Atrophic Vaginitis
Conditions
Brief summary
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
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
Interventions
DRUGEstriol
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.
DRUGEstradiol valerate
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
DRUGVanicream Lite
Vanicream Lite 0.5 grams applied to vaginal introitus daily for two weeks and then twice weekly for 10 weeks
Sponsors
National Center for Advancing Translational Sciences (NCATS)
Maire Mac Bride
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 75 Years
Healthy volunteers
Yes
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | baseline, 12 weeks | 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. |
Secondary
| Measure | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Estriol 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 | 18 |
| Estradiol 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 | 19 |
| Placebo Vanicream Lite 0.5 grams applied to vaginal introitus daily for two weeks and then twice weekly for 10 weeks | 19 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Estriol | Estradiol | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 19 Participants | 19 Participants | 56 Participants |
| Region of Enrollment United States | 18 participants | 19 participants | 19 participants | 56 participants |
| Sex: Female, Male Female | 18 Participants | 19 Participants | 19 Participants | 56 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 18 | 0 / 19 | 1 / 19 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 | 0 / 19 |
Outcome results
Primary
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.
Time frame: baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estriol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Dryness Severity | 3.2 units on a scale | Standard Deviation 2.3 |
| Estriol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Dryness Bothersomeness | 2.3 units on a scale | Standard Deviation 2.8 |
| Estriol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Itching Severity | 1.4 units on a scale | Standard Deviation 1.6 |
| Estriol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Itching Bothersomeness | 1.3 units on a scale | Standard Deviation 1.6 |
| Estriol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Burning Severity | 2.1 units on a scale | Standard Deviation 2.6 |
| Estriol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Burning Bothersomeness | 1.9 units on a scale | Standard Deviation 2.7 |
| Estradiol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Burning Bothersomeness | 1.5 units on a scale | Standard Deviation 2.6 |
| Estradiol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Dryness Severity | 2.0 units on a scale | Standard Deviation 3.3 |
| Estradiol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Itching Bothersomeness | 2.6 units on a scale | Standard Deviation 3 |
| Estradiol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Burning Severity | 1.5 units on a scale | Standard Deviation 2.5 |
| Estradiol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Dryness Bothersomeness | 2.1 units on a scale | Standard Deviation 2.7 |
| Estradiol | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Itching Severity | 2.6 units on a scale | Standard Deviation 2.9 |
| Placebo | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Dryness Bothersomeness | 3.6 units on a scale | Standard Deviation 3.1 |
| Placebo | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Itching Severity | 1.9 units on a scale | Standard Deviation 2.8 |
| Placebo | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Burning Bothersomeness | 1.1 units on a scale | Standard Deviation 3.1 |
| Placebo | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Itching Bothersomeness | 1.7 units on a scale | Standard Deviation 2.5 |
| Placebo | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Dryness Severity | 2.7 units on a scale | Standard Deviation 2.7 |
| Placebo | Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12 | Burning Severity | 1.0 units on a scale | Standard Deviation 2.9 |
Comparison: Dryness severity: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.42ANOVA
Comparison: Dryness bothersomeness: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.22ANOVA
Comparison: Itching severity: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.37ANOVA
Comparison: Itching bothersomeness: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.27ANOVA
Comparison: Burning severity: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.46ANOVA
Comparison: Burning bothersomeness: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.67ANOVA
Secondary
Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks
Time frame: baseline, 2 weeks, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estriol | Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 12 | -0.4 pg/ml | Standard Deviation 3 |
| Estriol | Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 2 | 0.0 pg/ml | Standard Deviation 1.1 |
| Estriol | Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks | Week 2 vs. Week 12 | -0.3 pg/ml | Standard Deviation 2.8 |
| Estradiol | Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 12 | 0.6 pg/ml | Standard Deviation 1.7 |
| Estradiol | Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 2 | -1.7 pg/ml | Standard Deviation 3.3 |
| Estradiol | Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks | Week 2 vs. Week 12 | 1.9 pg/ml | Standard Deviation 3.6 |
| Placebo | Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 2 | 0.5 pg/ml | Standard Deviation 1.2 |
| Placebo | Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks | Week 2 vs. Week 12 | -0.3 pg/ml | Standard Deviation 1.1 |
| Placebo | Change in Serum Estradiol (E2) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 12 | 0.2 pg/ml | Standard Deviation 1.6 |
Comparison: Baseline vs. week 2: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.007ANOVA
Comparison: Baseline vs. week 12: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.32ANOVA
Comparison: Week 2 vs. week 12: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.02ANOVA
Secondary
Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks
Time frame: baseline, 2 weeks, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estriol | Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 12 | 1.0 pg/ml | Standard Deviation 4.4 |
| Estriol | Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 2 | -0.9 pg/ml | Standard Deviation 4.6 |
| Estriol | Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks | Week 2 vs. Week 12 | 2.2 pg/ml | Standard Deviation 5.6 |
| Estradiol | Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 12 | 1.2 pg/ml | Standard Deviation 5 |
| Estradiol | Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 2 | -1.6 pg/ml | Standard Deviation 3.8 |
| Estradiol | Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks | Week 2 vs. Week 12 | 1.5 pg/ml | Standard Deviation 3.4 |
| Placebo | Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 2 | 0.5 pg/ml | Standard Deviation 4.5 |
| Placebo | Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks | Week 2 vs. Week 12 | 0.6 pg/ml | Standard Deviation 4.8 |
| Placebo | Change in Serum Estrone (E1) Levels Between Baseline, 2 Weeks, and 12 Weeks | Baseline vs. Week 12 | 1.1 pg/ml | Standard Deviation 3.5 |
Comparison: Baseline vs. week 2: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.33ANOVA
Comparison: Baseline vs. week 12: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.99ANOVA
Comparison: Week 2 vs. week 12: P-value for the global F-test testing for all treatment arm effects equal.p-value: 0.58ANOVA