Vaginal Atrophy
Conditions
Keywords
vaginal atrophy, breast cancer, vaginal dryness, aromatase inhibitor
Brief summary
This is a phase II, prospective, randomized, double-blind, placebo-controlled, international (Spain and Sweden) and multicentre study to explore the safety of 0.005% estriol vaginal gel in women with early stage breast cancer in treatment with Non-Steroidal Aromatase Inhibitors (NSAIs) in the adjuvant setting and symptoms of vaginal atrophy.
Detailed description
This is a phase II, prospective, randomized, double-blind, placebo-controlled, international (Spain and Sweden) and multicentre study. In the setting of postmenopausal hormone receptor positive breast cancer, treatment with aromatase inhibitors (AIs) is the most effective and well-studied therapy. Vaginal dryness is one of the most frequently reported symptom caused by this adjuvant therapy which may lead to a reduced adherence in breast cancer women. This study will explore the safety of 0.005% estriol vaginal gel in this oncological context, to demonstrate that this medicinal product is a safe option to treat the vaginal atrophy caused by AIs, without a clinically relevant influence in gonadotropins or systemic estrogen levels. The main objective is to evaluate the levels of Follicle Stimulating Hormone (FSH) after treatment with 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with Non-Steroidal Aromatase Inhibitors (NSAIs) in the adjuvant setting and symptoms of vaginal atrophy.
Interventions
DRUGestriol
0.005% estriol vaginal gel
DRUGPlacebo
placebo vaginal gel
Sponsors
Spanish Breast Cancer Research Group
ITF Research Pharma, S.L.U.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
Inclusion criteria
1. Written informed consent prior to beginning specific protocol procedures. 2. Patients must have histological confirmation of breast adenocarcinoma with stage I-IIIA, documented at a local pathology department. 3. The breast tumors must be estrogen-receptor positive and/or progesterone receptor positive (≥1% of stained tumor cells by Immunohistochemistry (IHC) as determined by the local laboratory) with any Human Epidermal Growth Factor Receptor 2(HER2) status. 4. Postmenopausal status defined as: 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels \> 40 Milli-international units per milliliter (mIU/ml) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. 5. Patient must be receiving the non-steroidal aromatase inhibitors anastrozole or letrozole as breast cancer treatment in the adjuvant setting for a minimum of 6 months. 6. Women suffering from moderate to severe vaginal dryness according to the FDA guidelines for drug development in postmenopausal women (Center for Drug Evaluation and Research, (CDER) Jan 2003). A moderate symptom will be considered if the symptom is present, bothersome and annoying, and a severe symptom will be considered if the symptom is present, bothersome and annoying, and interferes with the normal patient activity. 7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. 8. Adequate bone marrow as defined by the following laboratory values: 1. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L. 2. Platelets (plt) ≥ 100 x 109/L. 3. Hemoglobin (Hgb) ≥ 10 g/dl. 9. Patient has adequate organ function as defined by the following laboratory values: 1. Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN). 2. Bilirubin ≤ 1.5 × ULN. 3. Alkaline phosphatase ≤ 2 × ULN. 4. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2 × ULN. 10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
Exclusion criteria
1. Stage IIIB-IV breast cancer or bilateral breast cancer. 2. Treatment with any other current anti-tumoral therapy (chemotherapy, anti-Her2…etc) besides the NSAI. Pamidronate or Alendronate are permitted. 3. Prior history of other malignancy within 5 years of study entry, aside from non-melanoma skin cancer or carcinoma-in-situ of the uterine cervix adequately treated. 4. Postmenopausal uterine bleeding. Vaginal bleeding of unknown etiology. 5. Patients with endometrial thickness equal to or greater than 4 mm measured by transvaginal ultrasound. 6. Patients who have received any type of vulvovaginal treatment in the 15 days prior to the start of the study. 7. Use of any hormone, natural (phytoestrogens) or herbal products for the treatment of menopausal symptoms within the last 3 months. 