| Eligibility |
Inclusion Criteria:
1. Signed, IRB approved informed consent that meets all criteria of current FDA and local
regulations.
2. Females aged 40-75 years inclusive who are postmenopausal, with at least:
1. 12 months of spontaneous amenorrhea (women <55 year of age with history of
hysterectomy without bilateral oophorectomy prior to natural menopause must have
Serum follicle-stimulating hormone (FSH) level > 40 mIU/mL); or
2. 6 months of spontaneous amenorrhea with FSH levels >40mIU/mL; or
3. At least 6 weeks postsurgical bilateral oophorectomy
3. Have less than or equal to 5% superficial cells on vaginal cytological smear.
4. Vaginal pH > 5.0.
5. Moderate to severe symptom of vaginal pain associated with sexual activity considered
the most bothersome vaginal symptom (dyspareunia) of VVA by the patient at screening
visit. (i.e., a VVA Symptom Self-Assessment Questionnaire score of 2 or 3) (Appendix
B).
6. Women should be sexually active (for example, have sexual activity with vaginal
penetration within approximately one month of screening visit).
7. Women should anticipate having sexual activity (with vaginal penetration) during the
conduct of the study, and agree to at least one episode of sexual intercourse within
study days 10-13.
8. Baseline systolic blood pressure should be no greater than 150 mm Hg and diastolic
blood pressure no greater than 90 mm Hg.
9. Normal mammogram completed within 9 months before randomization and a normal clinical
breast examination prior to randomization in the study.
10. Patients who have underwent complete Hysterectomy, or in the case of patients with an
intact uterus (including patients who underwent a partial hysterectomy) the later must
have:
1. A documented papanicolaou (PAP) smear conducted within 12 months before
randomization with no findings that the Investigator believes would
contraindicate the use of topical vaginal estradiol.
2. Documented vaginal ultrasonography results within 3 months before randomization
to confirm an inactive endometrial lining, defined as endometrial thickness <4mm.
11. In the opinion of the Investigator, the patient will comply with the protocol and has
a high probability of completing the study.
Exclusion Criteria:
1. Premenopasual, perimenopausal, pregnant or lactating patient or planning a pregnancy.
2. Significant history or current evidence of chronic infectious disease, system
disorder, organ disorder or other medical condition that in the Investigator's opinion
would place the study patient at undue risk by participation or could jeopardize the
integrity of the study evaluations.
3. Any clinically significant laboratory finding that, in the Investigator's opinion
would contraindicate the use of estradiol or compromise patients' safety.
4. Significant history of cholestatic jaundice, hypertension, coronary heart disease or
other serious heart problems, uncontrolled diabetes, hypercholesterolemia,
hypercalcemia, hypoparathyroidism, hypertriglyceridemia, systemic lupus erythematosus,
renal impairment, residual endometriosis posthysterectomy, asthma, epilepsy, migraine,
porphyria, hepatic hemangiomas that in the Investigator's opinion would place the
study patient at undue risk by participation or could jeopardize the integrity of the
study evaluations.
5. History of Protein C, Protein S, or antithrombin deficiency, or other thrombophilic
disorder.
6. Patients with known concurrent vaginal infections including but not limited to:
Candida albicans, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhea or
Gardnerella vaginalis.
7. Patients with active vaginal herpes simplex infection or have had an outbreak within
40 days before Screening
8. History of sexual abuse that in the opinion of the investigator may interfere with the
patient's assessment of vaginal pain with sexual activity.
9. Past or current diagnosis of endometrial hyperplasia.
10. Patients with known, suspected or current history of carcinoma of the breast.
11. Any patients with past or current undiagnosed vaginal bleeding or significant risk
factors for endometrial cancer.
12. History of estrogen-dependent neoplasia (e.g., endometrial cancer).
13. Any patients with hypersensitivity to estrogens.
14. Liver impairment or disease or kidney dysfunction or disorder (e.g., chronic renal
failure or hepatitis C).
15. History of thrombophlebitis, thrombosis, or thromboembolic disorders.
16. History of cerebrovascular accident, stroke, or transient ischemic attack.
17. History of Myocardial infarction or ischemic heart disease.
18. History or active presence of endocrine disease (except for controlled hypo- or
hyper-thyroidism or controlled non-insulin dependent diabetes mellitus). Patients who
are on a stable thyroid medication prior to the study should have normal baseline
thyroid function test results and expect not to have to change thyroid hormone regimen
during the study.
19. Any clinically significant abnormalities on screening physical exam, assessments, ECG,
or laboratory tests such as:
1. Vulvar or vaginal inflammatory condition such as a contact or allergic
dermatitis, lichen sclerosis, or other pathological findings.
2. Presence of suspicious vulvar or vaginal lesions for dysplasia, malignancy, or
other pathology other than atrophy.
3. History of active or chronic pelvic pain.
4. Painful genital warts or localized areas of ulceration.
5. Interstitial cystitis.
6. Unresolved findings suspicious for malignancy on the breast exam; incomplete
mammogram result or unresolved findings suggestive of malignant changes or
findings requiring follow-up on the pre-study mammogram.
7. Patients with an intact uterus who have an endometrial thickness of 4mm or
greater.
20. Any prescription treatment for vaginal dryness/irritation within 2 weeks before
screening or any over the counter or natural remedies, vaginal lubricants or
moisturizers within 1 week before screening.
21. Taking inducers of CYP3A4 such as St. John's wort, anticonvulsants, phenylbutazone,
rifampin, rifabutin, nevirapine and efavirenz.
22. Taking inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole,
itraconazole, ritonavir, nelfinavir and grapefruit juice.
23. Fasting triglyceride levels > 350 mg/dL.
24. History of radiation therapy or recent (within previous 6 weeks) surgical therapy to
the vaginal or cervical areas.
25. Any known or suspected allergies that in the Investigator's opinion would compromise
the safety of the patient.
26. Patients who have used vaginal hormonal products (i.e. rings, creams, gels) within the
4 weeks before Screening.
27. Patients who have used transdermal estrogen and/or progestin therapy within the 4
weeks before Screening.
28. Patients who have used oral estrogen, progestin, androgen or selective estrogen
receptor modular (SERM) containing drug products within 8 weeks before Screening
visit.
29. Intrauterine progestin therapy within 8 weeks before Screening.
30. Use of an intrauterine device within 12 weeks before screening visit.
31. Patients who have used estrogen pellet therapy or progestin implants/ injectable drug
therapy within the 6 months before Screening.
32. Patients who have engaged in sexual intercourse or used vaginal douching within 24
hours of the screening visit.
33. Inability to understand the requirements of the study and the relative information or
are unable or not willing to comply with the study protocol.
34. Patients who are unable or unwilling to give informed consent.
35. Current history of heavy smoking (more than 15 cigarettes per day) or use of
e-cigarettes.
36. Current use of marijuana.
37. Recent history of known alcohol or drug abuse, within one year start of the study.
38. Employees of the Investigator or research center or their immediate family members.
39. Receipt of any drug as part of a research study within 60 days before Screening.
40. Previous participation in this study.
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