Estradiol Vaginal Softgel Capsules in Treating Symptoms of Vulvar and Vaginal Atrophy in Postmenopausal Women

NCT ID: NCT02253173

Last Updated: 2017-05-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 764 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-30
• Study Completion Date: 2015-10-31

Brief Summary

This study will assess the safety and efficacy of a new formulation of vaginal estradiol for the treatment of symptoms of vulvar and vaginal atrophy in postmenopausal women.

Conditions

Vulvovaginal Atrophy; Menopause; Dyspareunia; Painful Intercourse

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Estradiol 4mcg Vaginal Softgel Capsule

Estradiol 4mcg Vaginal Softgel Capsule

Group Type: EXPERIMENTAL

Estradiol

Intervention Type: DRUG

Estradiol 10mcg Vaginal Softgel Capsule

Estradiol 10mcg Vaginal Softgel Capsule

Group Type: EXPERIMENTAL

Estradiol

Intervention Type: DRUG

Estradiol 25mcg Vaginal Softgel Capsule

Estradiol 25mcg Vaginal Softgel Capsule

Group Type: EXPERIMENTAL

Estradiol

Intervention Type: DRUG

Placebo Vaginal Softgel Capsule

Placebo Vaginal Softgel Capsule

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Estradiol

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Postmenopausal female subjects between the ages of 40 and 75 years (at the time of randomization) with at least:

• 12 months of spontaneous amenorrhea (women <55 years of age with a history of hysterectomy without bilateral oophorectomy prior to natural menopause must have follicle stimulating hormone (FSH) levels > 40 mIU/mL), OR
• 6 months of spontaneous amenorrhea with follicle stimulating hormone (FSH) levels > 40mlU/mL OR
• At least 6 weeks postsurgical bilateral oophorectomy.

2. ≤5% superficial cells on vaginal cytological smear

3. Vaginal pH > 5.0

4. Moderate to severe symptom of vaginal pain associated with sexual activity considered the most bothersome vaginal symptom by the subject at screening visit 1A.

5. Moderate to severe symptom of vaginal pain associated with sexual activity at screening visit 1B.

6. Onset of moderate to severe dyspareunia in the postmenopausal years.

7. Subjects should be sexually active (i.e. have sexual activity with vaginal penetration within approximately 1 month of screening visit 1A).

8. Subjects should anticipate having sexual activity (with vaginal penetration) during the conduct of the trial.

9. For subjects with an intact uterus: Subjects must have an acceptable result from an evaluable screening endometrial biopsy.

10. Subjects who have a Body Mass Index (BMI) less than or equal to 38 kg/m2. BMI values should be rounded to the nearest integer (ex. 32.4 rounds down to 32, while 26.5 rounds up to 27).

11. In the opinion of the investigator, the subject will comply with the protocol and has a high probability of completing the study.

Exclusion Criteria

1. Use of the following:

1. Oral estrogen-, progestin-, androgen-, or SERM-containing drug products within 8 weeks before screening visit 1A (can enter washout);

2. Use of transdermal hormone products within 4 weeks before screening visit 1A (can enter washout);

3. Use of vaginal hormone products (rings, creams, gels) within 4 weeks before screening visit1A (can enter washout);

4. Use of intrauterine progestins within 8 weeks before screening visit 1A (can enter washout);

5. Use of progestin implants/injectables or estrogen pellets/injectables within 6 months before screening visit 1A (cannot enter washout);

6. Use of vaginal lubricants or moisturizers within 7 days before the screening visit 1B vaginal pH assessment.

2. A history or active presence of clinically important medical disease that might confound the study or be detrimental to the subject, examples include:

1. Hypersensitivity to estrogens;

2. Endometrial hyperplasia;

3. Undiagnosed vaginal bleeding;

4. Have a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis C or chronic renal failure);

5. Thrombophlebitis, thrombosis or thromboembolic disorders;

6. Cerebrovascular accident, stroke, or transient ischemic attack;

7. Myocardial infarction or ischemic heart disease;

8. Malignancy or treatment for malignancy, within the previous 5 years, with the exception of basal cell carcinoma of the skin or squamous cell carcinoma of the skin. A history of estrogen dependent neoplasia, breast cancer, melanoma or any gynecologic cancer, at any time, excludes the subject;

9. Endocrine disease (except for controlled hypothyroidism or controlled non-insulin dependent diabetes mellitus).

3. Recent history of known alcohol or drug abuse.

4. History of sexual abuse or spousal abuse that, in the opinion of the PI, may interfere with the subject's assessment of vaginal pain with sexual activity.

