Study to Evaluate Equivalence of Estradiol Vaginal Cream 0.01% to Estrace® Cream 0.01% in Atrophic Vaginitis
Condition: Atrophic Vaginitis
MeSH terms: Vaginitis; Atrophic Vaginitis; Atrophy
Intervention: Generic Estradiol Vaginal Cream USP, 0.01%; Estrace® Vaginal Cream USP, 0.01%; Vehicle Vaginal Cream
Intervention description: Vaginal cream, generic formulation of the brand product.; Vaginal cream, brand product.; Vaginal cream, placebo. Has no active ingredient
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 663.0
Sex: Female
Minimum age: 30 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      The objectives of this study were to evaluate the therapeutic equivalence of the Test
      formulation, generic Estradiol Vaginal Cream United States Pharmacopoeia (USP), 0.01% (Teva
      Pharmaceuticals, United States of America) to the marketed product, Estrace® Cream estradiol
      vaginal cream USP, 0.01% (Warner Chilcott) in participants with atrophic vaginitis; to
      demonstrate the superiority of the Test and Reference (active) treatments over Placebo
      (vehicle) cream in participants with atrophic vaginitis; and to compare the safety of Test,
      Reference, and Placebo treatments in participants with atrophic vaginitis.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed Informed Consent Form (ICF) that meets all criteria of current Food and Drug
             Administration (FDA) regulations.

          -  Females aged 30-75 years inclusive who are postmenopausal, defined as follows:

          -  At least 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea
             with serum follicle-stimulating hormone (FSH) level of >40 milli-international units
             per milliliter (mIU/mL); at least 6 weeks post-surgical bilateral oophorectomy, with
             or without hysterectomy; or hysterectomy without oophorectomy if of age that the
             Investigator believes would have been naturally reached 12 months of spontaneous
             amenorrhea.

          -  Vaginal pH >5.0.

          -  At least 1 of the following participant self-assessed moderate to severe symptoms of
             vulvar and vaginal atrophy (VVA) from the following list that is identified by the
             participant as being most bothersome to her:

               1. Vaginal Dryness

               2. Vaginal and/or vulvar irritation/itching

               3. Dysuria

               4. Vaginal pain or bleeding associated with sexual activity, provided that
                  participant is currently sexually active and plans to remain so throughout study.

          -  "Normal" Screening mammogram completed within 9 months prior to Screening in all
             participants >40 years old.

          -  Normal clinical breast examination at the Screening Visit.

          -  Documented papanicolaou (PAP) smear conducted within the previous 12 months with no
             findings that the Investigator believes would contraindicate the use of topical
             vaginal estradiol.

          -  Participants with an intact uterus should have vaginal ultrasonography results to
             confirm an inactive endometrial lining, defined as endometrial thickness less than 4
             millimeters (mm).

        Exclusion Criteria:

          1. Females younger than 30 years of age or older than 75 years of age.

          2. Participants with a Serum follicle-stimulating hormone (FSH) level of ≤40 mIU/mL at
             Screening.

          3. Greater than 5% superficial cells on vaginal cytology.

          4. Vaginal pH ≤5.

          5. Significant history or current evidence of chronic infectious disease, system
             disorder, organ disorder (including significant liver/kidney impairment) or other
             medical condition that in the Investigator's opinion would place the study participant
             at undue risk by participation or could jeopardize the integrity of the study
             evaluations.

          6. Participants with an intact uterus should have vaginal ultrasonography results to
             confirm an inactive endometrial lining. Participants with an endometrial thickness
             equal to or greater than 4 mm.

          7. Documented PAP smear conducted within the previous 12 months with findings that the
             Investigator believes would contraindicate the use of topical vaginal estradiol.

          8. Participants with known concurrent vaginal infections including but not limited to:

             Candida albicans, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhea,
             or Gardnerella vaginalis.

          9. Participants with active vaginal herpes simplex infection or have had an outbreak
             within 30 days of the first dosing day.

         10. Participants with known, suspected, or current history of carcinoma of the breast. All
             participants over the age of 40 must have had a mammogram performed within 9 months of
             the study start and all participants will have a physical breast exam performed at
             Screening.

         11. Participants with known, suspected or current history of hormone dependent tumor.

         12. Participants with baseline systolic blood pressure of >150 millimetres of mercury
             (mmHg) and/or diastolic pressure >90 mmHg.

         13. Any participant with undiagnosed vaginal bleeding or significant risk factors for
             endometrial cancer.

         14. Any history of estrogen-dependent neoplasia (for example, endometrial cancer).

         15. History of acute thrombophlebitis or thromboembolic disorder.

         16. Any current or recent (within the previous 6 months) genital bleeding of unknown
             etiology.

         17. Any prescription treatment or over-the-counter (OTC) or natural remedies for vaginal
             dryness/irritation within 28 days of Screening. Products used for lubrication during
             sexual intercourse within 7 days of Screening.

         18. Participants whose fasting triglyceride levels are greater than 350 mg/dL.

         19. Any participant with a history of radiation therapy or recent (within previous 6
             weeks) surgical therapy to the vaginal or cervical areas.

         20. Any known or suspected allergies that in the Investigator's opinion would compromise
             the safety of the participant.

         21. Participants who have used vaginal hormonal products (rings, creams, gels) within the
             28 days prior to Screening.

         22. Any participant who has used transdermal estrogen and/or progestin therapy within the
             28 days prior to Screening.

         23. Participants who have used oral estrogen and/ or progestin therapy or intrauterine
             progestin therapy within the 56 days prior to Screening.

         24. Participants who have used progestin implants or estrogen alone injectable drug
             therapy within the 3 months before Screening.

         25. Participants who have used estrogen pellet therapy or progestin injectable drug
             therapy within the 6 months before Screening.

         26. Participants who, in the opinion of the Investigator, would be non-compliant with the
             requirements of the study protocol.

         27. Participants who are unable or unwilling to give informed consent.

         28. Receipt of any drug as part of a research study within 30 days prior to Screening.

         29. Participants who have participated in this study previously.