormal Biopsy: Polyp	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Endometrial Biopsy Results at Final Visit Unknown: Unsatisfactory With Endometrial Thickness >4 mm	0 Participants	1 Participants	0 Participants	6 Participants
Number of Participants With Endometrial Biopsy Results at Final Visit Unknown: Missing Biopsy With Endometrial Thickness >4 mm	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Endometrial Biopsy Results at Final Visit Unknown: Unsatisfactory Without TVU Result	0 Participants	2 Participants	0 Participants	3 Participants

SECONDARY outcome

Timeframe: Baseline (Baseline/Visit 1 for this study was the same as Final Visit/Visit 5 for completers of PR-04409.3) to Weeks 4, 8, 16, 24, 32, 40 and Final Visit (Day closest to Day 281)

Population: All participants who received at least 1 dose of study drug in Study PR-04509. Number analyzed is the number of participants with available data at the given timepoint.

Self-Assessment of the symptoms of VVA was evaluated for vaginal dryness, vaginal Itching, dysuria, and dyspareunia by a questionnaire. Questionnaire consisted of 5 questions scaled from 0 to 3 level of intensity, where 0-none indicated symptom not present; 1-mild indicated symptom is present but may be intermittent; does not interfere with your activities or lifestyle; 2-moderate indicated symptom is present, aware of the symptom but activities and lifestyle are only occasionally affected; 3-severe indicated usually aware and bothered by the symptom and have modified your activities and/or lifestyle due to the symptom. Higher score indicated most bothersome symptoms. A negative change from Baseline indicates improvement. Participants at Final visit/Visit 7 included those who were to complete all the evaluations in the study including who prematurely withdrew from the study.

