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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

Primary Purpose

Vaginal Atrophy

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Estriol

Placebo

About this trial

This is an interventional treatment trial for Vaginal Atrophy

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.
For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Arm Label

0.005% estriol vaginal gel

0.002% estriol vaginal gel

0.0008% estriol vaginal gel

estriol vaginal gel

Arm Description

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

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT02967510

First Posted

November 11, 2016

Last Updated

August 22, 2019

Sponsor

ITF Research Pharma, S.L.U.

1. Study Identification

Unique Protocol Identification Number

NCT02967510

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2019

Overall Recruitment Status

Completed

Study Start Date

October 2016 (undefined)

Primary Completion Date

May 2018 (Actual)

Study Completion Date

May 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

ITF Research Pharma, S.L.U.

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Vaginal Atrophy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

283 (Actual)

8. Arms, Groups, and Interventions

Arm Title

0.005% estriol vaginal gel

Arm Type

Experimental

Arm Description

Arm Title

0.002% estriol vaginal gel

Arm Type

Experimental

Arm Description

Arm Title

0.0008% estriol vaginal gel

Arm Type

Experimental

Arm Description

Arm Title

estriol vaginal gel

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Estriol

Intervention Type

Drug

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

Change From Baseline to Week 12 in the Severity of Vaginal Dryness

Description

Time Frame

From baseline to week 12

Title

Change From Baseline to Week 12 in Vaginal pH

Description

Change from Baseline to Week 12 in Vaginal pH was reported. A decrease in pH compare to Baseline represents a positive outcome.

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Proportion of Superficial Cells of the Vaginal Epithelium.

Description

Change from Baseline to week 12 in the proportion of superficial cells of the vaginal epithelium was reported.

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Proportion of Parabasal Cells of the Vaginal Epithelium.

Description

Time Frame

Baseline to Week 12

Secondary Outcome Measure Information:

Title

Change From Baseline to Week 12 in the Severity of Dyspareunia

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Severity of Pruritus or Itching

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Severity of Burning

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Severity of Dysuria

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Global Symptom Score 1

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Global Symptom Score 2

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Severity of Pallor.

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Severity of Friability

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Severity of Thinning or Flattening of Folds

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Severity of Petechiae

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 12 in the Severity of Dry Mucosa

Description

Time Frame

Baseline to Week 12

Title

Change From Baseline to Week 3 in the Severity of Vaginal Dryness

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Severity of Dyspareunia

Description

Time Frame

From baseline to week 3

Title

Change From Baseline to Week 3 in the Severity of Pruritus or Itching

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Severity of Burning

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Severity of Dysuria

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Global Symptom Score 1

Description

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.

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Global Symptom Score 2

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Severity of Pallor

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Severity of Friability

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Severity of Thinning or Flattening of Folds

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Severity of Presence of Petechiae

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Severity of Dry Mucosa

Description

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in Vaginal pH

Description

Change from Baseline to Week 3 in vaginal pH was reported. A decrease in pH compared to Baseline represents a positive outcome.

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Proportion of Superficial Cells of the Vaginal Epithelium

Description

Change from baseline to week 3 in the proportion of superficial cells of the vaginal epithelium was reported.

Time Frame

Baseline to Week 3

Title

Change From Baseline to Week 3 in the Proportion of Parabasal Cells of the Vaginal Epithelium

Description

Time Frame

Baseline to Week 3

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Facility Information:

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U

City

Brno

ZIP/Postal Code

602 00

Country

Czechia

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Ceske Budejovice

ZIP/Postal Code

370 01

Country

Czechia

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Olomouc

ZIP/Postal Code

779 00

Country

Czechia

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Olomouc

Country

Czechia

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Pisek

ZIP/Postal Code

397 01

Country

Czechia

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Prague

Country

Czechia

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Vsetin

Country

Czechia

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U

City

Szeged

ZIP/Postal Code

6725

Country

Hungary

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U

City

Szekesfehervar

ZIP/Postal Code

8000

Country

Hungary

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Szentes

ZIP/Postal Code

6725

Country

Hungary

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Tatabanya

ZIP/Postal Code

2800

Country

Hungary

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Catania

ZIP/Postal Code

95123

Country

Italy

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Catanzaro

ZIP/Postal Code

88100

Country

Italy

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Modena

ZIP/Postal Code

41124

Country

Italy

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Pavia

ZIP/Postal Code

27100

Country

Italy

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Siena

ZIP/Postal Code

53100

Country

Italy

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Barcelona

ZIP/Postal Code

80022

Country

Spain

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Murcia

ZIP/Postal Code

30120

Country

Spain

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Santander

ZIP/Postal Code

39008

Country

Spain

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Valencia

ZIP/Postal Code

46010

Country

Spain

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Huddinge

ZIP/Postal Code

141 86

Country

Sweden

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Kungsbacka

ZIP/Postal Code

434 30

Country

Sweden

Facility Name

For additional information regarding investigative sites for this trial, contact ITF Research Pharma S.L.U.

City

Stockholm

ZIP/Postal Code

171 76

Country

Sweden

12. IPD Sharing Statement

Learn more about this trial

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