A Trial to Evaluate the Efficacy of Low Dose Vaginal Estrogens in the Treatment of Atrophic Vaginitis

Study Overview
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Brief Summary
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Atrophic vaginitis is a common problem that occurs in up to 40% of postmenopausal women. The main symptoms are dryness, itching and burning in and around the vagina. These symptoms in turn can cause pain with intercourse. Other symptoms can include urinary frequency and urinary urgency. These symptoms are caused by the decreasing levels of estrogens in postmenopausal women. The current treatment options include hormone replacement therapy by mouth and patch and vaginal creams, tablets and rings. The current guideline recommend using hormone therapy at the lowest dose for the shortest time. We are trying to find the lowest effective dose of estrogen cream that helps with symptoms without causing an increase in estrogens in the blood stream. We want to compare two estrogen creams, estradiol and estriol, each at very low doses, with a placebo cream. Estradiol cream is available on prescription but we want to see how effective it is at one tenth the commonly prescribed dose. Estriol cream is not commonly prescribed and is only available at compounding pharmacies. We want to see if either of these estrogens is effective at one tenth the usual dose. We also want to see if these creams are effective when massaged onto the outer part of the vagina, rather than the usual method of treatment, which is inserting them into the vagina.

Detailed Description
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This trial will measure the effects of very low doses of estradiol or estriol cream applied to the vaginal introitus for the treatment of atrophic vaginitis, a common condition affecting up to 40% of postmenopausal women. We will conduct a randomized controlled trial with three arms-estradiol, estriol and placebo. The intervention will last for 12 weeks. The outcomes we will be most interested in are the efficacy of the treatments for symptoms of atrophic vaginitis compared to placebo and whether there is any measurable systemic absorption from the locally applied estrogen creams. These outcomes will be measured, primarily, by the use of patient questionnaires and secondarily, clinical examination scores. Safety will be evaluated with serum estrogen concentrations. All measures will be collected at baseline and at the termination of the study. Hormone concentrations will be collected, additionally, at week 2. This trial will answer important questions regarding the impact of very low doses of locally applied estrogens and symptoms of atrophic vaginitis. It will provide information on effect size and validity of outcome measures. It will also give information about whether low doses of estrogen creams, locally applied to the vaginal introitus, result in systemic absorption

Official Title
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A Randomized Controlled Trial to Evaluate the Efficacy of Low Dose Vaginal Estrogens in the Treatment of Atrophic Vaginitis

Conditions
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Atrophic Vaginitis

Intervention / Treatment
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* Drug: Estriol
* Drug: Estradiol valerate
* Drug: Vanicream Lite


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women (no menses for the previous 12 months) Dryness, itching or burning in and around the vagina Discontinued hormone replacement therapy (either local or systemic) at least 3 months Exclusion Criteria: Known, suspected, or history of cancer of the breast. Known, or suspected estrogen dependent neoplasia (ovarian, endometrial). Known hypersensitivity to any component of the medications or base creams. Active deep vein thrombosis, pulmonary embolism, or history of these conditions. Active or recent (within the past year) arterial thromboembolic disease (stroke, myocardial infarct). Liver dysfunction or disease with elevation of aspartate aminotransferase (AST)>1.5x upper level of normal (ULN); Normal for females is 8-43 U/L. Undiagnosed abnormal genital bleeding. Known chronic lichen sclerosis. Known, untreated vaginal infection. Not had a normal screening mammogram within the last 15 months. Hysterectomy without oophorectomy unless 60 years or older. Women taking aromatase inhibitors or tamoxifen. Hgb <12.0 or >15.5 g/dL Urinalysis showing a urinary tract infection (UTI).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Estriol<br>Estriol 10 micrograms added to Vanicream Lite 0.5 grams applied to vaginal introitus daily for two weeks and then twice weekly for 10 weeks | Drug: Estriol<br>* Estriol 10 micrograms added to Vanicream Lite 0.5 grams applied to vaginal introitus daily for 2 weeks and then twice weekly for 10 weeks.<br>|
| Active Comparator: Estradiol<br>Estradiol valerate 10 micrograms added to Vanicream Lite 0.5 grams applied to vaginal introitus daily for two weeks and then twice weekly for 10 weeks | Drug: Estradiol valerate<br>* Estradiol valerate 10 micrograms added to Vanicream Lite 0.5 grams applied to vaginal introitus daily for two weeks and then twice weekly for 10 weeks<br>* Other names: Delestrogen;|
| Placebo Comparator: Vanicream Lite<br>Vanicream Lite 0.5 grams applied to vaginal introitus daily for two weeks and then twice weekly for 10 weeks | Drug: Vanicream Lite<br>* Vanicream Lite 0.5 grams applied to vaginal introitus daily for two weeks and then twice weekly for 10 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | The VVAQ consists of three questions asking the participant to rate the severity and how bothersome each of the symptoms of atrophic vaginitis are (dryness, itching, and burning). It is graded 0 through 10. A higher number indicates less severe and less bothersomeness of the symptom, that is, 0= very severe or bothersome, 10= least severe or bothersome. | baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks |  | baseline, 2 weeks, 12 weeks | 
| Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks |  | baseline, 2 weeks, 12 weeks |