Trial Outcomes & Findings for Effect of Preoperative Estrogen Treatment on Connective Tissues of the Pelvic Floor (NCT NCT01778985)

NCT ID: NCT01778985

Last Updated: 2014-10-02

Results Overview

Will assess vaginal wall histology - thickness of lamina propria.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 30 participants
• Primary outcome timeframe: Time of surgery, i.e. after 6-8 weeks of intervention
• Results posted on: 2014-10-02

Participant Flow

Participant milestones

Measure	Premarin Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Overall Study STARTED	15	15
Overall Study COMPLETED	8	12
Overall Study NOT COMPLETED	7	3

Reasons for withdrawal

Measure	Premarin Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Overall Study Lost to Follow-up	1	0
Overall Study Physician Decision	2	2
Overall Study Protocol Violation	4	1

Baseline Characteristics

Effect of Preoperative Estrogen Treatment on Connective Tissues of the Pelvic Floor

Baseline characteristics by cohort

Measure	Premarin n=15 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=15 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo	Total n=30 Participants Total of all reporting groups
Age, Continuous	55.1 years STANDARD_DEVIATION 5.4 • n=5 Participants	58.9 years STANDARD_DEVIATION 5.1 • n=7 Participants	57.2 years STANDARD_DEVIATION 5.5 • n=5 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	15 Participants n=7 Participants	30 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Non-Hispanic White	7 participants n=5 Participants	2 participants n=7 Participants	9 participants n=5 Participants
Race/Ethnicity, Customized Non-Hispanic Black	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants
Race/Ethnicity, Customized Hispanic White	7 participants n=5 Participants	10 participants n=7 Participants	17 participants n=5 Participants
Parity	3 deliveries n=5 Participants	4 deliveries n=7 Participants	4 deliveries n=5 Participants
Body mass index	29.2 kg/m^2 STANDARD_DEVIATION 5.4 • n=5 Participants	31.7 kg/m^2 STANDARD_DEVIATION 4.1 • n=7 Participants	30.5 kg/m^2 STANDARD_DEVIATION 4.9 • n=5 Participants

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Population: Patients completing surgery with biopsy specimens available for analysis ("intention to treat")

Will assess vaginal wall histology - thicknesses of epithelium

Outcome measures

Measure	Premarin n=12 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Vaginal Wall Composition: Epithelium (Intention to Treat)	413.9 microns Standard Error 63.7	314.1 microns Standard Error 42.6

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Population: Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication ("per protocol")

Will assess vaginal wall histology - thicknesses of epithelium

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Vaginal Wall Composition: Epithelium (Per-Protocol)	550.5 microns Standard Error 45.1	314.1 microns Standard Error 42.6

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Population: Patients completing surgery with biopsy specimens available for analysis ("intention to treat")

Will assess vaginal wall histology - thicknesses of muscularis

Outcome measures

Measure	Premarin n=12 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Vaginal Wall Composition: Muscularis (Intention to Treat)	5670.4 microns Standard Error 2154.7	2807.1 microns Standard Error 622.5

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Population: Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication ("per protocol")

Will assess vaginal wall histology - thicknesses of muscularis

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Vaginal Wall Composition: Muscularis (Per-Protocol)	7570.7 microns Standard Error 3193.1	2807.1 microns Standard Error 622.5

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Population: Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication ("per protocol")

Data represent ratio of total mRNA relative to postmenopausal external control.

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
hCOL1A1, Per-Protocol	2.19 ratio Interval 1.52 to 2.91	0.37 ratio Interval 0.18 to 0.7

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Population: Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication ("per protocol")

Will assess hydroxy-proline assays as index of amount of collagen

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Total Collagen Content in Vaginal Muscularis, (Per-Protocol)	302.6 mg collagen per mg muscularis wet weight Standard Error 146.1	94.86 mg collagen per mg muscularis wet weight Standard Error 29.86

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Population: All specimens with sufficient amount of tissue available for zymography analysis were used.

Will assess zymograms for total matrix metalloprotease (MMP) 9 activity

Outcome measures

Measure	Premarin n=7 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=8 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Vaginal Wall Degradative Activity, Muscularis, MMP-9	37.03 Relative Units/mg protein Standard Error 15.06	132.34 Relative Units/mg protein Standard Error 35.48

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Will assess vaginal wall histology - thickness of lamina propria.