8. Current or previous history of thromboembolic disease or coagulopathies. 9. Severe cardiovascular or respiratory diseases in the previous 6 months. 10. Renal Impairment. 11. Hepatitis B and/or hepatitis C carriers (unless with normal hepatic function). 12. Known human immunodeficiency virus infection. 13. Known hypersensitivity to NSAI. 14. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study. 15. Previous investigational treatment for any condition or participation in any clinical trial within 4 weeks of inclusion date.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Variation in Serum Levels of Follicle Stimulating Hormone (FSH) | from baseline to 12 weeks of treatment | Change from Baseline (mean screening-baseline) to Week 12 in Serum Levels of Follicle Stimulating Hormone (FSH) compare to natural physiological variability (screening-baseline variation) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Variation in Serum Levels of Luteinizing Hormone (LH) | Change from baseline to week 1, week 3, week 8 and week 12 | Change from (mean screening-baseline) in plasma levels of LH to Week 1, Week 3, Week 8 and Week 12 in Serum Levels of LH compare to natural physiological variability ( screening-baseline variation) |
| Variation in Plasma Levels of Estriol | Change from baseline to week 1, week 3, week 8 and week 12 | Change in plasma levels of estriol at weeks 1, 3, 8 and 12 compared to baseline |
| Variation in Plasma Levels of Estradiol | Change from baseline to week 1, week 3, week 8 and week 12 | Change in plasma levels of estradiol at weeks 1, 3, 8 and 12 compared to baseline. |
| Variation in Plasma Levels of Estrona | Change from baseline to week 1, week 3, week 8 and week 12 | Change in plasma levels of estrona at weeks 1, 3, 8 and 12 compared to baseline. |
| Changes in Vaginal pH Between Baseline and Week 3 and Week 12 | week 3 and week 12 vs baseline | Measurement of vaginal pH on the vaginal secretion using a reactive strip and compare pH value between baseline and the diferent timepoints |
| Changes in Dyspareunia | week 3 and week 12 vs baseline | Changes in dyspareunia from baseline to week 3 and week 12 Each symptom will be scored in a numeric scale from 0 to 3, as shown 0 Absence. The symptom is not present 1. The symptom is of mild intensity, without interfering in the patient's activity 2. The symptom is of moderate intensity, causing obvious discomfort to the patient 3. The symptom is stated as very irritating and severe in intensity |
| Change in Pruritus or Itching From Baseline to Week 3 and Week 12 | Change from baseline to week 3 and week 12 | Change in pruritus or itching from baseline to week 3 and week 12 Each symptom will be scored in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present 1. The symptom is of mild intensity, without interfering in the patient's activity 2. The symptom is of moderate intensity, causing obvious discomfort to the patient 3. The symptom is stated as very irritating and severe in intensity |
| Variation in Serum Levels of FSH at Week 1, Week 3 and Week 8 | Change from baseline to week 1, week 3 and week 8 | Change from Baseline (mean screening-baseline) to Week 1, Week 3 and Week 8 in Serum Levels of Follicle Stimulating Hormone (FSH) compare to natural physiological variability ( screening-baseline variation) |
| Changes in Total Score of Symptoms of Vaginal Atrophy | week 3 and week 12 vs baseline | Changes in Symptoms of vaginal atrophy (vaginal dryness, dyspareunia and pruritus) at week 3 and week 12 vs baseline. Each symptom will be scored in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present 1. The symptom is of mild intensity, without interfering in the patient's activity 2. The symptom is of moderate intensity, causing obvious discomfort to the patient 3. The symptom is stated as very irritating and severe in intensity A Global Symptoms Score will be calculated by summing the intensities of all the three symptoms of vaginal atrophy in a certain time point, thus ranging between 0 and 9. |
| Changes in Dryness of the Mucosa | week 3 and week 12 vs baseline | It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. 1. The sign is present and is considered a mild alteration 2. The sign is present and is considered a moderate alteration 3. The sign is present and is considered a severe alteration |