5. Current history of Heavy smoking (more than 15 cigarettes per day) or use of e-cigarettes.

6. Use of an intrauterine device within 12 weeks before screening visit 1A.

7. Use of an investigational drug within 60 days before screening visit 1A.

8. Any clinically important abnormalities on screening physical exam, assessments, ECG, or laboratory tests, such as:

1. Unresolved cervical cytologic smear report of atypical glandular cells of undetermined significance (AGUS) or atypical squamous cells of undetermined significance (ASCUS).

Cervical cytologic smear report of low-grade squamous intraepithelial lesion (SIL) or greater, CIN1 or greater, or any reported dysplasia; Subjects with ASCUS are eligible only if high risk human papilloma virus (HPV) result is negative.

2. Unresolved findings suspicious for malignancy on the breast exam; incomplete mammogram result (BI-RADS 0) or unresolved findings suggestive of malignant changes or findings requiring short interval follow-up on the prestudy mammogram (subjects must have mammography result of BI-RADS 1 or 2 to enroll.) Mammogram may be performed within 9 months prior to Visit 2 (randomization) with documentation available. (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);

3. In subjects with intact uterus: have a screening endometrial biopsy sample that is found by both primary pathologists to have endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified. (With the approval of the Medical Monitor, the screening endometrial biopsy may be repeated once);

4. In subjects with intact uterus: an endometrial biopsy report by one central pathologist at screening with one of the following:

• Endometrial hyperplasia endometrial cancer, proliferative endometrium, weakly proliferative endometrium, disordered proliferative pattern; OR
• Endometrial polyps with hyperplasia, glandular atypia of any degree (e.g., atypical nuclei) or cancer;

5. Vulvar or vaginal inflammatory condition such as a contact or allergic dermatitis, lichen sclerosis or other pathological findings;

6. Presence of suspicious vulvar or vaginal lesions for dysplasia, malignancy or other pathology other than atrophy;

7. Painful genital warts or localized areas of ulceration;

8. A history of active, chronic pelvic pain;

9. Interstitial cystitis;

10. Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal for the laboratory used;

11. Fasting total cholesterol greater than 300 mg/dL (7.77 mmol/L) or triglycerides greater than 300 mg/dL (3.39 mmol/L);

12. Fasting blood glucose greater than 125 mg/dL (6.94 mmol/L) with a hemoglobin A1C of greater than or equal to 6.5%;

13. Uncontrolled hypertension; subjects with elevated sitting blood pressure, greater than 140 mm Hg systolic or greater than 90 mm Hg diastolic and may not be using more than 2 antihypertensive medications for the treatment of hypertension;

14. Clinically significant abnormal 12-lead ECG (such as myocardial infarction or other findings suggestive of ischemia)

9. Be known to be pregnant or have a positive urine pregnancy test. (Note: A pregnancy test is not required for subjects who have had bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or are 55 years old or greater and have experienced cessation of menses for at least 1 year.

10. Current use of marijuana.

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

TherapeuticsMD

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Medical Affiliated Research Center

Huntsville, Alabama, United States

Montogomery Women's Health

Montgomery, Alabama, United States

Cactus Clinical Research

Mesa, Arizona, United States

Arizona Wellness Center for Women

Phoenix, Arizona, United States

Radiant Research

Scottsdale, Arizona, United States

Visions Clinical Research - Tucson

Tucson, Arizona, United States

Sutter East Bay Medical Foundation

Berkeley, California, United States

Torrance Clinical Research Institute Inc

Lomita, California, United States

Futura Research

Norwalk, California, United States

Northern California Research

Sacramento, California, United States

Medical Center for Clinical Research

San Diego, California, United States

San Diego Sexual Medicine

San Diego, California, United States

Women's Health Care Research Corp.