Outcome measures

Measure	WC3011 Estradiol Vaginal Cream: Less Than 92 Days n=101 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for a median exposure of less than 92 days.	WC3011 Estradiol Vaginal Cream: 92-182 Days n=56 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 92 to 182 days.	WC3011 Estradiol Vaginal Cream: 183-273 Days n=99 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 183 to 273 days.	WC3011 Estradiol Vaginal Cream: More Than 273 Days n=52 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of more than 273 days.
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Dryness-Baseline	1.2 score on a scale Standard Deviation 0.92	1.5 score on a scale Standard Deviation 0.91	1.2 score on a scale Standard Deviation 0.87	1.5 score on a scale Standard Deviation 1.06
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Dryness-Change From Baseline to Week 4	-0.3 score on a scale Standard Deviation 0.71	-0.3 score on a scale Standard Deviation 0.79	-0.3 score on a scale Standard Deviation 0.62	-0.2 score on a scale Standard Deviation 0.61
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Dryness-Change From Baseline to Week 8	-0.4 score on a scale Standard Deviation 0.81	-0.5 score on a scale Standard Deviation 0.80	-0.4 score on a scale Standard Deviation 0.65	-0.4 score on a scale Standard Deviation 0.64
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Dryness-Change From Baseline to Week 16	-0.5 score on a scale Standard Deviation 0.75	-0.6 score on a scale Standard Deviation 0.91	-0.4 score on a scale Standard Deviation 0.72	-0.3 score on a scale Standard Deviation 0.80
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Dryness-Change From Baseline to Week 24	-0.6 score on a scale Standard Deviation 0.80	-0.6 score on a scale Standard Deviation 0.78	-0.3 score on a scale Standard Deviation 0.72	-0.3 score on a scale Standard Deviation 0.85
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Dryness-Change From Baseline to Week 32	-0.5 score on a scale Standard Deviation 0.88	-0.7 score on a scale Standard Deviation 0.75	-0.3 score on a scale Standard Deviation 0.68	-0.4 score on a scale Standard Deviation 0.95
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Dryness-Change From Baseline to Week 40	-0.5 score on a scale Standard Deviation 0.87	-0.6 score on a scale Standard Deviation 0.86	-0.4 score on a scale Standard Deviation 0.78	-0.5 score on a scale Standard Deviation 0.94
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Dryness-Change From Baseline to Final Visit	-0.4 score on a scale Standard Deviation 0.89	-0.6 score on a scale Standard Deviation 0.89	-0.3 score on a scale Standard Deviation 0.76	-0.5 score on a scale Standard Deviation 0.90
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Itching-Baseline	0.6 score on a scale Standard Deviation 0.73	0.5 score on a scale Standard Deviation 0.71	0.5 score on a scale Standard Deviation 0.70	0.5 score on a scale Standard Deviation 0.67
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Itching-Change From Baseline to Week 4	-0.3 score on a scale Standard Deviation 0.63	-0.0 score on a scale Standard Deviation 0.66	-0.2 score on a scale Standard Deviation 0.60	-0.0 score on a scale Standard Deviation 0.80
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Itching-Change From Baseline to Week 8	-0.2 score on a scale Standard Deviation 0.74	-0.1 score on a scale Standard Deviation 0.64	-0.3 score on a scale Standard Deviation 0.63	0.0 score on a scale Standard Deviation 0.68
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Itching-Change From Baseline to Week 16	-0.3 score on a scale Standard Deviation 0.77	-0.0 score on a scale Standard Deviation 0.69	-0.1 score on a scale Standard Deviation 0.70	0.1 score on a scale Standard Deviation 0.47
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Itching-Change From Baseline to Week 24	-0.3 score on a scale Standard Deviation 0.74	-0.2 score on a scale Standard Deviation 0.59	-0.2 score on a scale Standard Deviation 0.72	0.0 score on a scale Standard Deviation 0.58
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Itching-Change From Baseline to Week 32	-0.2 score on a scale Standard Deviation 0.69	-0.2 score on a scale Standard Deviation 0.64	-0.2 score on a scale Standard Deviation 0.64	-0.1 score on a scale Standard Deviation 0.59
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Itching-Change From Baseline to Week 40	-0.3 score on a scale Standard Deviation 0.80	-0.3 score on a scale Standard Deviation 0.66	-0.3 score on a scale Standard Deviation 0.71	-0.0 score on a scale Standard Deviation 0.47
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Vaginal Itching-Change From Baseline to Final Visit	-0.3 score on a scale Standard Deviation 0.78	-0.3 score on a scale Standard Deviation 0.67	-0.3 score on a scale Standard Deviation 0.71	-0.0 score on a scale Standard Deviation 0.64
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dysuria-Baseline	0.1 score on a scale Standard Deviation 0.42	0.2 score on a scale Standard Deviation 0.49	0.1 score on a scale Standard Deviation 0.33	0.1 score on a scale Standard Deviation 0.43
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dysuria-Change From Baseline to Week 4	-0.1 score on a scale Standard Deviation 0.37	-0.0 score on a scale Standard Deviation 0.50	-0.0 score on a scale Standard Deviation 0.25	-0.1 score on a scale Standard Deviation 0.33
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dysuria-Change From Baseline to Week 8	-0.1 score on a scale Standard Deviation 0.41	-0.0 score on a scale Standard Deviation 0.44	0.0 score on a scale Standard Deviation 0.35	-0.0 score on a scale Standard Deviation 0.20
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dysuria-Change From Baseline to Week 16	-0.1 score on a scale Standard Deviation 0.41	-0.1 score on a scale Standard Deviation 0.51	-0.0 score on a scale Standard Deviation 0.28	0.0 score on a scale Standard Deviation 0.14
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dysuria-Change From Baseline to Week 24	-0.1 score on a scale Standard Deviation 0.29	-0.2 score on a scale Standard Deviation 0.47	-0.0 score on a scale Standard Deviation 0.28	0.0 score on a scale Standard Deviation 0.21
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dysuria-Change From Baseline to Week 32	-0.1 score on a scale Standard Deviation 0.33	-0.1 score on a scale Standard Deviation 0.54	-0.0 score on a scale Standard Deviation 0.29	0.0 score on a scale Standard Deviation 0.22
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dysuria-Change From Baseline to Week 40	-0.1 score on a scale Standard Deviation 0.30	-0.1 score on a scale Standard Deviation 0.41	0.0 score on a scale Standard Deviation 0.37	0.0 score on a scale Standard Deviation 0.27
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dysuria-Change From Baseline to Final Visit	-0.1 score on a scale Standard Deviation 0.32	-0.1 score on a scale Standard Deviation 0.49	0.0 score on a scale Standard Deviation 0.40	0.0 score on a scale Standard Deviation 0.28
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dyspareunia-Baseline	1.3 score on a scale Standard Deviation 1.14	1.3 score on a scale Standard Deviation 1.14	1.2 score on a scale Standard Deviation 1.08	1.6 score on a scale Standard Deviation 1.24
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dyspareunia-Change From Baseline to Week 4	-0.3 score on a scale Standard Deviation 0.69	-0.5 score on a scale Standard Deviation 0.69	-0.2 score on a scale Standard Deviation 0.66	-0.5 score on a scale Standard Deviation 0.80
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dyspareunia-Change From Baseline to Week 8	-0.3 score on a scale Standard Deviation 0.82	-0.5 score on a scale Standard Deviation 0.77	-0.3 score on a scale Standard Deviation 0.63	-0.5 score on a scale Standard Deviation 1.13
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dyspareunia-Change From Baseline to Week 16	-0.5 score on a scale Standard Deviation 0.93	-0.6 score on a scale Standard Deviation 0.85	-0.4 score on a scale Standard Deviation 0.83	-0.5 score on a scale Standard Deviation 0.88
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dyspareunia-Change From Baseline to Week 24	-0.6 score on a scale Standard Deviation 0.96	-0.6 score on a scale Standard Deviation 0.85	-0.4 score on a scale Standard Deviation 0.86	-0.6 score on a scale Standard Deviation 1.01
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dyspareunia-Change From Baseline to Week 32	-0.5 score on a scale Standard Deviation 0.95	-0.7 score on a scale Standard Deviation 0.94	-0.4 score on a scale Standard Deviation 0.78	-0.6 score on a scale Standard Deviation 0.93
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dyspareunia-Change From Baseline to Week 40	-0.6 score on a scale Standard Deviation 0.99	-0.5 score on a scale Standard Deviation 0.82	-0.3 score on a scale Standard Deviation 0.72	-0.7 score on a scale Standard Deviation 1.06
Change From Baseline in Participants Self-Assessment of the Symptoms of Vulvovaginal Atrophy (VVA) at Each Post-baseline Timepoints Dyspareunia-Change From Baseline to Final Visit	-0.5 score on a scale Standard Deviation 0.94	-0.6 score on a scale Standard Deviation 0.91	-0.3 score on a scale Standard Deviation 0.72	-0.6 score on a scale Standard Deviation 1.15

