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The Vaginal Health Trial

Primary Purpose

Atrophy of Vagina, Menopause, Dyspareunia (Female)

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Vagifem
Replens
Placebo tablet
Placebo gel
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Atrophy of Vagina

Eligibility Criteria

45 Years - 70 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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)

Sites / Locations

  • University of Minnesota
  • Kaiser Permanente Washington Health Research Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Vagifem

Replens

Placebo

Arm 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 gel visually similar to Replens composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks.

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.

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).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
Treatment Satisfaction
Likert Scale 0 = no to 10 = complete satisfaction.
Patient Benefit Evaluation
Patient Benefit Evaluation: Overall, do you believe that you experienced a meaningful benefit from the study medication? (Yes/No).
pH
Objective measures of genitourinary atrophy: pH (<5 or >5) at 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

Full Information

First Posted
August 3, 2015
Last Updated
June 13, 2018
Sponsor
Fred Hutchinson Cancer Center
Collaborators
University of Minnesota, Massachusetts General Hospital, University of California, San Diego, University of Washington, Kaiser Permanente
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1. Study Identification

Unique Protocol Identification Number
NCT02516202
Brief Title
The Vaginal Health Trial
Official Title
The Vaginal Health Trial - Effects of Vaginal Estradiol Tablet and Moisturizing Gel on Postmenopausal Vaginal Symptoms
Study Type
Interventional

2. Study Status

Record Verification Date
June 2018
Overall Recruitment Status
Completed
Study Start Date
April 2016 (Actual)
Primary Completion Date
May 2017 (Actual)
Study Completion Date
July 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
University of Minnesota, Massachusetts General Hospital, University of California, San Diego, University of Washington, Kaiser Permanente

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atrophy of Vagina, Menopause, Dyspareunia (Female)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
302 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Vagifem
Arm Type
Active Comparator
Arm 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 gel visually similar to Replens composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks.
Arm Title
Replens
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Vagifem
Other Intervention Name(s)
vaginal estradiol
Intervention Description
One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.
Intervention Type
Device
Intervention Name(s)
Replens
Other Intervention Name(s)
non-hormonal hydrophilic non-prescriptive vaginal gel
Intervention Description
2.5 gm to be applied vaginally every 3 days over 12 weeks.
Intervention Type
Other
Intervention Name(s)
Placebo tablet
Intervention Description
Dispensed in visually identical bottle and tablet form to Vagifem.
Intervention Type
Other
Intervention Name(s)
Placebo gel
Intervention Description
Dispensed in visually identical tube and gel form to Replens.
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
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
Title
Treatment Satisfaction
Description
Likert Scale 0 = no to 10 = complete satisfaction.
Time Frame
Week 12
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
Title
pH
Description
Objective measures of genitourinary atrophy: pH (<5 or >5) at week 12
Time Frame
Week 12
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

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Katherine A Guthrie, PhD
Organizational Affiliation
Fred Hutchinson Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Susan D Reed, MD
Organizational Affiliation
University of Washington
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Andrea Z LaCroix, PhD
Organizational Affiliation
University of California, San Diego
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Caroline Mitchell, MD, MPH
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Kaiser Permanente Washington Health Research Institute
City
Seattle
State/Province
Washington
ZIP/Postal Code
98101
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The MsFLASH Data Coordinating Center will perform the statistical analyses for the primary and secondary study results papers. Within a 12-month period after publication of the main study results, the Data Coordinating Center will prepare datasets for public release that include all data elements in the main publication with certain deletions and recoding to protect study subject confidentiality. The public release datasets will include substantial documentation in electronic form, thus allowing external investigators to independently analyze the data.
Citations:
PubMed Identifier
36374501
Citation
Mitchell CM, Larson JC, Crandall CJ, Bhasin S, LaCroix AZ, Ensrud KE, Guthrie KA, Reed SD. Association of Vaginal Estradiol Tablet With Serum Estrogen Levels in Women Who Are Postmenopausal: Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2022 Nov 1;5(11):e2241743. doi: 10.1001/jamanetworkopen.2022.41743.
Results Reference
derived
PubMed Identifier
35353163
Citation
Srinivasan S, Hua X, Wu MC, Proll S, Valint DJ, Reed SD, Guthrie KA, LaCroix AZ, Larson JC, Pepin R, Bhasin S, Raftery D, Fredricks DN, Mitchell CM. Impact of Topical Interventions on the Vaginal Microbiota and Metabolome in Postmenopausal Women: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2022 Mar 1;5(3):e225032. doi: 10.1001/jamanetworkopen.2022.5032.
Results Reference
derived
PubMed Identifier
33675793
Citation
Mitchell CM, Ma N, Mitchell AJ, Wu MC, Valint DJ, Proll S, Reed SD, Guthrie KA, Lacroix AZ, Larson JC, Pepin R, Raftery D, Fredricks DN, Srinivasan S. Association between postmenopausal vulvovaginal discomfort, vaginal microbiota, and mucosal inflammation. Am J Obstet Gynecol. 2021 Aug;225(2):159.e1-159.e15. doi: 10.1016/j.ajog.2021.02.034. Epub 2021 Mar 4.
Results Reference
derived
PubMed Identifier
33367735
Citation
Hudson PL, Ling W, Wu MC, Hayward MR, Mitchell AJ, Larson J, Guthrie KA, Reed SD, Kwon DS, Mitchell CM. Comparison of the Vaginal Microbiota in Postmenopausal Black and White Women. J Infect Dis. 2021 Dec 1;224(11):1945-1949. doi: 10.1093/infdis/jiaa780.
Results Reference
derived
PubMed Identifier
30994576
Citation
Mitchell CM, Guthrie KA, Larson J, Diem S, LaCroix AZ, Caan B, Shifren JL, Woods NF, Heiman JR, Lindau ST, Reed SD. Sexual frequency and pain in a randomized clinical trial of vaginal estradiol tablets, moisturizer, and placebo in postmenopausal women. Menopause. 2019 Aug;26(8):816-822. doi: 10.1097/GME.0000000000001341.
Results Reference
derived
PubMed Identifier
29738424
Citation
Diem SJ, Guthrie KA, Mitchell CM, Reed SD, Larson JC, Ensrud KE, LaCroix AZ. Effects of vaginal estradiol tablets and moisturizer on menopause-specific quality of life and mood in healthy postmenopausal women with vaginal symptoms: a randomized clinical trial. Menopause. 2018 Oct;25(10):1086-1093. doi: 10.1097/GME.0000000000001131.
Results Reference
derived
PubMed Identifier
29554173
Citation
Mitchell CM, Reed SD, Diem S, Larson JC, Newton KM, Ensrud KE, LaCroix AZ, Caan B, Guthrie KA. Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms: A Randomized Clinical Trial. JAMA Intern Med. 2018 May 1;178(5):681-690. doi: 10.1001/jamainternmed.2018.0116.
Results Reference
derived

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The Vaginal Health Trial

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