Study Evaluating the Efficacy and Safety of Three Formulations of Ultra-low Dose Estriol Vaginal Gel (0.005%, 0.002%, 0.0008% Estriol Vaginal Gel) for the Treatment of Vaginal Dryness in Postmenopausal Women With Vulvovaginal Atrophy

Study Overview
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Brief Summary
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A Phase 2, Dose-ranging, 12-week Randomized, Double-blind, Placebo controlled, Parallel-group Study Evaluating the Efficacy and Safety of Three Formulations of Ultra-low Dose Estriol Vaginal Gel (0.005% Estriol Vaginal Gel, 0.002% Estriol Vaginal Gel, 0.0008% Estriol Vaginal Gel) for the Treatment of Vaginal Dryness in Postmenopausal Women with Vulvovaginal Atrophy. Vulvovaginal atrophy is a natural consequence of the progressive estrogen deficiency that occurs in menopause. Epidemiological data have indicated that about 50% of otherwise healthy women over 60 years of age experience symptoms related to urogenital atrophy such as vaginal dryness, dyspareunia, burning, itching, as well as urinary complaints or infections of the lower urinary tract. As these alterations frequently affect the quality of life of postmenopausal women, it is important for doctors to detect their presence and offer treatment options. Estrogen therapy is the most effective treatment of moderate to severe symptoms of vulvar and vaginal atrophy. One advantage of local treatment with estrogen is avoidance of first-pass liver metabolism, making it possible to use lower doses of estrogen compared with oral therapy; the local route also minimize systemic adverse effects. The search for therapeutic alternatives which may present improvements in relation to the current products has been encouraged.

Official Title
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A Phase 2, Dose-ranging, 12-week Randomized, Double-blind, Placebo Controlled, Parallel-group Study Evaluating the Efficacy and Safety of Three Formulations of Ultra-low Dose Estriol Vaginal Gel (0.005% Estriol Vaginal Gel, 0.002% Estriol Vaginal Gel, 0.0008% Estriol Vaginal Gel) for the Treatment of Vaginal Dryness in Postmenopausal Women With Vulvovaginal Atrophy

Conditions
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Vaginal Atrophy

Intervention / Treatment
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* Drug: Estriol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with the protocol procedures and assessments Age >40 and <80 years Postmenopausal (≥12 months since last spontaneous menstrual period, or having 6 months of spontaneous amenorrhea with serum FSH levels >40 IU/L, or ≥6 weeks since bilateral oophorectomy with or without hysterectomy) BMI ≤36 kg/m2 Vaginal Maturation Index ≤ 5% superficial cells on a vaginal smear Vaginal pH >5 Moderate to severe vaginal dryness currently reported as the most bothersome symptom of vaginal atrophy. Documented negative mammogram within 9 months prior to randomization, with normal breast examination at screening. Negative Papanicolau test at screening (in women with cervix). Exclusion Criteria: Subjects with contraindications for hormone therapy with estrogens such as those diagnosed or history of: malignant and premalignant lesions of the breast and/or endometrium, malignancy of the colon, malignant melanoma, hepatic tumor, venous thromboembolic conditions (including deep vein thrombosis or pulmonary embolism), arterial thromboembolic conditions (including angina pectoris, myocardial infarction, or cerebrovascular accident), coagulopathies, vaginal bleeding of unknown etiology, acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal, or porphyria. Subjects who have abnormal laboratory values at screening that the investigator considers clinically relevant for the purposes of the study. Subjects with any medical-surgical pathology which is not controlled at the time of inclusion in the study Subjects with any acute or chronic condition whose management or progression may interfere with the subject´s participation in the study. Subject with uncontrolled hypertension (>140 mmHg systolic blood pressure and/or ≥90 mmHg diastolic blood pressure). Subjects with Grade II or higher utero-vaginal prolapse. Subjects with uterine polyps. Subjects with symptomatic and/or large uterine fibroids (>3 cm) and/or palpable fibroids at gynecological examination. Subjects who have had urogenital surgery within 3 months of baseline visit. Subjects with signs and symptoms suggestive of infection of the genital or urinary tract requiring treatment at the start of the study. In women who have a uterus, evidence of hyperplasia, cancer or other endometrial pathology in endometrial biopsy. Subjects who have received the following treatments within the specified time periods prior to screening procedures: any type of non-hormonal vulvovaginal treatment in the 7 days (including cosmetics expected to have an impact on vaginal pH such as special feminine wash gels); phytoestrogens by any route within 1 month; vaginal hormone therapy within 1 month; hormone therapy (estrogen alone, progestin alone or estrogen/progestin combination) by oral, intrauterine or transdermal route within 2 months; progestational implants, estrogen, or estrogen/progestational injectable within 3 months; estrogen pellet therapy or progestin injectable drug therapy within 6 months; percutaneous estrogen lotions or gels within 1 month; testosterone or testosterone derivatives, DHEA, tibolone, or SERMs by any route within 2 months; Subjects receiving antiepileptic drugs (barbiturates, hydantoins, carbamazepine), certain antibiotics and other antiinfective medicinal products; phenylbutazone; preparations based on medicinal plants that contain St. John's Wort. Subjects who are allergic to any of the components of the medication under study. Subjects who are currently participating or have participated in the experimental evaluation of any product within 8 weeks of the start of the study

