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
Condition: Vaginal Atrophy
MeSH terms: Atrophy
Intervention: Estriol; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 283.0
Sex: Female
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No

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.
    

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