The Vaginal Health Trial

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02516202
• Collaborator: University of Minnesota (Other), Massachusetts General Hospital (Other), University of California, San Diego (Other), University of Washington (Other), Kaiser Permanente (Other)
• Enrollment: 302
• Locations: 2
• Arms: 3
• Actual Duration (Months): 15
• Patients Per Site: 151
• Patients Per Site Per Month: 10.1

Study Details

Study Description

Brief Summary

This is a new application from the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) Clinical Trials network. Here we propose to conduct a large multicenter trial comparing two common treatments, a vaginal hormone tablet and an over-the-counter gel, with placebo to evaluate their effects on bothersome vaginal symptoms and sexual function, and to create a biorepository of specimens for future translational, mechanistic research on the etiology of vaginal symptoms.

Condition or Disease	Intervention/Treatment	Phase
Atrophy of Vagina; Menopause; Dyspareunia (Female)	Drug: Vagifem; Device: Replens; Other: Placebo tablet; Other: Placebo gel	Phase 3

Detailed Description

The Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) Clinical Trials network was established in 2009. By the end of 2014, the network completed 4 clinical trials testing 7 interventions in approximately 1000 women ages 40-62 with vasomotor (VMS) and other menopause symptoms.

The current trial will evaluate a relatively understudied area of menopause - vaginal health and sexual function. This is a 3-arm, randomized, controlled, double-blind, clinical trial among postmenopausal women ages 45-70.

Our primary aim is to evaluate the effectiveness of ultra-low dose vaginal estradiol (Vagifem 10 mcg), non-hormonal hydrophilic non-prescriptive vaginal gel (Replens) and placebo in reducing the Most Bothersome Symptom (MBS) severity. Choices for MBS include vulvovaginal itching, pain, dryness, irritation, or pain with penetration.

Secondary aims include an evaluation of a composite score of vaginal symptoms, sexual function, treatment satisfaction, menopause quality of life, and objective measures of genitourinary atrophy. We will also create a biorepository of vaginal and blood specimens. In a subset of women, we will examine whether treatment response is related to: a) the post-menopausal vaginal microbiome; b) vaginal mucosal inflammation; and c) reproductive hormone profiles. The in-depth focus on the mechanisms associated with postmenopausal vaginal symptoms will use state of the art microbiologic techniques on longitudinally collected biologic specimens and will guide future translational studies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 302 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Vaginal Health Trial - Effects of Vaginal Estradiol Tablet and Moisturizing Gel on Postmenopausal Vaginal Symptoms
• Actual Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Vagifem One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo gel visually similar to Replens composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks.	Drug: Vagifem; One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.; Other Names: vaginal estradiol ; Other: Placebo gel; Dispensed in visually identical tube and gel form to Replens.
Active Comparator: Replens One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel, with 2.5 gm applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks.	Device: Replens; 2.5 gm to be applied vaginally every 3 days over 12 weeks.; Other Names: non-hormonal hydrophilic non-prescriptive vaginal gel ; Other: Placebo tablet; Dispensed in visually identical bottle and tablet form to Vagifem.
Placebo Comparator: Placebo One hundred participants will be randomized into the 'placebo' arm of the study. This arm is comprised of two placebo preparations; placebo tablet and placebo gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo gel. The product is an inert hydroxyethylcellulose gel (pH adjusted).	Other: Placebo tablet; Dispensed in visually identical bottle and tablet form to Vagifem.; Other: Placebo gel; Dispensed in visually identical tube and gel form to Replens.

Outcome Measures

Primary Outcome Measures

1. Most Bothersome Symptom (MBS) Severity [Baseline, Week 4, Week 12]

   Mean change from baseline to 12 weeks in the severity of the MBS on a scale of 0-3, better to worse.

Secondary Outcome Measures

1. Vaginal Symptoms Index [Baseline, Week 4, Week 12]

   Mean change from baseline to 12 weeks in composite Vaginal Symptoms Index (VSI). The VSI is a Modified Bachman scale measuring vulvovaginal itching, dryness, irritation, soreness, and pain with sexual activity among sexually active women, each rated 0=none to 3=severe, and then averaged for a total score of 0-3.

2. Female Sexual Function Index [Baseline, Week 4, Week 12]

   Female Sexual Function Index (FSFI); Evaluate dyspareunia, sexual function and distress. A composite score from 2 (not sexually active and no desire) to 36 and 6 domains.