| Changes in Fragility of the Mucosa [Time Frame: Week 3 and Week 12 vs Baseline] | from baseline to week 3 and 12 | It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. 1. The sign is present and is considered a mild alteration 2. The sign is present and is considered a moderate alteration 3. The sign is present and is considered a severe alteration |
| Changes in Vaginal Mucosa With Flattening of Folds or Thinning | week 3 and week 12 vs baseline | It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. 1. The sign is present and is considered a mild alteration 2. The sign is present and is considered a moderate alteration 3. The sign is present and is considered a severe alteration |
| Changes in Total Score of Signs of Vaginal Atrophy Between Week 3 and Week 12 to Baseline | week 3 and week 12 vs baseline | The signs evaluated Will be the following: vaginal mucosa with flattening of folds or thinning, dryness of the mucosa and Fragility of the mucosa. It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. 1. The sign is present and is considered a mild alteration 2. The sign is present and is considered a moderate alteration 3. The sign is present and is considered a severe alteration A Total Signs Score will be calculated by summing the intensities of all the three signs of vaginal atrophy in a certain time point, thus ranging between 0 and 9. |
| Changes in Vaginal Maturation Value | week 3 and week 12 vs baseline | Vaginal cytology sample to evaluate the vaginal Maturation Value. For the cytologic evaluation, the number of parabasal, intermediate and superficial cells will be calculated in duplicate on 100 consecutive cells of vaginal cytology. The average of the two percentages obtained for each cell type will be calculated, which will serve to determine the maturation value (MV) based on the following formula: 0.2 x (% parabasal) + 0.6 x (% intermediate) + 1.0 x (% superficial). |
| Changes in Vaginal Dryness | week 3 and week 12 vs baseline | Change in vaginal dryness puntuation score from baseline to w3 and w12 Each symptom will be scored in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present 1. The symptom is of mild intensity, without interfering in the patient's activity 2. The symptom is of moderate intensity, causing obvious discomfort to the patient 3. The symptom is stated as very irritating and severe in intensity |
Countries
Spain, Sweden
Participant flow
Recruitment details
The study had an initial safety phase of the trial started on March 30th, 2015; the treatment phase of the trial started in October 16th, 2015 and the study ended globally on February 10th, 2017
Pre-assignment details
After Inform Consent signature and prior randomization the following data was collected for subject's eligibility: Medical and surgical history and demographics; physical examination, ECOG PS, hematology, blood chemistry, urine test, transvaginal ultrasound, Blood (serum) samples for FSH and LH determination and evaluation of vaginal dryness.
Participants by arm
| Arm | Count |
|---|---|
| 0.005% Estriol Vaginal Gel Route: Vaginal. Administration by an applicator inserted deep inside the vagina Dose: 1 g of gel, containing 50 Mcg of estriol Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: twice weekly administration
estriol | 50 |
| Placebo Vaginal Gel Route: Vaginal. Administration by an applicator inserted deep inside the vagina Dose: 1 g of gel. Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: twice weekly administration
Placebo | 11 |
| Total | 61 |
Baseline characteristics
| Characteristic | Placebo Vaginal Gel | Total | 0.005% Estriol Vaginal Gel |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 6 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 55 Participants | 46 Participants |
| Age, Continuous | 61.4 years STANDARD_DEVIATION 4.7 | 59.3 years STANDARD_DEVIATION 7.1 | 58.9 years STANDARD_DEVIATION 7.6 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Spain | 7 participants | 40 participants | 33 participants |
| Region of Enrollment Sweden | 4 participants | 21 participants | 17 participants |
| Sex/Gender, Customized Female | 11 Participants | 61 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 11 |
