The Vaginal Health Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Vaginal Health Trial - Effects of Vaginal Estradiol Tablet and Moisturizing Gel on Postmenopausal Vaginal Symptoms

Conditions
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Atrophy of Vagina, Menopause, Dyspareunia (Female)

Intervention / Treatment
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* Drug: Vagifem
* Device: Replens
* Other: Placebo tablet
* Other: Placebo gel


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vagifem<br>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<br>* One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.<br>* Other names: vaginal estradiol;Other: Placebo gel<br>* Dispensed in visually identical tube and gel form to Replens.<br>|
| Active Comparator: Replens<br>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<br>* 2.5 gm to be applied vaginally every 3 days over 12 weeks.<br>* Other names: non-hormonal hydrophilic non-prescriptive vaginal gel;Other: Placebo tablet<br>* Dispensed in visually identical bottle and tablet form to Vagifem.<br>|
| Placebo Comparator: Placebo<br>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<br>* Dispensed in visually identical bottle and tablet form to Vagifem.<br>Other: Placebo gel<br>* Dispensed in visually identical tube and gel form to Replens.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaginal Symptoms Index | 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. | Baseline, Week 4, Week 12 | 
| Female Sexual Function Index | 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. | Baseline, Week 4, Week 12 | 
| Treatment Satisfaction | Likert Scale 0 = no to 10 = complete satisfaction. | Week 12 | 
| Patient Benefit Evaluation | Patient Benefit Evaluation: Overall, do you believe that you experienced a meaningful benefit from the study medication? (Yes/No). | Week 12 | 
| pH | Objective measures of genitourinary atrophy: pH (<5 or >5) at week 12 | Week 12 | 
| Vaginal Maturation Index | Objective Measures of Genitourinary Atrophy: Vaginal Maturation Index (VMI) described by % parabasal, intermediate, and superficial cells (≤ 5% or >5% superficial cells) at week 12 | Week 12 |