SECONDARY outcome

Timeframe: Baseline (Baseline/Visit 1 for this study was the same as Final Visit/Visit 5 for completers of PR-04409.3) to Week 40 and Final Visit (Day closest to Day 281)

Population: All participants who received at least 1 dose of study drug in Study PR-04509. Number analyzed is the number of participants with available data at the given timepoint.

Vaginal wall smears were collected from each participant. The smears were sent to the central laboratory for analysis to determine the percentage of superficial cells. Participants at Final visit/Visit 7 included those who were to complete all the evaluations in the study including who prematurely withdrew from the study.

Outcome measures

Measure	WC3011 Estradiol Vaginal Cream: Less Than 92 Days n=101 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for a median exposure of less than 92 days.	WC3011 Estradiol Vaginal Cream: 92-182 Days n=56 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 92 to 182 days.	WC3011 Estradiol Vaginal Cream: 183-273 Days n=99 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 183 to 273 days.	WC3011 Estradiol Vaginal Cream: More Than 273 Days n=52 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of more than 273 days.
Change From Baseline in Vaginal Cytology: Percentage of Superficial Vaginal Cells Baseline	10.4 percentage of superficial cells Standard Deviation 11.73	4.0 percentage of superficial cells Standard Deviation 7.72	16.1 percentage of superficial cells Standard Deviation 18.77	3.1 percentage of superficial cells Standard Deviation 7.99
Change From Baseline in Vaginal Cytology: Percentage of Superficial Vaginal Cells Change From Baseline to Week 40	12.8 percentage of superficial cells Standard Deviation 21.26	17.6 percentage of superficial cells Standard Deviation 18.21	0.5 percentage of superficial cells Standard Deviation 20.69	13.9 percentage of superficial cells Standard Deviation 24.56
Change From Baseline in Vaginal Cytology: Percentage of Superficial Vaginal Cells Change From Baseline to Final Visit	11.0 percentage of superficial cells Standard Deviation 20.98	15.9 percentage of superficial cells Standard Deviation 17.59	-0.2 percentage of superficial cells Standard Deviation 21.79	13.0 percentage of superficial cells Standard Deviation 23.02

