Estradiol Vaginal Softgel Capsules in Treating Symptoms of Vulvar and Vaginal Atrophy in Postmenopausal Women

Inclusion Criteria

• Postmenopausal female subjects between the ages of 40 and 75 years (at the time of randomization) with at least:
• 12 months of spontaneous amenorrhea (women 40 mIU/mL), OR
• 6 months of spontaneous amenorrhea with follicle stimulating hormone (FSH) levels > 40mlU/mL OR
• At least 6 weeks postsurgical bilateral oophorectomy.
• ≤5% superficial cells on vaginal cytological smear
• Vaginal pH > 5.0
• Moderate to severe symptom of vaginal pain associated with sexual activity considered the most bothersome vaginal symptom by the subject at screening visit 1A.
• Moderate to severe symptom of vaginal pain associated with sexual activity at screening visit 1B.
• Onset of moderate to severe dyspareunia in the postmenopausal years.
• Subjects should be sexually active (i.e. have sexual activity with vaginal penetration within approximately 1 month of screening visit 1A).
• Subjects should anticipate having sexual activity (with vaginal penetration) during the conduct of the trial.
• For subjects with an intact uterus: Subjects must have an acceptable result from an evaluable screening endometrial biopsy.
• Subjects who have a Body Mass Index (BMI) less than or equal to 38 kg/m2. BMI values should be rounded to the nearest integer (ex. 32.4 rounds down to 32, while 26.5 rounds up to 27).
• In the opinion of the investigator, the subject will comply with the protocol and has a high probability of completing the study.

Exclusion Criteria

• Use of the following:
• Oral estrogen-, progestin-, androgen-, or SERM-containing drug products within 8 weeks before screening visit 1A (can enter washout);
• Use of transdermal hormone products within 4 weeks before screening visit 1A (can enter washout);
• Use of vaginal hormone products (rings, creams, gels) within 4 weeks before screening visit1A (can enter washout);
• Use of intrauterine progestins within 8 weeks before screening visit 1A (can enter washout);
• Use of progestin implants/injectables or estrogen pellets/injectables within 6 months before screening visit 1A (cannot enter washout);
• Use of vaginal lubricants or moisturizers within 7 days before the screening visit 1B vaginal pH assessment.
• A history or active presence of clinically important medical disease that might confound the study or be detrimental to the subject, examples include:
• Hypersensitivity to estrogens;
• Endometrial hyperplasia;
• Undiagnosed vaginal bleeding;
• Have a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis C or chronic renal failure);
• Thrombophlebitis, thrombosis or thromboembolic disorders;
• Cerebrovascular accident, stroke, or transient ischemic attack;
• Myocardial infarction or ischemic heart disease;
• Malignancy or treatment for malignancy, within the previous 5 years, with the exception of basal cell carcinoma of the skin or squamous cell carcinoma of the skin. A history of estrogen dependent neoplasia, breast cancer, melanoma or any gynecologic cancer, at any time, excludes the subject;
• Endocrine disease (except for controlled hypothyroidism or controlled non-insulin dependent diabetes mellitus).
• Recent history of known alcohol or drug abuse.
• History of sexual abuse or spousal abuse that, in the opinion of the PI, may interfere with the subject's assessment of vaginal pain with sexual activity.
• Current history of Heavy smoking (more than 15 cigarettes per day) or use of e-cigarettes.
• Use of an intrauterine device within 12 weeks before screening visit 1A.
• Use of an investigational drug within 60 days before screening visit 1A.
• Any clinically important abnormalities on screening physical exam, assessments, ECG, or laboratory tests, such as:
• Unresolved cervical cytologic smear report of atypical glandular cells of undetermined significance (AGUS) or atypical squamous cells of undetermined significance (ASCUS).

Cervical cytologic smear report of low-grade squamous intraepithelial lesion (