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

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.

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

Study Overview

• Status: Completed
• Conditions: Vaginal Atrophy
• Intervention / Treatment: Drug: Estriol; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 167
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Granada, Spain, 18014
    • Complejo Hospitalario Virgen de las Nieves
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz
  • Madrid, Spain, 28046
    • Complejo Universitario La Paz
  • Murcia, Spain, 30120
    • Hospital Universitario Virgen de la Arrixaca
  • Oviedo, Spain, 33006
    • Hospital Universitario Central de Asturias
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Valencia, Spain, 46600
    • Hospital la Ribera de Alzira
  • Vigo, Spain, 36200
    • Hospital Do Meixoeiro
  • Cantabria
    • Torrelavega, Cantabria, Spain, 39300
      • Hospital Sierrallana
  • Castiglia
    • Madrid, Castiglia, Spain, 28034
      • Hospital Ruber Internacional
  • Catalogna
    • Barcelona, Catalogna, Spain, 08022
      • Centre Mèdic Teknon S.L.
    • Barcelona, Catalogna, Spain, 08025
      • Fundació de Gestió Sanitària de l'Hospital de la Santa. Creu i Sant Pau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 0.005% Estriol group; 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; Gel for vaginal application; Other Names: 16α-hydroxyestradiol or as estra-1,3,5(10)-triene-3,16α,17β-triol
Placebo Comparator: Placebo group; 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; Gel for vaginal application

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Italfarmaco S.A
• Investigators: Principal Investigator: Javier Ferrer Barriendos, MD, PhD, Hospital Universitario Central de Asturias

Publications and helpful links

General Publications

• Cano A, Estevez J, Usandizaga R, Gallo JL, Guinot M, Delgado JL, Castellanos E, Moral E, Nieto C, del Prado JM, Ferrer J. The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase III study. Menopause. 2012 Oct;19(10):1130-9. doi: 10.1097/gme.0b013e3182518e9a.

Helpful Links

• The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase III study

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2008
• Primary Completion (Actual): February 23, 2009
• Study Completion (Actual): February 23, 2009

Study Registration Dates

• First Submitted: September 21, 2020
• First Submitted That Met QC Criteria: October 2, 2020
• First Posted (Actual): October 5, 2020

Study Record Updates

• Last Update Posted (Actual): December 11, 2020
• Last Update Submitted That Met QC Criteria: November 17, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Postmenopausal women
• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Atrophy
• Other Study ID Numbers: ITFE-2026C2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No