SECONDARY outcome

Timeframe: Baseline (Baseline/Visit 1 for this study was the same as Final Visit/Visit 5 for completers of PR-04409.3) to Week 40 and Final Visit (Day closest to Day 281)

Population: All participants who received at least 1 dose of study drug in Study PR-04509. Number analyzed is the number of participants with available data at the given timepoint.

Vaginal wall smears were collected from each participant. The smears were sent to the central laboratory for analysis to determine the percentage of parabasal cells. Participants at Final visit/Visit 7 included those who were to complete all the evaluations in the study including who prematurely withdrew from the study.

Outcome measures

Measure	WC3011 Estradiol Vaginal Cream: Less Than 92 Days n=101 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for a median exposure of less than 92 days.	WC3011 Estradiol Vaginal Cream: 92-182 Days n=56 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 92 to 182 days.	WC3011 Estradiol Vaginal Cream: 183-273 Days n=99 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 183 to 273 days.	WC3011 Estradiol Vaginal Cream: More Than 273 Days n=52 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of more than 273 days.
Change From Baseline in Vaginal Cytology: Percentage of Parabasal Vaginal Cells Baseline	9.7 percentage of parabasal cells Standard Deviation 24.34	42.2 percentage of parabasal cells Standard Deviation 41.46	12.0 percentage of parabasal cells Standard Deviation 29.28	34.2 percentage of parabasal cells Standard Deviation 38.74
Change From Baseline in Vaginal Cytology: Percentage of Parabasal Vaginal Cells Change From Baseline to Week 40	0.0 percentage of parabasal cells Standard Deviation 20.78	-42.2 percentage of parabasal cells Standard Deviation 42.00	-1.5 percentage of parabasal cells Standard Deviation 33.28	-21.2 percentage of parabasal cells Standard Deviation 36.83
Change From Baseline in Vaginal Cytology: Percentage of Parabasal Vaginal Cells Change From Baseline to Final Visit	-0.4 percentage of parabasal cells Standard Deviation 22.30	-36.3 percentage of parabasal cells Standard Deviation 43.18	1.2 percentage of parabasal cells Standard Deviation 34.67	-24.0 percentage of parabasal cells Standard Deviation 36.80

SECONDARY outcome

Timeframe: Baseline (Baseline/Visit 1 for this study was the same as Final Visit/Visit 5 for completers of PR-04409.3) to Week 40 and Final Visit (Day closest to Day 281)

Population: All participants who received at least 1 dose of study drug in Study PR-04509. Number analyzed is the number of participants with available data at the given timepoint.

Vaginal pH was obtained at final visit of the study. The pH was a numeric value from 0 to 14 expressing the acidity or alkalinity of the vaginal fluids where 7 was neutral, lower values were more acidic (values of 0-6) and higher values more alkaline (values of 8-14). A negative change from Baseline indicates improvement. Participants at Final visit/Visit 7 included those who were to complete all the evaluations in the study including who prematurely withdrew from the study.

Outcome measures

Measure	WC3011 Estradiol Vaginal Cream: Less Than 92 Days n=101 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for a median exposure of less than 92 days.	WC3011 Estradiol Vaginal Cream: 92-182 Days n=56 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 92 to 182 days.	WC3011 Estradiol Vaginal Cream: 183-273 Days n=99 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 183 to 273 days.	WC3011 Estradiol Vaginal Cream: More Than 273 Days n=52 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of more than 273 days.
Change From Baseline in Vaginal pH Baseline	5.5 score on a scale Standard Deviation 0.81	6.2 score on a scale Standard Deviation 1.06	5.4 score on a scale Standard Deviation 0.80	6.1 score on a scale Standard Deviation 0.99
Change From Baseline in Vaginal pH Change From Baseline to Week 40	-0.3 score on a scale Standard Deviation 0.97	-1.0 score on a scale Standard Deviation 1.24	-0.2 score on a scale Standard Deviation 1.04	-0.8 score on a scale Standard Deviation 0.95
Change From Baseline in Vaginal pH Change From Baseline to Final Visit	-0.2 score on a scale Standard Deviation 1.04	-1.0 score on a scale Standard Deviation 1.19	-0.1 score on a scale Standard Deviation 1.08	-1.0 score on a scale Standard Deviation 1.04

