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

A Phase 3, Randomized, Double-blind, Placebo-controlled, Multi-center Trial to Evaluate the Safety and Efficacy of TX-004HR in Postmenopausal Women With Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy

This study will assess the safety and efficacy of a new formulation of vaginal estradiol for the treatment of symptoms of vulvar and vaginal atrophy in postmenopausal women.

Inclusion Criteria:

1. 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 <55 years of age with a history of hysterectomy without bilateral oophorectomy prior to natural menopause must have follicle stimulating hormone (FSH) levels > 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.

2. ≤5% superficial cells on vaginal cytological smear

3. Vaginal pH > 5.0

4. Moderate to severe symptom of vaginal pain associated with sexual activity considered the most bothersome vaginal symptom by the subject at screening visit 1A.

5. Moderate to severe symptom of vaginal pain associated with sexual activity at screening visit 1B.

6. Onset of moderate to severe dyspareunia in the postmenopausal years.

7. Subjects should be sexually active (i.e. have sexual activity with vaginal penetration within approximately 1 month of screening visit 1A).

8. Subjects should anticipate having sexual activity (with vaginal penetration) during the conduct of the trial.

9. For subjects with an intact uterus: Subjects must have an acceptable result from an evaluable screening endometrial biopsy.

10. 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).

11. In the opinion of the investigator, the subject will comply with the protocol and has a high probability of completing the study.

Exclusion Criteria:

1. Use of the following:

   1. Oral estrogen-, progestin-, androgen-, or SERM-containing drug products within 8 weeks before screening visit 1A (can enter washout);
   2. Use of transdermal hormone products within 4 weeks before screening visit 1A (can enter washout);
   3. Use of vaginal hormone products (rings, creams, gels) within 4 weeks before screening visit1A (can enter washout);
   4. Use of intrauterine progestins within 8 weeks before screening visit 1A (can enter washout);
   5. Use of progestin implants/injectables or estrogen pellets/injectables within 6 months before screening visit 1A (cannot enter washout);
   6. Use of vaginal lubricants or moisturizers within 7 days before the screening visit 1B vaginal pH assessment.

2. A history or active presence of clinically important medical disease that might confound the study or be detrimental to the subject, examples include:

   1. Hypersensitivity to estrogens;
   2. Endometrial hyperplasia;
   3. Undiagnosed vaginal bleeding;
   4. Have a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis C or chronic renal failure);
   5. Thrombophlebitis, thrombosis or thromboembolic disorders;
   6. Cerebrovascular accident, stroke, or transient ischemic attack;
   7. Myocardial infarction or ischemic heart disease;
   8. 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;
   9. Endocrine disease (except for controlled hypothyroidism or controlled non-insulin dependent diabetes mellitus).

3. Recent history of known alcohol or drug abuse.

4. 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.

5. Current history of Heavy smoking (more than 15 cigarettes per day) or use of e-cigarettes.

6. Use of an intrauterine device within 12 weeks before screening visit 1A.

7. Use of an investigational drug within 60 days before screening visit 1A.

8. Any clinically important abnormalities on screening physical exam, assessments, ECG, or laboratory tests, such as:

   1. 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 (SIL) or greater, CIN1 or greater, or any reported dysplasia; Subjects with ASCUS are eligible only if high risk human papilloma virus (HPV) result is negative.

   2. Unresolved findings suspicious for malignancy on the breast exam; incomplete mammogram result (BI-RADS 0) or unresolved findings suggestive of malignant changes or findings requiring short interval follow-up on the prestudy mammogram (subjects must have mammography result of BI-RADS 1 or 2 to enroll.) Mammogram may be performed within 9 months prior to Visit 2 (randomization) with documentation available. (The site must obtain a copy of the official report for the subject's study file, and it must be verified that the mammogram itself is available if needed for additional assessment);

   3. In subjects with intact uterus: have a screening endometrial biopsy sample that is found by both primary pathologists to have endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified. (With the approval of the Medical Monitor, the screening endometrial biopsy may be repeated once);

   4. In subjects with intact uterus: an endometrial biopsy report by one central pathologist at screening with one of the following:

      • Endometrial hyperplasia endometrial cancer, proliferative endometrium, weakly proliferative endometrium, disordered proliferative pattern; OR
      • Endometrial polyps with hyperplasia, glandular atypia of any degree (e.g., atypical nuclei) or cancer;

   5. Vulvar or vaginal inflammatory condition such as a contact or allergic dermatitis, lichen sclerosis or other pathological findings;

   6. Presence of suspicious vulvar or vaginal lesions for dysplasia, malignancy or other pathology other than atrophy;

   7. Painful genital warts or localized areas of ulceration;

   8. A history of active, chronic pelvic pain;

   9. Interstitial cystitis;

   10. Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal for the laboratory used;

   11. Fasting total cholesterol greater than 300 mg/dL (7.77 mmol/L) or triglycerides greater than 300 mg/dL (3.39 mmol/L);

   12. Fasting blood glucose greater than 125 mg/dL (6.94 mmol/L) with a hemoglobin A1C of greater than or equal to 6.5%;

   13. Uncontrolled hypertension; subjects with elevated sitting blood pressure, greater than 140 mm Hg systolic or greater than 90 mm Hg diastolic and may not be using more than 2 antihypertensive medications for the treatment of hypertension;

   14. Clinically significant abnormal 12-lead ECG (such as myocardial infarction or other findings suggestive of ischemia)

9. Be known to be pregnant or have a positive urine pregnancy test. (Note: A pregnancy test is not required for subjects who have had bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or are 55 years old or greater and have experienced cessation of menses for at least 1 year.

10. Current use of marijuana.