| other Total, other adverse events | 3 / 50 | 1 / 11 |
| serious Total, serious adverse events | 1 / 50 | 0 / 11 |
Outcome results
Primary
Variation in Serum Levels of Follicle Stimulating Hormone (FSH)
Change from Baseline (mean screening-baseline) to Week 12 in Serum Levels of Follicle Stimulating Hormone (FSH) compare to natural physiological variability (screening-baseline variation)
Time frame: from baseline to 12 weeks of treatment
Population: postmenopausal participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.005% Estriol Vaginal Gel | Variation in Serum Levels of Follicle Stimulating Hormone (FSH) | -2.8 mIU/ml |
| Placebo Vaginal Gel | Variation in Serum Levels of Follicle Stimulating Hormone (FSH) | 1.4 mIU/ml |
Comparison: The variations of the levels of FSH after treatment was studied in each women at baseline, week 3 and week12 weeks, the variation of levels between two arms were analysed using a non-parametric test Mann-Whitney-Wilcoxon.~The intra individual variation (differences between the pre study determinations screening and baseline) was compared to the variation between baseline and the values obtained at every study visit.p-value: 0.1Wilcoxon (Mann-Whitney)
Comparison: The variations in the intensities for each one of the symptoms and signs of the vaginal atrophy, after 3 and 12 weeks, in each treatment arm, will be compared using the non-parametric test Mann-Whitney-Wilcoxon.p-value: 0.413Wilcoxon (Mann-Whitney)
p-value: 0.15Wilcoxon (Mann-Whitney)
Secondary
Change in Pruritus or Itching From Baseline to Week 3 and Week 12
Change in pruritus or itching from baseline to week 3 and week 12 Each symptom will be scored in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present 1. The symptom is of mild intensity, without interfering in the patient's activity 2. The symptom is of moderate intensity, causing obvious discomfort to the patient 3. The symptom is stated as very irritating and severe in intensity
Time frame: Change from baseline to week 3 and week 12
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Change in Pruritus or Itching From Baseline to Week 3 and Week 12 | Changes between baseline and week 3 | 0.0 units on a scale |
| 0.005% Estriol Vaginal Gel | Change in Pruritus or Itching From Baseline to Week 3 and Week 12 | Changes between baseline and week 12 | 0.0 units on a scale |
| Placebo Vaginal Gel | Change in Pruritus or Itching From Baseline to Week 3 and Week 12 | Changes between baseline and week 3 | 0.0 units on a scale |
| Placebo Vaginal Gel | Change in Pruritus or Itching From Baseline to Week 3 and Week 12 | Changes between baseline and week 12 | 0.0 units on a scale |
Comparison: Change from baseline to week 3p-value: 0.28Wilcoxon (Mann-Whitney)
Comparison: Change from baseline to week 12p-value: 0.34Wilcoxon (Mann-Whitney)
Secondary
Changes in Dryness of the Mucosa
It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. 1. The sign is present and is considered a mild alteration 2. The sign is present and is considered a moderate alteration 3. The sign is present and is considered a severe alteration
Time frame: week 3 and week 12 vs baseline
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Changes in Dryness of the Mucosa | Changes between baseline and week 3 | 2.0 score on a scale |
| 0.005% Estriol Vaginal Gel | Changes in Dryness of the Mucosa | Changes between baseline and week 12 | 2.0 score on a scale |
| Placebo Vaginal Gel | Changes in Dryness of the Mucosa | Changes between baseline and week 3 | 1.0 score on a scale |
| Placebo Vaginal Gel | Changes in Dryness of the Mucosa | Changes between baseline and week 12 | 1.0 score on a scale |
Comparison: Changes in dryness of the mucosa between baseline and week 3p-value: <0.001Wilcoxon (Mann-Whitney)
Comparison: Changes in dryness of the mucosa betweeen baseline and week 12p-value: <0.01Wilcoxon (Mann-Whitney)
Secondary
Changes in Dyspareunia
Changes in dyspareunia from baseline to week 3 and week 12 Each symptom will be scored in a numeric scale from 0 to 3, as shown 0 Absence. The symptom is not present 1. The symptom is of mild intensity, without interfering in the patient's activity 2. The symptom is of moderate intensity, causing obvious discomfort to the patient 3. The symptom is stated as very irritating and severe in intensity