SECONDARY outcome

Timeframe: Baseline (Baseline/Visit 1 for this study was the same as Final Visit/Visit 5 for completers of PR-04409.3) to Week 40 and Final Visit (Day closest to Day 281)

Population: All participants who received at least 1 dose of study drug in Study PR-04509. Number analyzed is the number of participants with available data at the given timepoint.

Investigator's assessment of vaginal health was performed by visual inspection of the vagina with respect to the signs of VVA: atrophy, pallor, vaginal dryness, friability, and petechiae scored on a 4-point scale where: 0=none, 1=mild, 2=moderate, or 3= severe. The negative change from Baseline indicates improvement. Participants at Final visit/Visit 7 included those who were to complete all the evaluations in the study including who prematurely withdrew from the study.

Outcome measures

Measure	WC3011 Estradiol Vaginal Cream: Less Than 92 Days n=101 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for a median exposure of less than 92 days.	WC3011 Estradiol Vaginal Cream: 92-182 Days n=56 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 92 to 182 days.	WC3011 Estradiol Vaginal Cream: 183-273 Days n=99 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 183 to 273 days.	WC3011 Estradiol Vaginal Cream: More Than 273 Days n=52 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of more than 273 days.
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Atrophy-Baseline	1.1 score on a scale Standard Deviation 0.70	1.5 score on a scale Standard Deviation 0.76	1.1 score on a scale Standard Deviation 0.69	1.4 score on a scale Standard Deviation 0.80
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Atrophy-Change From Baseline to Week 40	-0.3 score on a scale Standard Deviation 0.79	-0.7 score on a scale Standard Deviation 0.82	-0.3 score on a scale Standard Deviation 0.81	-0.5 score on a scale Standard Deviation 0.77
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Atrophy-Change From Baseline to Final Visit	-0.2 score on a scale Standard Deviation 0.82	-0.6 score on a scale Standard Deviation 0.80	-0.2 score on a scale Standard Deviation 0.84	-0.6 score on a scale Standard Deviation 0.84
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Pallor-Baseline	1.1 score on a scale Standard Deviation 0.78	1.5 score on a scale Standard Deviation 0.83	1.0 score on a scale Standard Deviation 0.74	1.3 score on a scale Standard Deviation 0.77
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Pallor-Change From Baseline to Week 40	-0.4 score on a scale Standard Deviation 0.81	-0.8 score on a scale Standard Deviation 1.00	-0.3 score on a scale Standard Deviation 0.79	-0.5 score on a scale Standard Deviation 0.77
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Pallor-Change From Baseline to Final Visit	-0.4 score on a scale Standard Deviation 0.83	-0.6 score on a scale Standard Deviation 0.99	-0.2 score on a scale Standard Deviation 0.82	-0.6 score on a scale Standard Deviation 0.77
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Dryness-Baseline	1.0 score on a scale Standard Deviation 0.81	1.4 score on a scale Standard Deviation 0.89	1.0 score on a scale Standard Deviation 0.78	1.1 score on a scale Standard Deviation 1.01
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Dryness-Change From Baseline to Week 40	-0.4 score on a scale Standard Deviation 0.73	-1.0 score on a scale Standard Deviation 0.92	-0.4 score on a scale Standard Deviation 0.87	-0.4 score on a scale Standard Deviation 0.86
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Dryness-Change From Baseline to Final Visit	-0.4 score on a scale Standard Deviation 0.75	-0.8 score on a scale Standard Deviation 0.97	-0.3 score on a scale Standard Deviation 0.92	-0.5 score on a scale Standard Deviation 0.94
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Friability-Baseline	0.4 score on a scale Standard Deviation 0.67	0.6 score on a scale Standard Deviation 0.82	0.3 score on a scale Standard Deviation 0.59	0.5 score on a scale Standard Deviation 0.75
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Friability-Change From Baseline to Week 40	-0.2 score on a scale Standard Deviation 0.57	-0.5 score on a scale Standard Deviation 0.85	-0.2 score on a scale Standard Deviation 0.67	-0.2 score on a scale Standard Deviation 0.69
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Friability-Change From Baseline to Final Visit	-0.2 score on a scale Standard Deviation 0.55	-0.4 score on a scale Standard Deviation 0.88	-0.1 score on a scale Standard Deviation 0.73	-0.3 score on a scale Standard Deviation 0.73
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Petechiae-Baseline	0.3 score on a scale Standard Deviation 0.63	0.6 score on a scale Standard Deviation 0.80	0.2 score on a scale Standard Deviation 0.59	0.4 score on a scale Standard Deviation 0.75
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Petechiae-Change From Baseline at Week 40	-0.1 score on a scale Standard Deviation 0.45	-0.5 score on a scale Standard Deviation 0.80	-0.1 score on a scale Standard Deviation 0.56	-0.1 score on a scale Standard Deviation 0.65
Change From Baseline as Per Investigator's Assessment of Each of the Signs of VVA Petechiae-Change From Baseline to Final Visit	-0.1 score on a scale Standard Deviation 0.44	-0.5 score on a scale Standard Deviation 0.79	-0.1 score on a scale Standard Deviation 0.54	-0.2 score on a scale Standard Deviation 0.63