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.005% estriol vaginal gel<br>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 | Drug: Estriol<br> <br> |
| Experimental: 0.002% estriol vaginal gel<br>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 | Drug: Estriol<br> <br> |
| Experimental: 0.0008% estriol vaginal gel<br>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 | Drug: Estriol<br> <br> |
| Placebo Comparator: estriol vaginal gel<br>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 | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in the Severity of Vaginal Dryness | Percentage of Subjects with change from baseline to week 12 in the severity of vaginal dryness was reported. Severity was defined as: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to Baseline represented a positive outcome. | From baseline to week 12 | 
| Change From Baseline to Week 12 in Vaginal pH | Change from Baseline to Week 12 in Vaginal pH was reported. A decrease in pH compare to Baseline represents a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Proportion of Superficial Cells of the Vaginal Epithelium. | Change from Baseline to week 12 in the proportion of superficial cells of the vaginal epithelium was reported. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Proportion of Parabasal Cells of the Vaginal Epithelium. | Change from Baseline to Week 12 in the proportion of parabasal cells of the vaginal epithelium was reported. A decrease in proportion of parabasal cells compared to Baseline represents a positive outcome. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in the Severity of Dyspareunia | Percentage of subjects with change from baseline to week 12 in the severity of dyspareunia was reported. Dyspareunia was only applicable in subjects who had experienced sexual activity with penetration since the previous study visit. Symptom scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to Baseline represented a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Severity of Pruritus or Itching | Percentage of subjects with cvhange from Baseline to Week 12 in the severity of pruritus or itching was reported. Symptom scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to Baseline represented a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Severity of Burning | Percentage of subjects with change from Baseline to Week 12 in the severity of burning was reported. Symptom scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to Baseline represented a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Severity of Dysuria | Percentage of subjects with change from Baseline to Week 12 in the severity of dysuria was reported. Symptom scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive putcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Global Symptom Score 1 | Global Symptom Score 1 was defined as the sum of all 5 individual symptom scores at a given visit, and was calculated only when all 5 symptom scores had a response available. the Global Symptom Score 1 ranged at Screening/Baseline between 2 (at least moderate vaginal dryness -per inclusion criteria) to 15 (all 5 studied symptoms severe in intensity). At Week 12/ET visit, the Global Symptom Score ranged between 0 (no symptoms) and 15 (all symptoms severe in intensity). A decrease in score compared to Baseline represented a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Global Symptom Score 2 | Change from Baseline to Week 12 in the Global Symptom Score 2 was reported. Global Symptom Score 2 was defined as the sum of all 4 individual symptoms excluding dyspareunia (vaginal dryness, pruritus or itching, burning, and dysuria) for each subject at each time point: Screening/Baseline, Week 3 and Week 12/ET., and was calculated only when all 4 symptom scores had a response available. The maximum score possible to be obtained at a visit with the Global Symptom Score 2 was 12 (all symptoms severe in intensity). A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Severity of Pallor. | Percentage of subjects with change from Baseline to Week 12 in the severity of pallor was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive putcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Severity of Friability | Percentage of subjects with change from Baseline to Week 12 in the severity of friability was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Severity of Thinning or Flattening of Folds | Percentage of subjects with change from Baseline to Week 12 in the severity of thinning or flattening of folds was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Severity of Petechiae | Percentage of subjects with change from Baseline to Week 12 in the severity of presence of petechiae was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 12 in the Severity of Dry Mucosa | Percentage of subjects with change from Baseline to Week 12 in the severity of dry mucosa was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 12 | 
