A Comparison of Estradiol Vaginal Cream to Estrace® Cream in 350 Postmenopausal Females With Atrophic Vaginitis
Condition: Atrophic Vaginitis
MeSH terms: Vaginitis; Atrophic Vaginitis; Atrophy
Intervention: Estradiol Vaginal Cream, 0.01%; Estrace® 0.01% cream; Placebo Vaginal Cream
Intervention description: Estradiol Vaginal Cream, 0.01% (1 x 2g for 7 days); Estrace® 0.01% vaginal cream ( 1 x 2g for 7 days); Placebo Vaginal Cream ( 1 x 2 g for 7 days)
Intervention MeSH terms: Estradiol
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 366.0
Sex: Female
Minimum age: 40 Years
Maximum age: 70 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: vaginal dryness; vaginal and/or vulvar irritation/itching; dysuria; vaginal pain and bleeding associated with sexual activity; vaginal atrophy

Summary:

      The purpose of this study is to determine the therapeutic equivalence of Mylan's estradiol
      vaginal cream to Estrace® cream and superiority of both products to placebo. The protocol
      describes a randomized, double-blind, multi-dose, placebo-controlled, parallel study of a 7
      day treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Capable of providing informed consent.

          2. Age: 40-70 years old.

          3. Sex: Female

          4. Postmenopausal defined as at least 12 months of spontaneous amenorrhea or at least 6
             months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml or at least 6 weeks
             postsurgical bilateral oophorectomy with or without hysterectomy.

          5. Weight: At least 48 kg with all subjects having a Body Mass Index less than or equal
             to 38 kg/m2 but greater than or equal to 19 kg/m2.

          6. Baseline evaluation requirements:

               -  ≤5% superficial cells on vaginal smear cytology

               -  Vaginal pH > 5.0

               -  At least one patient self-assessed moderate to severe symptom of vulvar and/or
                  vaginal atrophy (VVA) from the following list that is identified by the subject:

               -  Vaginal dryness

               -  Vaginal and/or vulvar irritation/itching

               -  Dysuria

               -  Vaginal pain associated with sexual activity

               -  Vaginal bleeding associated with sexual activity (absence vs. presence)

          7. All subjects should be judged to be eligible for participation in this study by the
             principal or sub-investigator physician during a pre-study medical evaluation
             performed within 28 days of the initial dose of study medication which will include:

               1. a normal or non-clinically significant physical examination, including vital
                  signs

               2. a normal or non-clinically significant pelvic examination that was consistent
                  with hypoestrogenemia

               3. a normal or non-clinically significant breast exam and mammogram

               4. a normal or non-clinically significant ASCUS Papanicolaou ("Pap") smear that is
                  negative for HPV for subjects with an intact uterus and cervix

               5. within normal limits or non-clinically significant laboratory evaluation results
                  (unless otherwise noted in the exclusion criteria) for the following tests:

                    -  Serum Chemistry

                    -  Hematology

                    -  Coagulogram

                    -  Urinalysis

               6. normal or non-clinically significant 12- Lead ECG.

               7. negative urine drug screen including amphetamine, barbiturates, benzodiazepines,
                  cannabinoid, cocaine, opiates, methadone and phencyclidine with the following
                  exceptions: positive tests for amphetamines, barbiturates, benzodiazepines, or
                  opiates may be allowed provided the subject has a valid prescription and is on a
                  stable regimen that complies with Exclusion Criteria, Section 6.3.2.

               8. negative urine cotinine test.

          8. For women with an intact uterus, an endometrial thickness < 5 mm as determined by
             vaginal ultrasonography.

          9. If warranted, other tests or examinations may be performed at the discretion of the
             Principal Investigator or responsible physician.

         10. Ability to use applicator properly.

        Exclusion Criteria:

          1. Institutionalized subjects will not be used.

          2. Any contraindication to estrogen therapy.

          3. Social Habits:

               1. Use of any tobacco-containing products within 1 year of the start of the study.

               2. Regular intake of more than 7 units of alcohol per week.

               3. Beginning any new regimens of vitamins or herbal products within 7 days prior to
                  the initial dose of the study medication.