3. Treatment Satisfaction [Week 12]

   Likert Scale 0 = no to 10 = complete satisfaction.

4. Patient Benefit Evaluation [Week 12]

   Patient Benefit Evaluation: Overall, do you believe that you experienced a meaningful benefit from the study medication? (Yes/No).

5. pH [Week 12]

   Objective measures of genitourinary atrophy: pH (<5 or >5) at week 12

6. Vaginal Maturation Index [Week 12]

   Objective Measures of Genitourinary Atrophy: Vaginal Maturation Index (VMI) described by % parabasal, intermediate, and superficial cells (≤ 5% or >5% superficial cells) at week 12

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 70 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Females aged 45-70 years

• 2 or more years since last natural menstrual period, or surgical menopause (bilateral oophorectomy)

• At least 1 vaginal symptom (inside or outside the vagina) reported from the following list, experienced in the past 30 days which is moderate or severe:

• Dryness at least once a week

• Itching at least once a week

• Irritation at least once a week

• Soreness/Pain at least once a week

• Pain associated with sexual activity at least once

• Signed informed consent

Exclusion Criteria

• Current unexplained abnormal genital bleeding (or any unevaluated bleeding since menopause)

• Currently pregnant, attempting pregnancy or breast feeding

• Current acute vaginal infection (as indicated by wet mount at V1)

• Pelvic or vaginal surgery in prior 60 days

• Antibiotic use in the past 30 days

• Women under age 55 with endometrial ablation

• Women under age 55 with hysterectomy and at least one ovary

• Current cancer treatment (exception basal or squamous skin cell cancers)

• Current or past thromboembolic disease (pulmonary embolus or deep vein thrombosis, not including thrombophlebitis), myocardial infarction or stroke

• Current severe liver disease

• Current or past breast or endometrial cancer or pre-cancer

• Blood clotting disorder (e.g., Factor V Leiden, prothrombin mutation, protein C, protein or antithrombin deficiency)

• Porphyria

• Current or past lichen sclerosus or lichen planus

• History of adverse reaction to vaginal estrogen or Replens

• Use of any systemic reproductive hormones (hormonal contraception, postmenopausal hormone therapies, SERMS) in the past 2 months

• Use of hormonal contraception in the past year

• Use of any type of vaginal estrogen product (however interested women will be allowed to join the study if they abstain from use during the month preceding enrollment)

• Use of any type of vaginal moisturizer, douche, vaginal prebiotic or probiotic, or soap in the vagina in the past month (however interested women will be allowed to join the study if they abstain from use during the month preceding enrollment)

• Unwilling to abstain from use of any non-study vaginal moisturizer, vaginal estrogen, douche, or soap in the vagina throughout the trial

• Unable to follow instructions, complete questionnaires, or physically unable to place product in the vagina

• Current participation in another drug trial or intervention study

• Chronic vulvo-vaginal symptoms in the 5 years before menopause (defined as a vaginal or vulvar condition requiring more than 4 visits to a health care provider in a given year)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota	Minneapolis	Minnesota	United States	55455
2	Kaiser Permanente Washington Health Research Institute	Seattle	Washington	United States	98101

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• University of Minnesota
• Massachusetts General Hospital
• University of California, San Diego
• University of Washington
• Kaiser Permanente

Investigators

• Principal Investigator: Katherine A Guthrie, PhD, Fred Hutchinson Cancer Center
• Principal Investigator: Susan D Reed, MD, University of Washington
• Principal Investigator: Andrea Z LaCroix, PhD, University of California, San Diego
• Principal Investigator: Caroline Mitchell, MD, MPH, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 1, 2016
• Informed Consent Form - Nov 1, 2016

More Information

Publications

None provided.

