TXV13-01 Estradiol Vaginal Softgel Capsules in Treating Postmenopausal Women With Symptoms of Vulvar and Vaginal Atrophy

A Phase 1, Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of TX-12-004-HR in Postmenopausal Women With Symptoms of Vulvar and Vaginal Atrophy (VVA)

The study was designed to evaluate the efficacy and safety of TX-12-004-HR 10 μg in treating moderate to severe symptoms of vaginal atrophy associated with menopause after 14 days of treatment, and to estimate the effect size and variability of vulvovaginal atrophy endpoints. In addition, the systemic exposure to estradiol from single and multiple doses of TX-12-004-HR was to be investigated.

This study was a randomized, double-blind, placebo-controlled trial to evaluate safety and efficacy of the TX-12-004-HR formulation in reducing moderate to severe symptoms of vaginal atrophy associated with menopause and to investigate the systemic exposure to estradiol following once daily intravaginal administrations of TX-12-004-HR for 14 days.

Postmenopausal subjects who met the study entry criteria were randomized to one of two treatment groups (TX-12-004-HR or Placebo). During the Screening period subjects were asked to self-assess the symptoms of vulvar and/or vaginal atrophy, including vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity and vaginal bleeding associated with sexual activity. Subjects with at least one self-assessed moderate to severe symptom of vulvar and/or vaginal atrophy identified by the subject as being most bothersome to her were eligible to participate in the study.

Inclusion Criteria:

1. Be a female between 40 and 75 years (at the time of randomization) who is willing to participate in the study, as documented by signing the informed consent form.

2. Be a postmenopausal woman. Postmenopausal is defined with at least 12 months of spontaneous amenorrhea or 12 months post bilateral oophorectomy, with or without hysterectomy (documented by an operative report or patient reported). Women ≥ 60 years of age who have had a hysterectomy without bilateral oophorectomy prior to natural menopause are considered menopausal.

3. Have a baseline evaluation requirements:

   • ≤5% superficial cells on vaginal smear cytology

   • Vaginal pH > 5.0

   • Estradiol level ≤ 50 pg/ml

   • At least one self-assessed moderate to severe symptom of vulvar and/or vaginal atrophy from the following list that is identified by the subject as being most bothersome to her:

     • Vaginal dryness
     • Vaginal pain associated with sexual activity
     • Vaginal and/or vulvar irritation/itching
     • Dysuria
     • Vaginal bleeding associated with sexual activity (absence vs. presence)

4. Have a Body Mass Index (BMI) less than or equal to 34 kg/m2. (BMI values should be rounded to the nearest integer [e.g., 34.4 rounds down to 34, while 26.5 rounds up to 27]).

5. Be willing to abstain from using products (other than study medication) that contain estrogen throughout study participation.

6. Be judged by the Principal Investigator or Sub-investigator as being in otherwise generally good health based on a pre-study medical evaluation performed within 28 days prior to the initial dose of study medication. The medical evaluation findings must include:

   • a normal or non-clinically significant physical examination, including vital signs (sitting blood pressure, heart rate, respiratory rate and temperature).
   • a normal or non-clinically significant pelvic examination.
   • a mammogram that shows no sign of significant disease (can be performed within previous 9 months prior to initial dose of study medication). An acceptable mammogram is defined as a mammogram in which no masses or other findings are identified that is suspicious of malignancy. 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.
   • a normal or non-clinically significant clinical breast examination. An acceptable breast examination is defined as no masses or other findings identified that are suspicious of malignancy.
   • a normal Screening Papanicolaou ("Pap") smear (ASCUS with high risk- human papillomavirus (HPV) negative is acceptable).
   • within normal limits or non-clinically significant laboratory evaluation results
   • sitting systolic blood pressure ≤140 mmHg and diastolic blood pressure ≤90 mmHg at Screening. A subject may be taking up to two antihypertensive medications.

7. Be willing to abstain from sexual activity and use of vaginal douching within 24 hours prior to screening and Visit 3 vaginal pH measurements.

Exclusion Criteria:

1. Be currently hospitalized.

2. Have a history of thrombosis of deep veins or arteries or a thromboembolic disorder.

3. Have a history of coronary artery or cerebrovascular disease.

4. Have a history of liver or kidney dysfunction/disorder.

5. Have a history of gallbladder dysfunction/disorders (e.g., cholangitis, cholecystitis), unless gallbladder has been removed.

6. Have a history of diabetes, thyroid disease (subjects with diet-controlled diabetes, or controlled hypothyroid disease at Screening are not excluded), or any other endocrinological disease.

7. Have a history of estrogen-dependent neoplasia.

8. Have a history of atypical ductal hyperplasia of the breast.

9. Have a history of undiagnosed vaginal bleeding.

10. Have a vaginal infection requiring treatment

11. Have any history of endometrial hyperplasia or uterine/endometrial, breast or ovarian cancer.

12. Have any history of other malignancy within the last 5 years, with the exception of basal cell (excluded if within 1 year) or non-invasive squamous cell (excluded if within 1 year) carcinoma of the skin.

13. Have a history of any other cardiovascular, hepatic, renal, pulmonary, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, psychological, or musculoskeletal disease or disorder that is clinically significant in the opinion of the Principal Investigator or Medical Sub-Investigator.

14. Have contraindication to estrogen therapy or allergy to the use of estradiol or any components of the investigational drugs.

15. Use 15 or more cigarettes per day.

16. Have a history of drug and/or alcohol abuse within one year of start of study.

17. Have used, within 28 days prior to Screening, or plan to use during the study, any prescription or over-the-counter (OTC) medications (including herbal products) that would be expected to interact with estradiol therapy.

18. Use of any type of vaginal preparation (including lubricants and moisturizers) within 14 days prior to Screening.

19. Have used estrogen alone or estrogen/progestin for any of the following time periods:

    • Vaginal hormonal products (rings, creams, gels) within 3 months prior to Screening.
    • Transdermal estrogen alone or estrogen/progestin products within 8 weeks prior to Screening.
    • Oral estrogen and/or progestin therapy within 8 weeks prior to Screening.
    • Progestational implants, estrogen or estrogen/progestational injectable drug therapy within 3 months prior to Screening.
    • Estrogen pellet therapy or progestational injectable drug therapy within 6 months prior to Screening.
    • Percutaneous estrogen lotions/gels within 8 weeks prior to Screening.
    • Oral, topical, vaginal, patch, implantable or injectable androgen therapy within 8 weeks prior to Screening.

20. Have any reason which, in the opinion of the Principal Investigator or Medical Sub-Investigator, would prevent the subject from safely participating in the study or complying with protocol requirements.

21. Have contraindication to any planned study procedure (e.g., blood collection).

22. Have participated in another clinical trial within 30 days prior to screening, have received an investigational drug within the three months prior to the initial dose of study medication, or be likely to participate in a clinical trial or receive another investigational medication during the study.