               4. Any recent, significant change in dietary or exercise habits.

               5. History of drug and/or alcohol abuse within one year of start of study.

          4. Medications:

               1. Use of any new prescription or over-the-counter (OTC) medication regimens within
                  fourteen (14) days prior to the initial dose of study medication (any necessary
                  medication, unless otherwise noted in the exclusion criteria, for which dosing
                  has been stabilized for a period of at least 14 days prior to initial dosing of
                  study drug and is expected to remain stable for the entire study period is
                  allowed, with the exception of acetaminophen, which may be administered as needed
                  to treat minor adverse events).

               2. Use of hormonal replacement therapies for the following time periods:

                    -  within 2 weeks of baseline assessment for vaginal therapy (rings, creams,
                       gels)

                    -  within 4 weeks of baseline assessment for transdermal estrogen alone or
                       estrogen/progestin therapy

                    -  within 8 weeks of baseline assessment for oral estrogen and/or progestin
                       therapy or intrauterine progestin therapy

                    -  within 3 months of baseline assessments for progestin implants or estrogen
                       alone injectable therapy

                    -  within 6 months of baseline assessments for estrogen pellet or progestin
                       injectable therapy

               3. A depot injection or implant of any drug within 3 months prior to administration
                  of study medication.

               4. Currently taking medication indicated for anticoagulation as a result of an
                  excluded condition listed in #5 below. This includes but is not limited to
                  warfarin, heparin, NSAIDs, clopidogrel, dabigatran, etc.

          5. Diseases:

               1. History of any significant cardiovascular, hepatic, renal, pulmonary,
                  hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic,
                  psychological, urinary, musculoskeletal disease or malignancies unless under
                  medical control and/or deemed not clinically significant by the Principal
                  Investigator or Medical Sub-investigator.

               2. Manifestation or treatment for significant cardiovascular disease (congestive
                  heart failure, stroke or ischemic attack, myocardial infarction, coronary artery
                  bypass, percutaneous angioplasty or > 50% angiographic narrowing of coronary
                  artery, thrombosis of deep veins and arteries, thromboembolic disorders,
                  pulmonary embolism) or history of these conditions.

               3. Coronary artery or cerebrovascular disease.

               4. Current clinically significant liver or kidney dysfunction/disorders.

               5. Current clinically significant gallbladder dysfunction/disorders.

               6. Abnormal or clinically significant breast examination. Acceptable breast
                  examination is defined as no masses or other findings identified that are
                  suspicious of malignancy.

               7. First degree family history of breast cancer.

               8. Current non diet controlled diabetes mellitus or other clinically significant
                  endocrinological disease.

               9. Estrogen-dependent neoplasia

              10. Postmenopausal uterine bleeding

              11. Endometrial hyperplasia

              12. Uncontrolled hypothyroidism

              13. Urinalysis showing an ongoing clinically significant urinary tract infection that
                  requires treatment.

              14. Current clinically significant vaginal infection that requires treatment.

              15. Known chronic lichen sclerosis

              16. Acute illness at the time of either the pre-study medical evaluation or dosing.

              17. History of allergy or hypersensitivity to estradiol, other related products, or
                  any inactive ingredients.

              18. Undiagnosed vaginal bleeding or history of significant risk factors for
                  endometrial cancer.

              19. Increased frequency or severity of headaches while on previous hormone or
                  estrogen therapy.

              20. History of psychiatric disorders occurring within the last 6 months that require
                  hospitalization or medication.

              21. Current hypercalcemia, hypocalcemia, and/or hypertriglyceridemia.

              22. Clinically significant eye/visual abnormalities such as retinal vascular
                  thrombosis, partial or complete loss of vision, proptosis, diplopia, papilledema,
                  retinal vascular lesions.

          6. Any reason which, in the opinion of the Principal Investigator or Medical
             Sub-Investigator, would prevent the subject from safely participating in the study.

          7. Subjects who have received an investigational drug within 30 days prior to the initial
             dose of study medication.

          8. Sitting blood pressure higher than 150/90 mmHg at screening.

          9. Baseline serum estradiol levels >30 pg/mL at screening.