| Change From Baseline to Week 3 in the Severity of Vaginal Dryness | Percentage of subjects with change from Baseline to Week 3 in the severity of vaginal dryness was reported. Severity was defined as: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Severity of Dyspareunia | Percentage of subjects with change from Baseline to Week 3 in severity of dyspareunia was reported. Dyspareunia was only applicable in subjects who had experienced sexual activity with penetration since the previous study visit. Symptom scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | From baseline to week 3 | 
| Change From Baseline to Week 3 in the Severity of Pruritus or Itching | Percentage of subjects with change from Baseline to Week 3 in the severity of pruritus or itching was reported. Symptom scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Severity of Burning | Percentage of subjects with change from Baseline to Week 3 in severity of burning was reported. Symptom scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Severity of Dysuria | Percentage of subjects with change from Baseline to Week 3 in severity of dysuria was reported. Symptom scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Global Symptom Score 1 | Global Symptom Score 1 was defined as the sum of all 5 individual symptom scores at a given visit, and was calculated only when all 5 symptom scores had a response available. the Global Symptom Score 1 ranged at Screening/Baseline between 2 (at least moderate vaginal dryness -per inclusion criteria) to 15 (all 5 studied symptoms severe in intensity). At Week 3 visit, the Global Symptom Score ranged between 0 (no symptoms) and 15 (all symptoms severe in intensity). A decrease in score compared to Baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Global Symptom Score 2 | Change from Baseline to Week 3 in the Global Symptom Score 2 was reported. Global Symptom Score 2 was defined as the sum of all 4 individual symptoms excluding dyspareunia (vaginal dryness, pruritus or itching, burning, and dysuria) for each subject at each time point: Screening/Baseline, Week 3 and Week 12/ET., and was calculated only when all 4 symptom scores had a response available. The maximum score possible to be obtained at a visit with the Global Symptom Score 2 was 12 (all symptoms severe in intensity). A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Severity of Pallor | Percentage of subjects with change from Baseline to Week 3 in severity of pallor was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Severity of Friability | Percentage of subjects with change from Baseline to Week 3 in severity of friability was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Severity of Thinning or Flattening of Folds | Percentage of subjects with change from Baseline to Week 3 in severity of thinning or flattening of folds was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Severity of Presence of Petechiae | Percentage of subjects with change from Baseline to Week 3 in the severity of presence of petechiae was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Severity of Dry Mucosa | Percentage of subjects with change from Baseline to Week 3 in severity of dry mucosa was reported. Sign scores at each visit: 0= Absent, 1= Mild, 2= Moderate, 3= Severe. A decrease in score compared to baseline represented a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in Vaginal pH | Change from Baseline to Week 3 in vaginal pH was reported. A decrease in pH compared to Baseline represents a positive outcome. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Proportion of Superficial Cells of the Vaginal Epithelium | Change from baseline to week 3 in the proportion of superficial cells of the vaginal epithelium was reported. | Baseline to Week 3 | 
| Change From Baseline to Week 3 in the Proportion of Parabasal Cells of the Vaginal Epithelium | Change from Baseline to Week 3 in the proportion of parabasal cells of the vaginal epithelium was reported. A decrease in proportion of parabasal cells compared to baseline represents a positive outcome. | Baseline to Week 3 |