Study to Determine Efficacy & Safety of a Low Concentration Estriol (0.005%) in Postmenopausal Vaginal Atrophy.

Study Overview
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Brief Summary
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Randomized, double-blind, placebo-controlled multicentre study, with parallel groups, to determine the efficacy and safety of a new low-concentration estriol formulation (ITFE-2026 0.005%) for application by vaginal route in the treatment of postmenopausal vaginal atrophy. Primary objective: • To evaluate the efficacy of 0.005% Estriol vaginal gel by evaluation of the change in the maturation value of the vaginal epithelium (MV) after 12 weeks of treatment. Secondary objectives: To determine the variation of the vaginal pH, as well as symptoms and signs suggestive of vaginal atrophy after 12 weeks of treatment. To study the variation of the MV, pH and symptoms and signs suggestive of vaginal atrophy after an initial observation period of 3 weeks. To evaluate the safety of 0.005% Estriol vaginal gel To evaluate the acceptability of 0.005% Estriol vaginal gel

Detailed Description
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This is a randomized, double-blind, placebo-controlled multicentre study, with parallel groups, to determine the efficacy and safety of a new low-concentration estriol formulation (ITFE-2026 0.005%) for application by vaginal route in the treatment of postmenopausal vaginal atrophy. Eligible patients were randomised in a ratio of 2:1 to 0.005% Estriol vaginal gel : placebo. Each patient was treated for 12 weeks followed by a one-month observational period. The patients attended the study centre at baseline and at 3, 8 and 12 weeks after start of treatment. Vaginal cytology was performed at baseline and at weeks 3 and 12; the vaginal pH and the signs and symptoms of vaginal atrophy were recorded at baseline and after 3 and 12 weeks of treatment. Vital signs, gynaecological exploration and changes in health and concomitant medication were documented at each visit. Transvaginal ultrasound was performed at screening and week 12. The investigators telephoned the patient approximately one month after the final visit to check if the patient had experienced any adverse events since the final visit. Two independent cytopathologists assessed the maturation value of each cytology sample at the end of the study.

Official Title
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Randomized, Double-blind, Placebo-controlled, Parallel Groups, Multicentre Study, to Determine Efficacy and Safety of a Low Concentration Estriol (ITFE-2026 0.005%) by Vaginal Route in the Treatment of Postmenopausal Vaginal Atrophy.

