A Comparison of Estradiol Vaginal Cream to Estrace� Cream in 350 Postmenopausal Females With Atrophic Vaginitis

Condition(s) targeted: Atrophic Vaginitis

Intervention: Estradiol Vaginal Cream, 0.01% (Drug); Estrace® 0.01% cream (Drug); Placebo Vaginal Cream (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Mylan Inc.

Official(s) and/or principal investigator(s):
Matt Hummel, Ph.D., Study Chair, Affiliation: Mylan Pharmaceuticals
Ronald Ackerman, M.D., Principal Investigator, Affiliation: Comprehensive Clinical Trials, LLC
James Andersen, M.D., Principal Investigator, Affiliation: Meridien Research
Keith Aqua, M.D., Principal Investigator, Affiliation: Visions Clinical Research
Theodore Cooper, M.D., Principal Investigator, Affiliation: Horizons Clinical Research Center, LLC
Scott Eder, M.D., Principal Investigator, Affiliation: Women's Health Research Center/The Center for Women's Health & Wellness, LLC
William Koltun, M.D., Principal Investigator, Affiliation: Medical Center for Clinical Research
Gigi Lefebvre, M.D., Principal Investigator, Affiliation: Meridien Research
Leonard Ranasinghe, M.D., Principal Investigator, Affiliation: Northern CA Research
Rovena Reagan, M.D., Principal Investigator, Affiliation: Women's Health Care Research Corp.
Ronald Surowitz, D.O., Principal Investigator, Affiliation: Health Awareness, Inc.
Steven Sussman, M.D., Principal Investigator, Affiliation: Lawrence OB/GYN Clinical Research, LLC
G. Michael Swor, M.D., Principal Investigator, Affiliation: Physician Care Clinical Research LLC
Olga Tudela, M.D., Principal Investigator, Affiliation: Veritas Research., Corp.
Arthur Waldbaum, M.D., Principal Investigator, Affiliation: Downtown Women's Health Care

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.

Official title: Clinical Endpoint Therapeutic Equivalence Multi-Site Study Comparing Estradiol Vaginal Cream (0.01%; Mylan) to Estrace® Cream (0.01%; Warner Chilcott) in Postmenopausal Females With Atrophic Vaginitis

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Vaginal Cytology

Vaginal pH

Secondary outcome: Patient self-assessment of the symptoms of vulvar and vaginal atrophy

Minimum age: 40 Years. Maximum age: 70 Years. Gender(s): Female.

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.

Axis Clinical Trials, Los Angeles, California 90036, United States

Northern CA Research, Sacramento, California 95821, United States

MCCR, San Diego, California 92108, United States

Women's Health Care Research Corp., San Diego, California 92123, United States

MCB Clinical Research Centers, Colorado Springs, Colorado 80910, United States

Downtown Women's Health Care, Denver, Colorado 80209, United States

Horizons Clinical Research Center, LLC, Denver, Colorado 80220, United States

Sunrise Medical Research, Coral Springs, Florida 33065, United States

Health Awareness, Inc., Jupiter, Florida 33458, United States

Meridien Research, Lakeland, Florida 33805, United States

OB-GYN Associates of Mid Florida, Leesburg, Florida 34748, United States

Veritas Research, Corp., Miami Lakes, Florida 33014, United States

SouthCoast Research Center, Miami, Florida 33136, United States

Physician Care Clinical Research LLC, Sarasota, Florida 34239, United States

Meridien Research, St. Petersburg, Florida 33709, United States

Sunrise Medical Research, Tamarac, Florida 33351, United States

Comprehensive Clinical Trials, LLC, West Palm Beach, Florida 33409, United States

Georgia Center for Women, Atlanta, Georgia 30312, United States

Lawrence OB/GYN Clinical Research, LLC, Lawrenceville, New Jersey 08690, United States

Women's Health Research Center/The Center for Women's Health & Wellness, LLC, Plainsboro, New Jersey 08536, United States

Starting date: June 2014
Last updated: February 9, 2015