SECONDARY outcome

Timeframe: Up to Week 40

Population: All participants who received at least 1 dose of study drug in Study PR-04509.

An adverse event is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal (investigational) product, whether or not related to medicinal (investigational) product. TEAE are defined as those AEs with onset date on or after the first dose date of study drug in Study PR-04509, or adverse events that worsen after the first dose date of study drug in Study PR-04509.

Outcome measures

Measure	WC3011 Estradiol Vaginal Cream: Less Than 92 Days n=308 Participants WC3011 estradiol vaginal cream applied vaginally 3 times a week for a median exposure of less than 92 days.	WC3011 Estradiol Vaginal Cream: 92-182 Days WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 92 to 182 days.	WC3011 Estradiol Vaginal Cream: 183-273 Days WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of 183 to 273 days.	WC3011 Estradiol Vaginal Cream: More Than 273 Days WC3011 estradiol vaginal cream applied vaginally 3 times a week for median exposure of more than 273 days.
Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE)	195 Participants	—	—	—

Adverse Events

WC3011 Estradiol Vaginal Cream

Serious events: 8 serious events

Other events: 50 other events

Deaths: 0 deaths

Serious adverse events

Measure	WC3011 Estradiol Vaginal Cream n=308 participants at risk WC3011 estradiol vaginal cream applied vaginally 3 times a week for up to 40 weeks.
Hepatobiliary disorders Cholelithiasis	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Vascular disorders Femoral artery occlusion	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Nervous system disorders Dysarthria	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Psychiatric disorders Confusional state	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Ear and labyrinth disorders Vertigo	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Infections and infestations Appendicitis	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Cardiac disorders Atrial fibrillation	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Cardiac disorders Palpitations	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Nervous system disorders Transient ischaemic attack	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.32% 1/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.

Other adverse events

Measure	WC3011 Estradiol Vaginal Cream n=308 participants at risk WC3011 estradiol vaginal cream applied vaginally 3 times a week for up to 40 weeks.
Infections and infestations Vulvovaginal Mycotic Infection	7.5% 23/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Infections and infestations Upper Respiratory Tract Infection	5.5% 17/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.
Infections and infestations Sinusitis	5.2% 16/308 • Up to Week 40 All participants who received at least 1 dose of study drug in Study PR-04509.

Additional Information

Therapeutic Area, Head

Allergan

Phone: 714-246-4500

Email: clinicaltrials@allergan.com

Results disclosure agreements

• Principal investigator is a sponsor employee A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
• Publication restrictions are in place

Restriction type: OTHER