Time frame: week 3 and week 12 vs baseline
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Changes in Dyspareunia | Change between baseline and week 3 | 1.0 score on a scale |
| 0.005% Estriol Vaginal Gel | Changes in Dyspareunia | Change between baseline and week 12 | 2.0 score on a scale |
| Placebo Vaginal Gel | Changes in Dyspareunia | Change between baseline and week 3 | 1.0 score on a scale |
| Placebo Vaginal Gel | Changes in Dyspareunia | Change between baseline and week 12 | 1.0 score on a scale |
Comparison: Changes in dyspareunia from baseline to week 3p-value: 0.14Wilcoxon (Mann-Whitney)
Comparison: Changes in dyspareunia from baseline to week 12p-value: 0.25Wilcoxon (Mann-Whitney)
Secondary
Changes in Fragility of the Mucosa [Time Frame: Week 3 and Week 12 vs Baseline]
It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. 1. The sign is present and is considered a mild alteration 2. The sign is present and is considered a moderate alteration 3. The sign is present and is considered a severe alteration
Time frame: from baseline to week 3 and 12
Population: Postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Changes in Fragility of the Mucosa [Time Frame: Week 3 and Week 12 vs Baseline] | Changes from baseline to week 3 | 1.0 score on a scale |
| 0.005% Estriol Vaginal Gel | Changes in Fragility of the Mucosa [Time Frame: Week 3 and Week 12 vs Baseline] | Changes from baseline to week 12 | 1.5 score on a scale |
| Placebo Vaginal Gel | Changes in Fragility of the Mucosa [Time Frame: Week 3 and Week 12 vs Baseline] | Changes from baseline to week 3 | 0.0 score on a scale |
| Placebo Vaginal Gel | Changes in Fragility of the Mucosa [Time Frame: Week 3 and Week 12 vs Baseline] | Changes from baseline to week 12 | 0.5 score on a scale |
Comparison: Changes in dryness of the mucosa between baseline and week 3p-value: 0.13Wilcoxon (Mann-Whitney)
Comparison: Changes in dryness of the mucosa between baseline and week 12p-value: <0.01Wilcoxon (Mann-Whitney)
Secondary
Changes in Total Score of Signs of Vaginal Atrophy Between Week 3 and Week 12 to Baseline
The signs evaluated Will be the following: vaginal mucosa with flattening of folds or thinning, dryness of the mucosa and Fragility of the mucosa. It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. 1. The sign is present and is considered a mild alteration 2. The sign is present and is considered a moderate alteration 3. The sign is present and is considered a severe alteration A Total Signs Score will be calculated by summing the intensities of all the three signs of vaginal atrophy in a certain time point, thus ranging between 0 and 9.
Time frame: week 3 and week 12 vs baseline
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Changes in Total Score of Signs of Vaginal Atrophy Between Week 3 and Week 12 to Baseline | Change between baseline and week 3 | 4.0 score on a scale |
| 0.005% Estriol Vaginal Gel | Changes in Total Score of Signs of Vaginal Atrophy Between Week 3 and Week 12 to Baseline | Change between baseline and week 12 | 5.0 score on a scale |
| Placebo Vaginal Gel | Changes in Total Score of Signs of Vaginal Atrophy Between Week 3 and Week 12 to Baseline | Change between baseline and week 3 | 1.0 score on a scale |
| Placebo Vaginal Gel | Changes in Total Score of Signs of Vaginal Atrophy Between Week 3 and Week 12 to Baseline | Change between baseline and week 12 | 1.0 score on a scale |
Comparison: Change in total score of signs between week 3 and baselinep-value: <0.001Wilcoxon (Mann-Whitney)
Comparison: Change in total score of signs between week 12 and baselinep-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Changes in Total Score of Symptoms of Vaginal Atrophy
Changes in Symptoms of vaginal atrophy (vaginal dryness, dyspareunia and pruritus) at week 3 and week 12 vs baseline. Each symptom will be scored in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present 1. The symptom is of mild intensity, without interfering in the patient's activity 2. The symptom is of moderate intensity, causing obvious discomfort to the patient 3. The symptom is stated as very irritating and severe in intensity A Global Symptoms Score will be calculated by summing the intensities of all the three symptoms of vaginal atrophy in a certain time point, thus ranging between 0 and 9.