San Diego, California, United States

Lynn Institute of the Rockies

Colorado Springs, Colorado, United States

Downtown Women's Health Care

Denver, Colorado, United States

Horizons Clinical Research Center

Denver, Colorado, United States

Red Rocks OB/Gyn

Lakewood, Colorado, United States

Clinical Research Consulting

Milford, Connecticut, United States

Coastal Connecticut Research, LLC

New London, Connecticut, United States

James A. Simon, Women's Health & Research Consultants

Washington D.C., District of Columbia, United States

South Florida Medical Research

Aventura, Florida, United States

Nature Coast Clinical Research

Crystal River, Florida, United States

Avail Clinical Research

DeLand, Florida, United States

Clinical Physiology Associates

Fort Myers, Florida, United States

UF Health Physicians Women's & REI Springhill

Gainesville, Florida, United States

UF College of Medicine-Jacksonville, Dept. of Obstetrics and Gynecology

Jacksonville, Florida, United States

Jacksonville Center for Clinical Research

Jacksonville, Florida, United States

South Florida Wellness & Clinical Research Institute

Margate, Florida, United States

New Age Medical Research Corporation

Miami, Florida, United States

Suncoast Clinical Research, Inc.

New Port Richey, Florida, United States

Healthcare Clinical Data

North Miami, Florida, United States

Ideal Clinical Research

North Miami Beach, Florida, United States

Radiant Research

Pinellas Park, Florida, United States

All Women's Healthcare of West Broward

Plantation, Florida, United States

Physician Care Clinical Research

Sarasota, Florida, United States

Comprehensive Clinical Trials

West Palm Beach, Florida, United States

Women's Health Associates

Atlanta, Georgia, United States

Masters of Clinical Research, Inc.

Augusta, Georgia, United States

Soapstone Center for Clinical Research

Decatur, Georgia, United States

WR-Mount Vernon Clinical Research

Sandy Springs, Georgia, United States

Fellows Research Alliance, Inc.

Savannah, Georgia, United States

Advanced Clinical Research

Boise, Idaho, United States

Women's Healthcare Associates P.A.

Idaho Falls, Idaho, United States

Radiant Research

Chicago, Illinois, United States

American Health Network of Indiana, LLC

Avon, Indiana, United States

Lafayette Clinical Research Group

Lafayette, Indiana, United States

Cypress Medical Research Center

Wichita, Kansas, United States

Central Kentucky Research Associates, Inc.

Lexington, Kentucky, United States

Bluegrass Clinical Research, Inc.

Louisville, Kentucky, United States

Horizon Research Group of Opelousas

Eunice, Louisiana, United States

Capital Women's Care

Frederick, Maryland, United States

Maryland Center for Sexual Health

Lutherville, Maryland, United States

ClinSite, LLC

Ann Arbor, Michigan, United States

Beyer Research

Kalamazoo, Michigan, United States

Saginaw Valley Medical Research Group, L.L.C.

Saginaw, Michigan, United States

Montana Health

Billings, Montana, United States

Women's Clinic of Lincoln

Lincoln, Nebraska, United States

Office of Edmond E. Pack, MD

Las Vegas, Nevada, United States

Office of R. Garn Mabey, MD

Las Vegas, Nevada, United States

Lawrence OB-GYN Clinical Research, LLC

Lawrenceville, New Jersey, United States

Rutgers-Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States

Women's Health Research Center

Plainsboro, New Jersey, United States

Bosque Women's Care

Albuquerque, New Mexico, United States

Southwest Clinical Research

Albuquerque, New Mexico, United States

Columbia University Medical Center

New York, New York, United States

Suffolk OB/GYN

Port Jefferson, New York, United States

Women's Wellness Clinic

Durham, North Carolina, United States

Pinewest OB-GYN, Inc.

High Point, North Carolina, United States

Wake Research Associates

Raleigh, North Carolina, United States

Hawthorne Research

Winston-Salem, North Carolina, United States

Lyndhurst Clinical Research

Winston-Salem, North Carolina, United States

Lillestol Research

Fargo, North Dakota, United States

Radiant Research

Akron, Ohio, United States

University of Cincinnati Physicians Company

Cincinnati, Ohio, United States

Rapid Medical Research

Cleveland, Ohio, United States

Columbus Center for Women's Health Research

Columbus, Ohio, United States

HWC Women's Research Center

Englewood, Ohio, United States

Landerbrook Health Center

Mayfield Heights, Ohio, United States

Sunstone Medical Research

Medford, Oregon, United States

The Clinical Trial Center

Jenkintown, Pennsylvania, United States

Clinical Research of Philadelphia

Philadelphia, Pennsylvania, United States

Clinical Trials Research Services

Pittsburgh, Pennsylvania, United States

Fellows Research Alliance, Inc.

