Atrophy of Vagina, Dyspareunia (Female), Menopause
Conditions
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.
Interventions
DRUGVagifem
One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.
DEVICEReplens
2.5 gm to be applied vaginally every 3 days over 12 weeks.
OTHERPlacebo tablet
Dispensed in visually identical bottle and tablet form to Vagifem.
OTHERPlacebo gel
Dispensed in visually identical tube and gel form to Replens.
Sponsors
University of Minnesota
Massachusetts General Hospital
University of California, San Diego
University of Washington
Kaiser Permanente
Fred Hutchinson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 70 Years
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Treatment Satisfaction | Week 12 | Likert Scale 0 = no to 10 = complete satisfaction. |
| 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. |
| pH | Week 12 | Objective measures of genitourinary atrophy: pH (\<5 or \>5) at week 12 |
| 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 |
| Patient Benefit Evaluation | Week 12 | Patient Benefit Evaluation: Overall, do you believe that you experienced a meaningful benefit from the study medication? (Yes/No). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 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. | 102 |
| Replens 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. | 100 |
| Placebo 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. | 100 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 | 1 |
| Overall Study | Stopped Follow-up | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Replens | Placebo | Vagifem | Total |
|---|---|---|---|---|
| Age, Continuous | 61 years STANDARD_DEVIATION 4 | 61 years STANDARD_DEVIATION 4 | 61 years STANDARD_DEVIATION 4 | 61 years STANDARD_DEVIATION 4 |
| Alcohol Use 0 drinks / week | 31 Participants | 28 Participants | 30 Participants | 89 Participants |
| Alcohol Use 1-6 drinks / week | 46 Participants | 53 Participants | 50 Participants | 149 Participants |
| Alcohol Use ≥ 7 drinks / week | 23 Participants | 19 Participants | 21 Participants | 63 Participants |
| Alcohol Use Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Body Mass Index (BMI) | 26 kg/m^2 STANDARD_DEVIATION 4 | 26 kg/m^2 STANDARD_DEVIATION 6 | 27 kg/m^2 STANDARD_DEVIATION 5 | 26 kg/m^2 STANDARD_DEVIATION 5 |
| Education College graduate | 70 Participants | 63 Participants | 67 Participants | 200 Participants |
| Education High school diploma / GED or less | 3 Participants | 6 Participants | 2 Participants | 11 Participants |
| Education Missing | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Education School after high school | 27 Participants | 31 Participants | 31 Participants | 89 Participants |
| Female Sexual Distress Scale-Revised, item 1, distressed about sex life Frequently / always | 54 Participants | 49 Participants | 53 Participants | 156 Participants |
| Female Sexual Distress Scale-Revised, item 1, distressed about sex life Missing | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Female Sexual Distress Scale-Revised, item 1, distressed about sex life Never / rarely | 12 Participants | 18 Participants | 15 Participants | 45 Participants |
| Female Sexual Distress Scale-Revised, item 1, distressed about sex life Occasionally | 33 Participants | 33 Participants | 33 Participants | 99 Participants |
| Female Sexual Function Index total | 15.2 units on a scale STANDARD_DEVIATION 6.5 | 16.1 units on a scale STANDARD_DEVIATION 6.6 | 15.2 units on a scale STANDARD_DEVIATION 539 | 15.5 units on a scale STANDARD_DEVIATION 6.4 |
| Generalized Anxiety Disorder Questionnaire 7 Mild (5-9) | 21 Participants | 24 Participants | 25 Participants | 70 Participants |
| Generalized Anxiety Disorder Questionnaire 7 Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Generalized Anxiety Disorder Questionnaire 7 Moderate - severe (≥10) | 4 Participants | 12 Participants | 12 Participants | 28 Participants |
| Generalized Anxiety Disorder Questionnaire 7 None (0-4) | 75 Participants | 64 Participants | 64 Participants | 203 Participants |
| Marital status Divorced or widowed | 8 Participants | 12 Participants | 10 Participants | 30 Participants |
| Marital status Married or like relationship | 90 Participants | 84 Participants | 83 Participants | 257 Participants |
| Marital status Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Marital status Never married | 2 Participants | 4 Participants | 8 Participants | 14 Participants |
| Menopause Quality of Life Questionnaire total | 3.2 units on a scale STANDARD_DEVIATION 1.1 | 3.3 units on a scale STANDARD_DEVIATION 1 | 3.3 units on a scale STANDARD_DEVIATION 1.2 | 3.3 units on a scale STANDARD_DEVIATION 1.1 |