• Responsible Party: Katherine Guthrie, Principal Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT02516202
• Other Study ID Numbers: MsFLASH 05; 8378
• First Posted: Aug 5, 2015
• Last Update Posted: Jul 12, 2018
• Last Verified: Jun 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Additional relevant MeSH terms: Dyspareunia; Estradiol

Study Results

Participant Flow

Arm/Group Title	Vagifem	Replens	Placebo
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.	One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.	One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.
Period Title: Overall Study
STARTED	102	100	100
COMPLETED	100	99	97
NOT COMPLETED	2	1	3

Baseline Characteristics

Arm/Group Title	Vagifem	Replens	Placebo	Total
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.	One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.	One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.	Total of all reporting groups
Overall Participants	102	100	100	302
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (4)	61 (4)	61 (4)	61 (4)
Sex: Female, Male (Count of Participants)
Female	102 100%	100 100%	100 100%	302 100%
Male	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	87 85.3%	90 90%	90 90%	267 88.4%
African American	7 6.9%	3 3%	2 2%	12 4%
Other / unknown	8 7.8%	7 7%	8 8%	23 7.6%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27 (5)	26 (4)	26 (6)	26 (5)
Education (Count of Participants)
High school diploma / GED or less	2 2%	3 3%	6 6%	11 3.6%
School after high school	31 30.4%	27 27%	31 31%	89 29.5%
College graduate	67 65.7%	70 70%	63 63%	200 66.2%
Missing	2 2%	0 0%	0 0%	2 0.7%
Marital status (Count of Participants)
Never married	8 7.8%	2 2%	4 4%	14 4.6%
Divorced or widowed	10 9.8%	8 8%	12 12%	30 9.9%
Married or like relationship	83 81.4%	90 90%	84 84%	257 85.1%
Missing	1 1%	0 0%	0 0%	1 0.3%
Smoking (Count of Participants)
Never	66 64.7%	67 67%	66 66%	199 65.9%
Past	31 30.4%	33 33%	32 32%	96 31.8%
Current	4 3.9%	0 0%	2 2%	6 2%
Missing	1 1%	0 0%	0 0%	1 0.3%
Alcohol Use (Count of Participants)
0 drinks / week	30 29.4%	31 31%	28 28%	89 29.5%
1-6 drinks / week	50 49%	46 46%	53 53%	149 49.3%
≥ 7 drinks / week	21 20.6%	23 23%	19 19%	63 20.9%
Missing	1 1%	0 0%	0 0%	1 0.3%
Menopause Quality of Life Questionnaire total (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.3 (1.2)	3.2 (1.1)	3.3 (1.0)	3.3 (1.1)
Patient Health Questionnaire 8 depression (Count of Participants)
None (0-4)	69 67.6%	75 75%	69 69%	213 70.5%
Mild (5-9)	25 24.5%	22 22%	23 23%	70 23.2%
Moderate - severe (≥10)	7 6.9%	3 3%	8 8%	18 6%
Missing	1 1%	0 0%	0 0%	1 0.3%
Generalized Anxiety Disorder Questionnaire 7 (Count of Participants)
None (0-4)	64 62.7%	75 75%	64 64%	203 67.2%
Mild (5-9)	25 24.5%	21 21%	24 24%	70 23.2%
Moderate - severe (≥10)	12 11.8%	4 4%	12 12%	28 9.3%
Missing	1 1%	0 0%	0 0%	1 0.3%
Sexually active (Count of Participants)
Yes	81 79.4%	80 80%	84 84%	245 81.1%
No	20 19.6%	20 20%	16 16%	56 18.5%
Missing	1 1%	0 0%	0 0%	1 0.3%
Female Sexual Distress Scale-Revised, item 1, distressed about sex life (Count of Participants)
Never / rarely	15 14.7%	12 12%	18 18%	45 14.9%
Occasionally	33 32.4%	33 33%	33 33%	99 32.8%
Frequently / always	53 52%	54 54%	49 49%	156 51.7%
Missing	1 1%	1 1%	0 0%	2 0.7%
Female Sexual Function Index total (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	15.2 (539)	15.2 (6.5)	16.1 (6.6)	15.5 (6.4)
Vaginal pH (Count of Participants)
≤ 5	18 17.6%	12 12%	9 9%	39 12.9%
> 5	81 79.4%	87 87%	90 90%	258 85.4%
Missing	3 2.9%	1 1%	1 1%	5 1.7%
Vaginal maturation index (Count of Participants)
≤ 5% superficial cells	86 84.3%	78 78%	81 81%	245 81.1%
> 5% superficial cells	6 5.9%	11 11%	7 7%	24 7.9%
Missing	10 9.8%	11 11%	12 12%	33 10.9%
Most bothersome symptom (Count of Participants)
Vulvar and/or vaginal itching	10 9.8%	4 4%	6 6%	20 6.6%
Vulvar and/or vaginal pain	5 4.9%	7 7%	2 2%	14 4.6%
Vaginal dryness	23 22.5%	17 17%	23 23%	63 20.9%
Vulvar and/or vaginal irritation	7 6.9%	4 4%	8 8%	19 6.3%
Pain with vaginal penetration	54 52.9%	68 68%	60 60%	182 60.3%
Missing	3 2.9%	0 0%	1 1%	4 1.3%
Self-reported health (Count of Participants)
Excellent	26 25.5%	27 27%	20 20%	73 24.2%
Very good	41 40.2%	55 55%	47 47%	143 47.4%
Good	33 32.4%	15 15%	30 30%	78 25.8%
Fair / poor	1 1%	3 3%	3 3%	7 2.3%
Missing	1 1%	0 0%	0 0%	1 0.3%