Time frame: week 3 and week 12 vs baseline
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Changes in Total Score of Symptoms of Vaginal Atrophy | Change between baseline and week 3 | 3.0 score on a scale |
| 0.005% Estriol Vaginal Gel | Changes in Total Score of Symptoms of Vaginal Atrophy | Change between baseline and week 12 | 4.5 score on a scale |
| Placebo Vaginal Gel | Changes in Total Score of Symptoms of Vaginal Atrophy | Change between baseline and week 3 | 1.0 score on a scale |
| Placebo Vaginal Gel | Changes in Total Score of Symptoms of Vaginal Atrophy | Change between baseline and week 12 | 2.0 score on a scale |
Comparison: Changes in total score of symptoms of vaginal atrophy from baseline to week 3p-value: 0.03Wilcoxon (Mann-Whitney)
Comparison: Changes in total score of symptoms of vaginal atrophy from baseline to week 12p-value: 0.04Wilcoxon (Mann-Whitney)
Secondary
Changes in Vaginal Dryness
Change in vaginal dryness puntuation score from baseline to w3 and w12 Each symptom will be scored in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present 1. The symptom is of mild intensity, without interfering in the patient's activity 2. The symptom is of moderate intensity, causing obvious discomfort to the patient 3. The symptom is stated as very irritating and severe in intensity
Time frame: week 3 and week 12 vs baseline
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Changes in Vaginal Dryness | Change between baseline and week 3 | 1.0 units on a scale |
| 0.005% Estriol Vaginal Gel | Changes in Vaginal Dryness | Change between baseline and week 12 | 2.0 units on a scale |
| Placebo Vaginal Gel | Changes in Vaginal Dryness | Change between baseline and week 3 | 1.0 units on a scale |
| Placebo Vaginal Gel | Changes in Vaginal Dryness | Change between baseline and week 12 | 1.0 units on a scale |
Comparison: Changes in vaginal dryness from baseline to week 3p-value: 0.14Wilcoxon (Mann-Whitney)
Comparison: Changes in vaginal dryness from baseline to week 12p-value: <0.01Wilcoxon (Mann-Whitney)
Secondary
Changes in Vaginal Maturation Value
Vaginal cytology sample to evaluate the vaginal Maturation Value. For the cytologic evaluation, the number of parabasal, intermediate and superficial cells will be calculated in duplicate on 100 consecutive cells of vaginal cytology. The average of the two percentages obtained for each cell type will be calculated, which will serve to determine the maturation value (MV) based on the following formula: 0.2 x (% parabasal) + 0.6 x (% intermediate) + 1.0 x (% superficial).
Time frame: week 3 and week 12 vs baseline
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Changes in Vaginal Maturation Value | Change between baseline and week 3 | -62.0 % of cells |
| 0.005% Estriol Vaginal Gel | Changes in Vaginal Maturation Value | Change between baseline and week 12 | -37.2 % of cells |
| Placebo Vaginal Gel | Changes in Vaginal Maturation Value | Change between baseline and week 3 | -0.6 % of cells |
| Placebo Vaginal Gel | Changes in Vaginal Maturation Value | Change between baseline and week 12 | -1.0 % of cells |
Comparison: Change in maturation value from baseline to week 3p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: Change in maturation value from baseline to week 12p-value: 0.006Wilcoxon (Mann-Whitney)
Secondary
Changes in Vaginal Mucosa With Flattening of Folds or Thinning
It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. 1. The sign is present and is considered a mild alteration 2. The sign is present and is considered a moderate alteration 3. The sign is present and is considered a severe alteration
Time frame: week 3 and week 12 vs baseline
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Changes in Vaginal Mucosa With Flattening of Folds or Thinning | Change between baseline and week 3 | 1.0 score on a scale |
| 0.005% Estriol Vaginal Gel | Changes in Vaginal Mucosa With Flattening of Folds or Thinning | Change between baseline and week 12 | 1.0 score on a scale |
| Placebo Vaginal Gel | Changes in Vaginal Mucosa With Flattening of Folds or Thinning | Change between baseline and week 3 | 0.0 score on a scale |
| Placebo Vaginal Gel | Changes in Vaginal Mucosa With Flattening of Folds or Thinning | Change between baseline and week 12 | 0.0 score on a scale |
Comparison: Change from baseline to week 3p-value: <0.001Wilcoxon (Mann-Whitney)
Comparison: Change from baseline to week 12p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Changes in Vaginal pH Between Baseline and Week 3 and Week 12
Measurement of vaginal pH on the vaginal secretion using a reactive strip and compare pH value between baseline and the diferent timepoints
Time frame: week 3 and week 12 vs baseline
Population: postmenopausal women
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Changes in Vaginal pH Between Baseline and Week 3 and Week 12 | Change from baseline to Week 3 | 2.0 units on a scale |
| 0.005% Estriol Vaginal Gel | Changes in Vaginal pH Between Baseline and Week 3 and Week 12 | Change from baseline to Week 12 | 1.3 units on a scale |
| Placebo Vaginal Gel | Changes in Vaginal pH Between Baseline and Week 3 and Week 12 | Change from baseline to Week 3 | 0.5 units on a scale |
| Placebo Vaginal Gel | Changes in Vaginal pH Between Baseline and Week 3 and Week 12 | Change from baseline to Week 12 | 0.5 units on a scale |
Comparison: Change in pH between baseline and week 3p-value: <0.01Wilcoxon (Mann-Whitney)
Comparison: Change in pH between baseline and week 12p-value: 0.057Wilcoxon (Mann-Whitney)
Secondary
Variation in Plasma Levels of Estradiol
Change in plasma levels of estradiol at weeks 1, 3, 8 and 12 compared to baseline.
