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

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.


Eligibility Criteria:
Inclusion Criteria:

1. Capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with the protocol procedures and assessments
2. Age \>40 and \<80 years
3. 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)
4. BMI ≤36 kg/m2
5. Vaginal Maturation Index ≤ 5% superficial cells on a vaginal smear
6. Vaginal pH \>5
7. Moderate to severe vaginal dryness currently reported as the most bothersome symptom of vaginal atrophy.
8. Documented negative mammogram within 9 months prior to randomization, with normal breast examination at screening.
9. Negative Papanicolau test at screening (in women with cervix).

Exclusion Criteria:

1. 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.
2. Subjects who have abnormal laboratory values at screening that the investigator considers clinically relevant for the purposes of the study.
3. Subjects with any medical-surgical pathology which is not controlled at the time of inclusion in the study
4. Subjects with any acute or chronic condition whose management or progression may interfere with the subject´s participation in the study.
5. Subject with uncontrolled hypertension (\>140 mmHg systolic blood pressure and/or ≥90 mmHg diastolic blood pressure).
6. Subjects with Grade II or higher utero-vaginal prolapse.
7. Subjects with uterine polyps.
8. Subjects with symptomatic and/or large uterine fibroids (\>3 cm) and/or palpable fibroids at gynecological examination.
9. Subjects who have had urogenital surgery within 3 months of baseline visit.
10. Subjects with signs and symptoms suggestive of infection of the genital or urinary tract requiring treatment at the start of the study.
11. In women who have a uterus, evidence of hyperplasia, cancer or other endometrial pathology in endometrial biopsy.
12. 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;
13. 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.
14. Subjects who are allergic to any of the components of the medication under study.
15. Subjects who are currently participating or have participated in the experimental evaluation of any product within 8 weeks of the start of the study