Outcome measures

Measure	Premarin n=12 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Vaginal Wall Composition: Lamina Propria (Intention to Treat)	1042.3 microns Standard Error 169.8	895.1 microns Standard Error 153.3

PRIMARY outcome

Timeframe: Time of surgery, i.e. 6-8 weeks of intervention

Will assess vaginal wall histology - thickness of lamina propria

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Vaginal Wall Composition: Lamina Propria (Per-Protocol)	1133.4 microns Standard Error 166.2	895.1 microns Standard Error 153.3

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Data represent ratio of total mRNA relative to postmenopausal external control.

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
hCOL3, (Per-Protocol)	.92 ratio Interval 0.6 to 1.44	.37 ratio Interval 0.18 to 0.95

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Data represent ratio of total mRNA relative to postmenopausal external control.

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Lysyl Oxidase (LOX) (Per-Protocol)	.74 ratio Standard Error .14	.51 ratio Standard Error .09

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Data represent ratio of total mRNA relative to postmenopausal external control.

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
LOXL1 (Per-Protocol)	.64 ratio Standard Error .12	.69 ratio Standard Error .14

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Data represent ratio of total mRNA relative to postmenopausal external control.

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Tropoelastin (Per-Protocol)	.78 ratio Standard Error .24	.69 ratio Standard Error .11

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Data represent ratio of total mRNA relative to postmenopausal external control.

Outcome measures

Measure	Premarin n=8 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=12 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
TGFB1 (Per-Protocol)	.61 ratio Standard Error .13	.81 ratio Standard Error .11

PRIMARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Population: All specimens with sufficient amount of tissue available for zymography analysis were used.

Will assess zymograms for total matrix metalloprotease (MMP) 9 activity

Outcome measures

Measure	Premarin n=7 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=8 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Vaginal Wall Degradative Activity, Mucosa, MMP-9	8.97 Relative Units/mg protein Standard Error 1.77	56.73 Relative Units/mg protein Standard Error 23.20

SECONDARY outcome

Timeframe: Baseline

Outcome measures

Measure	Premarin n=15 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=15 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Serum Estrone Levels, Baseline	18.0 pg/mL Standard Error 2.3	18.5 pg/mL Standard Error 3.9

SECONDARY outcome

Timeframe: Time of surgery

Outcome measures

Measure	Premarin n=12 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=13 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Serum Estrone Levels, Surgery	22.8 pg/mL Standard Error 3.5	24.9 pg/mL Standard Error 6.5

SECONDARY outcome

Timeframe: Baseline

Outcome measures

Measure	Premarin n=15 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=15 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Serum Estradiol Levels, Baseline	11.1 pg/mL Standard Error 3.7	8.4 pg/mL Standard Error 1.6

SECONDARY outcome

Timeframe: Time of surgery

Outcome measures

Measure	Premarin n=12 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=13 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Serum Estradiol Levels, Surgery	7.8 pg/mL Standard Error 1.3	11.6 pg/mL Standard Error 2.7

SECONDARY outcome

Timeframe: Time of surgery, i.e. after 6-8 weeks of intervention

Population: In both study arms, 13 participants did undergo surgery and, therefore, had an estimated blood loss value available for analysis. However, one patient each from both study arms did not have biopsies taken (technical considerations/ intraoperative decision or conversion from total to supracervical hysterectomy without ability to collect biopsy).

Intraoperative estimated blood loss

Outcome measures

Measure	Premarin n=13 Participants Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=13 Participants Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Estimated Blood Loss	285 mL Standard Deviation 134	285 mL Standard Deviation 270

Adverse Events

Premarin

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Premarin n=15 participants at risk Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Premarin	Placebo n=15 participants at risk Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery. Placebo
Reproductive system and breast disorders Vulvovaginal pain	13.3% 2/15 • Number of events 2 • 6 - 8 weeks of preoperative use of vaginal estrogen (vs placebo) cream	0.00% 0/15 • 6 - 8 weeks of preoperative use of vaginal estrogen (vs placebo) cream
Reproductive system and breast disorders Annoyance with cream use	6.7% 1/15 • Number of events 1 • 6 - 8 weeks of preoperative use of vaginal estrogen (vs placebo) cream	0.00% 0/15 • 6 - 8 weeks of preoperative use of vaginal estrogen (vs placebo) cream

Additional Information

David D. Rahn, M.D.

University of Texas Southwestern Medical Center

Phone: 214-648-6430

Email: david.rahn@utsouthwestern.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place