| Most bothersome symptom Missing | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Most bothersome symptom Pain with vaginal penetration | 68 Participants | 60 Participants | 54 Participants | 182 Participants |
| Most bothersome symptom Vaginal dryness | 17 Participants | 23 Participants | 23 Participants | 63 Participants |
| Most bothersome symptom Vulvar and/or vaginal irritation | 4 Participants | 8 Participants | 7 Participants | 19 Participants |
| Most bothersome symptom Vulvar and/or vaginal itching | 4 Participants | 6 Participants | 10 Participants | 20 Participants |
| Most bothersome symptom Vulvar and/or vaginal pain | 7 Participants | 2 Participants | 5 Participants | 14 Participants |
| Patient Health Questionnaire 8 depression Mild (5-9) | 22 Participants | 23 Participants | 25 Participants | 70 Participants |
| Patient Health Questionnaire 8 depression Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Patient Health Questionnaire 8 depression Moderate - severe (≥10) | 3 Participants | 8 Participants | 7 Participants | 18 Participants |
| Patient Health Questionnaire 8 depression None (0-4) | 75 Participants | 69 Participants | 69 Participants | 213 Participants |
| Race/Ethnicity, Customized Race African American | 3 Participants | 2 Participants | 7 Participants | 12 Participants |
| Race/Ethnicity, Customized Race Other / unknown | 7 Participants | 8 Participants | 8 Participants | 23 Participants |
| Race/Ethnicity, Customized Race White | 90 Participants | 90 Participants | 87 Participants | 267 Participants |
| Self-reported health Excellent | 27 Participants | 20 Participants | 26 Participants | 73 Participants |
| Self-reported health Fair / poor | 3 Participants | 3 Participants | 1 Participants | 7 Participants |
| Self-reported health Good | 15 Participants | 30 Participants | 33 Participants | 78 Participants |
| Self-reported health Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Self-reported health Very good | 55 Participants | 47 Participants | 41 Participants | 143 Participants |
| Sex: Female, Male Female | 100 Participants | 100 Participants | 102 Participants | 302 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sexually active Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sexually active No | 20 Participants | 16 Participants | 20 Participants | 56 Participants |
| Sexually active Yes | 80 Participants | 84 Participants | 81 Participants | 245 Participants |
| Smoking Current | 0 Participants | 2 Participants | 4 Participants | 6 Participants |
| Smoking Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Smoking Never | 67 Participants | 66 Participants | 66 Participants | 199 Participants |
| Smoking Past | 33 Participants | 32 Participants | 31 Participants | 96 Participants |
| Vaginal maturation index ≤ 5% superficial cells | 78 Participants | 81 Participants | 86 Participants | 245 Participants |
| Vaginal maturation index > 5% superficial cells | 11 Participants | 7 Participants | 6 Participants | 24 Participants |
| Vaginal maturation index Missing | 11 Participants | 12 Participants | 10 Participants | 33 Participants |
| Vaginal pH ≤ 5 | 12 Participants | 9 Participants | 18 Participants | 39 Participants |
| Vaginal pH > 5 | 87 Participants | 90 Participants | 81 Participants | 258 Participants |
| Vaginal pH Missing | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 102 | 0 / 100 | 0 / 100 |
| other Total, other adverse events | 26 / 99 | 22 / 99 | 24 / 99 |
| serious Total, serious adverse events | 3 / 102 | 1 / 100 | 1 / 100 |
Outcome results
Primary
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.
Time frame: Baseline, Week 4, Week 12
Population: Analysis includes participants with MBS data at baseline and either week 4 or 12.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Vagifem | Most Bothersome Symptom (MBS) Severity | Week 4 minus baseline | -1.2 units on a scale |
| Vagifem | Most Bothersome Symptom (MBS) Severity | Week 12 minus baseline | -1.4 units on a scale |
| Replens | Most Bothersome Symptom (MBS) Severity | Week 4 minus baseline | -1.0 units on a scale |
| Replens | Most Bothersome Symptom (MBS) Severity | Week 12 minus baseline | -1.2 units on a scale |
| Placebo | Most Bothersome Symptom (MBS) Severity | Week 4 minus baseline | -0.2 units on a scale |
| Placebo | Most Bothersome Symptom (MBS) Severity | Week 12 minus baseline | -1.3 units on a scale |
p-value: 0.25Regression, Linear
p-value: 0.31Regression, Linear
Secondary
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.