Time frame: Change from baseline to week 1, week 3, week 8 and week 12
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estradiol | Change between baseline and week 1 | 0.0 pg/mL |
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estradiol | Change between baseline and week 3 | 0.0 pg/mL |
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estradiol | Change between baseline and week 8 | 0.0 pg/mL |
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estradiol | Change between baseline and week 12 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estradiol | Change between baseline and week 12 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estradiol | Change between baseline and week 1 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estradiol | Change between baseline and week 8 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estradiol | Change between baseline and week 3 | 0.0 pg/mL |
Comparison: Change from baseline to week 1 in plasma levels of estradiol.p-value: 0.342Wilcoxon (Mann-Whitney)
Comparison: Change from baseline to week 3 in plasma levels of estradiol.p-value: 0.523Wilcoxon (Mann-Whitney)
Comparison: Change in plasma levels of estradiol from baseline to week 8p-value: 0.523Wilcoxon (Mann-Whitney)
Comparison: Change in plasma levels of estradiol from baseline to week 12p-value: 0.163Wilcoxon (Mann-Whitney)
Secondary
Variation in Plasma Levels of Estriol
Change in plasma levels of estriol at weeks 1, 3, 8 and 12 compared to baseline
Time frame: Change from baseline to week 1, week 3, week 8 and week 12
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estriol | Change between baseline and week 1 | -1.7 pg/mL |
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estriol | Change between baseline and week 3 | 0.0 pg/mL |
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estriol | Change between baseline and week 8 | 0.0 pg/mL |
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estriol | Change between baseline and week 12 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estriol | Change between baseline and week 12 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estriol | Change between baseline and week 1 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estriol | Change between baseline and week 8 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estriol | Change between baseline and week 3 | 0.0 pg/mL |
Comparison: Change from baseline to week 1 in plasma levels of estriolp-value: 0.043Wilcoxon (Mann-Whitney)
Comparison: Change from baseline to week 3 in plasma levels of estriolp-value: 0.649Wilcoxon (Mann-Whitney)
Comparison: Change from baseline to week 8 in plasma levels of estriolp-value: 0.588Wilcoxon (Mann-Whitney)
Comparison: Change from baseline to week 12 in plasma levels of estriolp-value: 0.67Wilcoxon (Mann-Whitney)
Secondary
Variation in Plasma Levels of Estrona
Change in plasma levels of estrona at weeks 1, 3, 8 and 12 compared to baseline.