Outcome Measures

1. Primary Outcome

Title	Most Bothersome Symptom (MBS) Severity
Description	Mean change from baseline to 12 weeks in the severity of the MBS on a scale of 0-3, better to worse.
Time Frame	Baseline, Week 4, Week 12

Outcome Measure Data

Analysis Population Description

Analysis includes participants with MBS data at baseline and either week 4 or 12.

Arm/Group Title	Vagifem	Replens	Placebo
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.	One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.	One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.
Measure Participants	97	99	98
Week 4 minus baseline	-1.2	-1.0	-0.2
Week 12 minus baseline	-1.4	-1.2	-1.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vagifem, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments	P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
	Method	Regression, Linear
	Comments	Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Replens, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments	P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025
	Method	Regression, Linear
	Comments	Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures

2. Secondary Outcome

Title	Vaginal Symptoms Index
Description	Mean change from baseline to 12 weeks in composite Vaginal Symptoms Index (VSI). The VSI is a Modified Bachman scale measuring vulvovaginal itching, dryness, irritation, soreness, and pain with sexual activity among sexually active women, each rated 0=none to 3=severe, and then averaged for a total score of 0-3.
Time Frame	Baseline, Week 4, Week 12

Outcome Measure Data

Analysis Population Description

Analysis includes participants with VSI data at baseline and either week 4 or 12.

Arm/Group Title	Vagifem	Replens	Placebo
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.	One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.	One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.
Measure Participants	100	99	99
Week 4 minus baseline	-0.7	-0.5	-0.6
Week 12 minus baseline	-0.9	-0.7	-0.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vagifem, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments	P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
	Method	Regression, Linear
	Comments	Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Replens, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments	P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
	Method	Regression, Linear
	Comments	Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures

3. Secondary Outcome

Title	Female Sexual Function Index
Description	Female Sexual Function Index (FSFI); Evaluate dyspareunia, sexual function and distress. A composite score from 2 (not sexually active and no desire) to 36 and 6 domains.
Time Frame	Baseline, Week 4, Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vagifem	Replens	Placebo
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.	One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.	One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.
Measure Participants	70	81	82
Week 4 minus baseline	3.1	2.9	3.2
Week 12 minus baseline	5.4	3.1	4.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vagifem, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.64
	Comments	P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
	Method	Regression, Linear
	Comments	Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Replens, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments	P-values from active treatment vs. placebo contrasts in a repeated measures linear model of outcome as a function of treatment arm, clinical site, week, and baseline outcome. The a priori threshold for statistical significance was 0.025.
	Method	Regression, Linear
	Comments	Robust standard errors were calculated using generalized estimating equations to account for within-participant correlation between repeated measures

4. Secondary Outcome

Title	Treatment Satisfaction
Description	Likert Scale 0 = no to 10 = complete satisfaction.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vagifem	Replens	Placebo
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.	One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.	One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.
Measure Participants	98	99	95
Mean (Standard Deviation) [units on a scale]	8.6 (2.6)	7.7 (3.2)	8.1 (3.0)

5. Secondary Outcome

Title	Patient Benefit Evaluation
Description	Patient Benefit Evaluation: Overall, do you believe that you experienced a meaningful benefit from the study medication? (Yes/No).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vagifem	Replens	Placebo
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.	One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.	One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.
Measure Participants	102	100	100
Yes	79 77.5%	58 58%	62 62%
No	20 19.6%	41 41%	34 34%
Missing	3 2.9%	1 1%	4 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vagifem, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	p-value calculation includes 195 participants with known responses at week 12.
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	pH
Description	Objective measures of genitourinary atrophy: pH (<5 or >5) at week 12
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Sample includes 247 participants with pH > 5 at baseline and non-missing data on pH at week 12