Bluffton, South Carolina, United States

Vista Clinical Research

Columbia, South Carolina, United States

Coastal Carolina Research Center

Mt. Pleasant, South Carolina, United States

Chattanooga Medical Research

Chattanooga, Tennessee, United States

Advanced Research Associates

Corpus Christi, Texas, United States

Research Across America

Dallas, Texas, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Advances in Health

Houston, Texas, United States

Hwca, Pllc

Houston, Texas, United States

TMC Life Research

Houston, Texas, United States

Stone Oak, LLC dba Discovery Clinical Trials

San Antonio, Texas, United States

National Clinical Research-Norfolk

Norfolk, Virginia, United States

Clinical Research Center, EVMS

Norfolk, Virginia, United States

Virginia Women's Center, Inc.

Richmond, Virginia, United States

National Clinical Research-Richmond, Inc

Richmond, Virginia, United States

Tidewater Clinical Research

Virginia Beach, Virginia, United States

Seattle Women's Health, Research, and Gynecology

Seattle, Washington, United States

North Spokane Women's Health

Spokane, Washington, United States

Diex Research Montreal Inc.

Montreal, Quebec, Canada

Center for Research Saint-Louis

Québec, Quebec, Canada

Manna Research Inc

Saint Romuald, Quebec, Canada

Diex Research Sherbrooke Inc.

Sherbrooke, Quebec, Canada

Clinique RSF Inc.

Québec, , Canada

Countries

United States; Canada

References

Lara LA, Cartagena-Ramos D, Figueiredo JB, Rosa-E-Silva ACJ, Ferriani RA, Martins WP, Fuentealba-Torres M. Hormone therapy for sexual function in perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2023 Aug 24;8(8):CD009672. doi: 10.1002/14651858.CD009672.pub3.

Reference Type: DERIVED

PMID: 37619252 (View on PubMed)

Mirkin S, Simon JA, Liu JH, Archer DF, Castro PD, Graham S, Bernick B, Komm B. Evaluation of endometrial progesterone receptor expression after 12 weeks of exposure to a low-dose vaginal estradiol insert. Menopause. 2021 May 28;28(9):998-1003. doi: 10.1097/GME.0000000000001801.

Reference Type: DERIVED

PMID: 34054104 (View on PubMed)

Constantine G, Millheiser LS, Kaunitz AM, Parish SJ, Graham S, Bernick B, Mirkin S. Early onset of action with a 17beta-estradiol, softgel, vaginal insert for treating vulvar and vaginal atrophy and moderate to severe dyspareunia. Menopause. 2019 Nov;26(11):1259-1264. doi: 10.1097/GME.0000000000001394.

Reference Type: DERIVED

PMID: 31688572 (View on PubMed)

Constantine GD, Simon JA, Pickar JH, Archer DF, Bernick B, Graham S, Mirkin S. Estradiol vaginal inserts (4 microg and 10 microg) for treating moderate to severe vulvar and vaginal atrophy: a review of phase 3 safety, efficacy and pharmacokinetic data. Curr Med Res Opin. 2018 Dec;34(12):2131-2136. doi: 10.1080/03007995.2018.1527578. Epub 2018 Sep 28.

Reference Type: DERIVED

PMID: 30238814 (View on PubMed)

Constantine GD, Bouchard C, Pickar JH, Archer DF, Graham S, Bernick B, Mirkin S. Consistency of Effect with a Low-Dose, Estradiol Vaginal Capsule (TX-004HR): Evaluating Improvement in Vaginal Physiology and Moderate-to-Severe Dyspareunia in Subgroups of Postmenopausal Women. J Womens Health (Larchmt). 2017 Jun;26(6):616-623. doi: 10.1089/jwh.2016.6187. Epub 2017 Mar 29.

Reference Type: DERIVED

PMID: 28355090 (View on PubMed)

Other Identifiers

TXV14-01

Identifier Type: -

Identifier Source: org_study_id