Time frame: Change from baseline to week 1, week 3, week 8 and week 12
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estrona | change from baseline to week 8 | 0.0 pg/mL |
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estrona | Change from baseline to week 1 | 0.0 pg/mL |
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estrona | Change from baseline to week 12 | 0.0 pg/mL |
| 0.005% Estriol Vaginal Gel | Variation in Plasma Levels of Estrona | Change between baseline and week 3 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estrona | Change from baseline to week 12 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estrona | Change from baseline to week 1 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estrona | change from baseline to week 8 | 0.0 pg/mL |
| Placebo Vaginal Gel | Variation in Plasma Levels of Estrona | Change between baseline and week 3 | 0.0 pg/mL |
Comparison: Change in plasma levels of estrona from baseline to week 12p-value: 0.084Wilcoxon (Mann-Whitney)
Comparison: Change in plasma levels of estrona from baseline to week 1p-value: 0.418Wilcoxon (Mann-Whitney)
Comparison: Change in plasma levels of estrona from baseline to week 3p-value: 0.642Wilcoxon (Mann-Whitney)
Comparison: Change in plasma levels of estrona from baseline to week 8p-value: 0.175Wilcoxon (Mann-Whitney)
Secondary
Variation in Serum Levels of FSH at Week 1, Week 3 and Week 8
Change from Baseline (mean screening-baseline) to Week 1, Week 3 and Week 8 in Serum Levels of Follicle Stimulating Hormone (FSH) compare to natural physiological variability ( screening-baseline variation)
Time frame: Change from baseline to week 1, week 3 and week 8
Population: postmenopausal women
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Variation in Serum Levels of FSH at Week 1, Week 3 and Week 8 | change from baseline to week 8 | -2.6 mIU/ml |
| 0.005% Estriol Vaginal Gel | Variation in Serum Levels of FSH at Week 1, Week 3 and Week 8 | change from baseline to week 1 | -4.8 mIU/ml |
| 0.005% Estriol Vaginal Gel | Variation in Serum Levels of FSH at Week 1, Week 3 and Week 8 | change from baseline to week 3 | -4.2 mIU/ml |
| Placebo Vaginal Gel | Variation in Serum Levels of FSH at Week 1, Week 3 and Week 8 | change from baseline to week 1 | 4.2 mIU/ml |
| Placebo Vaginal Gel | Variation in Serum Levels of FSH at Week 1, Week 3 and Week 8 | change from baseline to week 3 | -0.9 mIU/ml |
| Placebo Vaginal Gel | Variation in Serum Levels of FSH at Week 1, Week 3 and Week 8 | change from baseline to week 8 | 5.2 mIU/ml |
Comparison: Variation in serum levels of FSH at week 1p-value: <0.05Dunn Test
Comparison: Variation in serum levels of FSH at week 3p-value: <0.05Dunn Test
Comparison: Variation in serum levels of FSH at week 8p-value: >0.05Dunn Test
Secondary
Variation in Serum Levels of Luteinizing Hormone (LH)
Change from (mean screening-baseline) in plasma levels of LH to Week 1, Week 3, Week 8 and Week 12 in Serum Levels of LH compare to natural physiological variability ( screening-baseline variation)
Time frame: Change from baseline to week 1, week 3, week 8 and week 12
Population: postmenopausal women
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.005% Estriol Vaginal Gel | Variation in Serum Levels of Luteinizing Hormone (LH) | change from LH baseline to week 1 | -0.6 mIU/ml |
| 0.005% Estriol Vaginal Gel | Variation in Serum Levels of Luteinizing Hormone (LH) | change from LH baseline to week 3 | -0.5 mIU/ml |
| 0.005% Estriol Vaginal Gel | Variation in Serum Levels of Luteinizing Hormone (LH) | change from LH baseline to week 8 | -0.3 mIU/ml |
| 0.005% Estriol Vaginal Gel | Variation in Serum Levels of Luteinizing Hormone (LH) | change from LH baseline to week 12 | -0.8 mIU/ml |
| Placebo Vaginal Gel | Variation in Serum Levels of Luteinizing Hormone (LH) | change from LH baseline to week 12 | 1.3 mIU/ml |
| Placebo Vaginal Gel | Variation in Serum Levels of Luteinizing Hormone (LH) | change from LH baseline to week 1 | 0.2 mIU/ml |
| Placebo Vaginal Gel | Variation in Serum Levels of Luteinizing Hormone (LH) | change from LH baseline to week 8 | -1.3 mIU/ml |
| Placebo Vaginal Gel | Variation in Serum Levels of Luteinizing Hormone (LH) | change from LH baseline to week 3 | 0.3 mIU/ml |
Comparison: Change in serum levels of Luteinizing hormone (LH) from baseline to week 1p-value: >0.05Dunn Test
Comparison: Change in serum levels of Luteinizing hormone (LH) from baseline to week 3p-value: >0.05Dunn Test
Comparison: Change in serum levels of Luteinizing hormone (LH) from baseline to week 8p-value: >0.05Dunn Test
Comparison: Change in serum levels of Luteinizing hormone (LH) from baseline to week 12p-value: 0.135Wilcoxon (Mann-Whitney)