Arm/Group Title	Vagifem	Replens	Placebo
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.	One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.	One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.
Measure Participants	78	85	84
Week 12 pH > 5	42 41.2%	77 77%	74 74%
Week 12 pH ≤ 5	36 35.3%	8 8%	10 10%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vagifem, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Replens, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Vaginal Maturation Index
Description	Objective Measures of Genitourinary Atrophy: Vaginal Maturation Index (VMI) described by % parabasal, intermediate, and superficial cells (≤ 5% or >5% superficial cells) at week 12
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Sample includes 223 participants with VMI ≤ 5% superficial cells at baseline and non-missing VMI data at week 12

Arm/Group Title	Vagifem	Replens	Placebo
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.	One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.	One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.
Measure Participants	79	73	71
Week 12 VMI ≤ 5%	34 33.3%	65 65%	63 63%
Week 12 VMI > 5%	45 44.1%	8 8%	8 8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vagifem, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Replens, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.95
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	Adverse event data was collected for each participant from randomization through the 12-week visit.
Arm/Group Title	Vagifem		Replens		Placebo
Arm/Group Description	One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study. Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol. A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks. Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.		One hundred participants will be randomized into the Replens® 'active' arm. These women will receive a tube containing Replens® vaginal gel. 2.5 gm to be applied vaginally every 3 days over 12 weeks. Replens® is a bioadhesive polycarbophil-based moisturizing vaginal gel containing; purified water (vehicle humectant), glycerin (moisturizer), mineral oil (as a moisturizer), polycarbophil and carbomer homopolymer type B (allow the product to stick to the vaginal wall), hydrogenated palm oil glyceride (moisturizer), sorbic acid (preservative, antimicrobial), methylparaben, sodium hydroxide (adjusts pH of product so it is suitable for vaginal use). A placebo vaginal tablet visually identical to Vagifem® is inserted daily for 2 weeks, then 2 days/week for remaining 10 weeks. Replens: 2.5 gm to be applied vaginally every 3 days over 12 weeks. Placebo: Dispensed in visually identical bottle and tablet form.		One hundred participants will be randomized into the 'placebo arm' of the study. This arm is comprised of two placebo preparations; placebo vaginal tablet and placebo vaginal gel applied on the same schedule as 'active' arms. The placebo tablet coating and excipient ingredients will be the same as are used for Vagifem®; the coating is made of hypromellose and polyethylene glycol and the excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Placebo vaginal gel. The product is a inert hydroxyethylcellulose gel (pH adjusted). Placebo: Dispensed in visually identical bottle and tablet form. Placebo: Dispensed in visually identical tube and gel form.
All Cause Mortality
	Vagifem		Replens		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/102 (0%)		0/100 (0%)		0/100 (0%)
Serious Adverse Events
	Vagifem		Replens		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/102 (2.9%)		1/100 (1%)		1/100 (1%)
Gastrointestinal disorders
Hospitalization for dehydration	0/102 (0%)		1/100 (1%)		0/100 (0%)
Musculoskeletal and connective tissue disorders
Hospitalization for back pain	0/102 (0%)		0/100 (0%)		1/100 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/102 (1%)		0/100 (0%)		0/100 (0%)
Lymphoma	1/102 (1%)		0/100 (0%)		0/100 (0%)
Breast cancer	1/102 (1%)		0/100 (0%)		0/100 (0%)
Other (Not Including Serious) Adverse Events
	Vagifem		Replens		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/99 (26.3%)		22/99 (22.2%)		24/99 (24.2%)
Reproductive system and breast disorders
Increased vaginal secretions	14/92 (15.2%)		16/99 (16.2%)		14/96 (14.6%)
Vaginal itching	6/75 (8%)		6/79 (7.6%)		6/84 (7.1%)
Breast tenderness	3/97 (3.1%)		0/98 (0%)		2/96 (2.1%)
Vaginal spotting or bleeding	0/99 (0%)		1/99 (1%)		0/99 (0%)
Skin and subcutaneous tissue disorders
Skin rash outside the vagina	4/96 (4.2%)		0/97 (0%)		1/97 (1%)
Body rash	2/95 (2.1%)		1/97 (1%)		5/98 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.