Conditions
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Vaginal Atrophy

Intervention / Treatment
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* Drug: Estriol
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Women of any age. Menopause with amenorrhea time ≥ 2 years, either due to natural or surgical menopause (bilateral oophorectomy). Presence of symptoms and signs of atrophy of the vaginal mucosa including at minimum vaginal dryness as a symptom stated by the patient, together with at least one sign of the disease verified by the investigator. As symptoms the patient could state vaginal dryness, pruritus, burning, dyspareunia, dysuria or any other symptom that the investigator considered related to the presence of vaginal atrophy. As signs the investigator assessed in the gynaecological examination with a speculum, a thinned vaginal mucosa or with flattening of folds, a dry, fragile and pale vaginal mucosa, the presence of petechiae or any other sign that the investigator considered indicative of the existence of vaginal atrophy Patients with mammography carried out in the period of one year prior to inclusion in the study. Patients able to understand the nature and purpose of the study, to cooperate with the investigator and meet the study requirements. Patients who gave written informed consent to participate in the study. Exclusion Criteria: Patients with contraindications for hormone therapy with estrogens because they had a history of: Malignant or premalignant lesions of the breasts or endometrium. Pathology of malignant colon tumour. Malignant melanoma Hepatic tumour pathology Venous thromboembolic conditions (deep vein thrombosis, pulmonary embolism) or arterial thromboembolic conditions (angor pectoris, myocardial infarction, cerebrovascular accident), peripheral arterial disease, mesenteric artery thrombosis, renal artery thrombosis Coagulopathies Vaginal bleeding of unknown etiology Patients who had abnormal laboratory values at the start of the study that the investigator considered clinically relevant for the purposes of the present study. Patients with signs and symptoms suggestive of infection of the genital or urinary tract at the start of the study. Patients with any medical-surgical pathology, which was uncontrolled at the time of inclusion in the study. Patients with any acute process whose handling or evolution the investigator considered could interfere in the development of the study. Patients with endometrial thickness equal to or greater than 4 mm measured by transvaginal ultrasound. Patients with grade II or higher uterovaginal prolapse. Patients who had received any type of vulvovaginal treatment in the 15 days prior to the start of the study. Patients who had received phytoestrogens in the period of one month prior to the start of the study, including administration by vaginal route. Patients who had received hormone therapy in the period of 3 months prior to the start of the study, including the administration of estrogens by vaginal route. Patients on treatment with drugs described in section 7.3 of the protocol Patients with a history of allergy to any of the components of the medication under study (see the composition in section 3.3. of the protocol). Patients who had participated in the experimental evaluation of any drug during the 8 weeks before the start of the present study.
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 group<br>0.005% Estriol (50 μg/g) gel for vaginal administration. Route: Vaginal by a cannula inserted deep inside the vagina Single dose: 1 g of gel Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: single application 2 times per week. | Drug: Estriol<br>* Gel for vaginal application<br>* Other names: 16α-hydroxyestradiol or as estra-1,3,5(10)-triene-3,16α,17β-triol;|
| Placebo Comparator: Placebo group<br>Placebo gel for vaginal administration. Route: Vaginal by a cannula inserted deep inside the vagina Single dose: 1 g of gel Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: single application 2 times per week. | Other: Placebo<br>* Gel for vaginal application<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 Maturation Value (MV) After 12 Weeks of Treatment | Maturation value (MV) is a cytologic parameter indicative of the degree of atrophy of the vaginal mucosa. This variable is a quantitative parameter indicative of the cytological status of the vaginal epithelium. The number of parabasal, intermediate and superficial cells was calculated from 300 consecutive cells of the samples of vaginal cytology, and the percentages of each type of cells obtained. The Maturation Value was obtained based on the following formula: 0.2 x (% parabasal) + 0.6 x (% intermediate) + 1.0 x (% superficial). The higher the value, the higher the maturation degree. | At week 12/Early withdrawal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 of the Vaginal pH After the 12-week Observation Period | As a consequence of reduced estrogen levels, the vaginal mucosa occurs loses its rugosity, its thickness decreases, and it becomes pale and friable. The production of glycogen decreases, which determines vaginal pH alkalinization. | At week 12 /early withdrawal | 
| Number of Participants With Variation of the Individual Signs and Symptoms of Vaginal Atrophy After the 12-week Observation Period | Signs and symptoms of vaginal atrophy are: vaginal dryness, pruritus or itching, burning, dyspareunia, dysuria. For each of these symptoms the subject indicates one the following status: present, absent, missing. Symptoms of vaginal atrophy were scored by the patients in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present The symptom is of mild intensity, without interfering in the patient's activity The symptom is of moderate intensity, causing obvious discomfort to the patient's The symptom is very irritating and severe in intensity Signs of vaginal atrophy were evaluated by the investigator and scored on a numerical scale as shown below: 0 Absence. The symptom is not present The sign is present and is considered a mild alteration The sign is present and is considered a moderate alteration The sign is present and is considered a severe alteration | At baseline and at 12 weeks / early withdrawal | 
| Change From Baseline to Week 3 in Maturation Value (MV) After 3 Weeks of Treatment | Maturation value (MV) is a cytologic parameter indicative of the degree of atrophy of the vaginal mucosa. This variable is a quantitative parameter indicative of the cytological status of the vaginal epithelium. The number of parabasal, intermediate and superficial cells was calculated from 300 consecutive cells of the samples of vaginal cytology, and the percentages of each type of cells obtained. The Maturation Value was obtained based on the following formula: 0.2 x (% parabasal) + 0.6 x (% intermediate) + 1.0 x (% superficial). The higher the value, the higher the maturation degree. | At week 3/ early withdrawal | 
| Change From Baseline to Week 3 of the Vaginal pH After the 3-week Observation Period | As a consequence of reduced estrogen levels, the vaginal mucosa occurs loses its rugosity, its thickness decreases, and it becomes pale and friable. The production of glycogen decreases, which determines vaginal pH alkalinization. | At week 3 / early withdrawal | 
| Number of Participants With Variation of the Individual Signs and Symptoms of Vaginal Atrophy After the 3-week Observation Period | Signs and symptoms of vaginal atrophy are: vaginal dryness, pruritus or itching, burning, dyspareunia, dysuria. For each of these symptoms the subject indicates one the following status: present, absent, missing. Symptoms of vaginal atrophy were scored by the patients in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present The symptom is of mild intensity, without interfering in the patient's activity The symptom is of moderate intensity, causing obvious discomfort to the patient's The symptom is very irritating and severe in intensity Signs of vaginal atrophy were evaluated by the investigator and scored on a numerical scale as shown below: 0 Absence. The symptom is not present The sign is present and is considered a mild alteration The sign is present and is considered a moderate alteration The sign is present and is considered a severe alteration | At 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postmenopausal women