Time frame: Baseline, Week 4, Week 12
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Vagifem | Female Sexual Function Index | Week 4 minus baseline | 3.1 units on a scale |
| Vagifem | Female Sexual Function Index | Week 12 minus baseline | 5.4 units on a scale |
| Replens | Female Sexual Function Index | Week 4 minus baseline | 2.9 units on a scale |
| Replens | Female Sexual Function Index | Week 12 minus baseline | 3.1 units on a scale |
| Placebo | Female Sexual Function Index | Week 4 minus baseline | 3.2 units on a scale |
| Placebo | Female Sexual Function Index | Week 12 minus baseline | 4.5 units on a scale |
p-value: 0.64Regression, Linear
p-value: 0.17Regression, Linear
Secondary
Patient Benefit Evaluation
Patient Benefit Evaluation: Overall, do you believe that you experienced a meaningful benefit from the study medication? (Yes/No).
Time frame: Week 12
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vagifem | Patient Benefit Evaluation | No | 20 Participants |
| Vagifem | Patient Benefit Evaluation | Yes | 79 Participants |
| Vagifem | Patient Benefit Evaluation | Missing | 3 Participants |
| Replens | Patient Benefit Evaluation | No | 41 Participants |
| Replens | Patient Benefit Evaluation | Yes | 58 Participants |
| Replens | Patient Benefit Evaluation | Missing | 1 Participants |
| Placebo | Patient Benefit Evaluation | Yes | 62 Participants |
| Placebo | Patient Benefit Evaluation | Missing | 4 Participants |
| Placebo | Patient Benefit Evaluation | No | 34 Participants |
p-value: 0.02Chi-squared
Secondary
pH
Objective measures of genitourinary atrophy: pH (\<5 or \>5) at week 12
Time frame: Week 12
Population: Sample includes 247 participants with pH \> 5 at baseline and non-missing data on pH at week 12
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vagifem | pH | Week 12 pH > 5 | 42 Participants |
| Vagifem | pH | Week 12 pH ≤ 5 | 36 Participants |
| Replens | pH | Week 12 pH > 5 | 77 Participants |
| Replens | pH | Week 12 pH ≤ 5 | 8 Participants |
| Placebo | pH | Week 12 pH > 5 | 74 Participants |
| Placebo | pH | Week 12 pH ≤ 5 | 10 Participants |
p-value: <0.001Chi-squared
p-value: 0.6Chi-squared
Secondary
Treatment Satisfaction
Likert Scale 0 = no to 10 = complete satisfaction.
Time frame: Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vagifem | Treatment Satisfaction | 8.6 units on a scale | Standard Deviation 2.6 |
| Replens | Treatment Satisfaction | 7.7 units on a scale | Standard Deviation 3.2 |
| Placebo | Treatment Satisfaction | 8.1 units on a scale | Standard Deviation 3 |
Secondary
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
Time frame: Week 12
Population: Sample includes 223 participants with VMI ≤ 5% superficial cells at baseline and non-missing VMI data at week 12
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vagifem | Vaginal Maturation Index | Week 12 VMI ≤ 5% | 34 Participants |
| Vagifem | Vaginal Maturation Index | Week 12 VMI > 5% | 45 Participants |
| Replens | Vaginal Maturation Index | Week 12 VMI ≤ 5% | 65 Participants |
| Replens | Vaginal Maturation Index | Week 12 VMI > 5% | 8 Participants |
| Placebo | Vaginal Maturation Index | Week 12 VMI ≤ 5% | 63 Participants |
| Placebo | Vaginal Maturation Index | Week 12 VMI > 5% | 8 Participants |
p-value: <0.001Chi-squared
p-value: 0.95Chi-squared
Secondary
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.
Time frame: Baseline, Week 4, Week 12
Population: Analysis includes participants with VSI data at baseline and either week 4 or 12.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Vagifem | Vaginal Symptoms Index | Week 4 minus baseline | -0.7 units on a scale |
| Vagifem | Vaginal Symptoms Index | Week 12 minus baseline | -0.9 units on a scale |
| Replens | Vaginal Symptoms Index | Week 4 minus baseline | -0.5 units on a scale |
| Replens | Vaginal Symptoms Index | Week 12 minus baseline | -0.7 units on a scale |
| Placebo | Vaginal Symptoms Index | Week 4 minus baseline | -0.6 units on a scale |
| Placebo | Vaginal Symptoms Index | Week 12 minus baseline | -0.9 units on a scale |
p-value: 0.99Regression, Linear
p-value: 0.05Regression, Linear