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

Menopause Clinical Trial

— REJOICE  

Official title:

A Phase 3, Randomized, Double-blind, Placebo-controlled, Multi-center Trial to Evaluate the Safety and Efficacy of TX-004HR in Postmenopausal Women With Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02253173
• Other study ID #: TXV14-01
• Status: Completed
• Phase: Phase 3
• First received: September 26, 2014
• Last updated: November 2, 2015
• Start date: September 2014
• Est. completion date: October 2015

Study information

• Verified date: November 2015
• Source: TherapeuticsMD
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 764
• Est. completion date: October 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 40 Years to 75 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Atrophy
• Dyspareunia
• Menopause
• Painful Intercourse
• Vulvovaginal Atrophy

Intervention

Drug:
• Estradiol

• Placebo

Locations

Country	Name	City	State
Canada	Diex Research Montreal Inc.	Montreal	Quebec
Canada	Center for Research Saint-Louis	Quebec
Canada	Clinique RSF Inc.	Quebec
Canada	Diex Research Sherbrooke Inc.	Sherbrooke	Quebec
Canada	Manna Research Inc	St-Romuald	Quebec
United States	Radiant Research	Akron	Ohio
United States	Bosque Women's Care	Albuquerque	New Mexico
United States	Southwest Clinical Research	Albuquerque	New Mexico
United States	ClinSite, LLC	Ann Arbor	Michigan
United States	Women's Health Associates	Atlanta	Georgia
United States	Masters of Clinical Research, Inc.	Augusta	Georgia
United States	South Florida Medical Research	Aventura	Florida
United States	American Health Network of Indiana, LLC	Avon	Indiana
United States	Sutter East Bay Medical Foundation	Berkeley	California
United States	Montana Health	Billings	Montana
United States	Fellows Research Alliance, Inc.	Bluffton	South Carolina
United States	Advanced Clinical Research	Boise	Idaho
United States	Chattanooga Medical Research	Chattanooga	Tennessee
United States	Radiant Research	Chicago	Illinois
United States	University of Cincinnati Physicians Company	Cincinnati	Ohio
United States	Rapid Medical Research	Cleveland	Ohio
United States	Lynn Institute of the Rockies	Colorado Springs	Colorado
United States	Vista Clinical Research	Columbia	South Carolina
United States	Columbus Center for Women's Health Research	Columbus	Ohio
United States	Advanced Research Associates	Corpus Christi	Texas
United States	Nature Coast Clinical Research	Crystal River	Florida
United States	Research Across America	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Soapstone Center for Clinical Research	Decatur	Georgia
United States	Avail Clinical Research	DeLand	Florida
United States	Downtown Women's Health Care	Denver	Colorado
United States	Horizons Clinical Research Center	Denver	Colorado
United States	Women's Wellness Clinic	Durham	North Carolina
United States	HWC Women's Research Center	Englewood	Ohio
United States	Horizon Research Group of Opelousas	Eunice	Louisiana
United States	Lillestol Research	Fargo	North Dakota
United States	Clinical Physiology Associates	Fort Myers	Florida
United States	Capital Women's Care	Frederick	Maryland
United States	UF Health Physicians Women's & REI Springhill	Gainesville	Florida
United States	Pinewest OB-GYN, Inc.	High Point	North Carolina
United States	Advances in Health	Houston	Texas
United States	Hwca, Pllc	Houston	Texas
United States	TMC Life Research	Houston	Texas
United States	Medical Affiliated Research Center	Huntsville	Alabama
United States	Women's Healthcare Associates P.A.	Idaho Falls	Idaho
United States	Jacksonville Center for Clinical Research	Jacksonville	Florida
United States	UF College of Medicine-Jacksonville, Dept. of Obstetrics and Gynecology	Jacksonville	Florida
United States	The Clinical Trial Center	Jenkintown	Pennsylvania
United States	Beyer Research	Kalamazoo	Michigan
United States	Lafayette Clinical Research Group	Lafayette	Indiana
United States	Red Rocks OB/Gyn	Lakewood	Colorado
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	Central Kentucky Research Associates, Inc.	Lexington	Kentucky
United States	Women's Clinic of Lincoln	Lincoln	Nebraska
United States	Torrance Clinical Research Institute Inc	Lomita	California
United States	Bluegrass Clinical Research, Inc.	Louisville	Kentucky
United States	Maryland Center for Sexual Health	Lutherville	Maryland
United States	South Florida Wellness & Clinical Research Institute	Margate	Florida
United States	Landerbrook Health Center	Mayfield Heights	Ohio
United States	Sunstone Medical Research	Medford	Oregon
United States	Cactus Clinical Research	Meza	Arizona
United States	New Age Medical Research Corporation	Miami	Florida
United States	Clinical Research Consulting	Milford	Connecticut
United States	Montogomery Women's Health	Montgomery	Alabama
United States	Coastal Carolina Research Center	Mt. Pleasant	South Carolina
United States	Rutgers-Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Coastal Connecticut Research, LLC	New London	Connecticut
United States	Suncoast Clinical Research, Inc.	New Port Richey	Florida
United States	Columbia University Medical Center	New York	New York
United States	Clinical Research Center, EVMS	Norfolk	Virginia
United States	National Clinical Research-Norfolk	Norfolk	Virginia
United States	Healthcare Clinical Data	North Miami	Florida
United States	Ideal Clinical Research	North Miami Beach	Florida
United States	Futura Research	Norwalk	California
United States	Clinical Research of Philadelphia	Philadelphia	Pennsylvania
United States	Arizona Wellness Center for Women	Phoenix	Arizona
United States	Radiant Research	Pinellas Park	Florida
United States	Clinical Trials Research Services	Pittsburgh	Pennsylvania
United States	Women's Health Research Center	Plainsboro	New Jersey
United States	All Women's Healthcare of West Broward	Plantation	Florida
United States	Suffolk OB/GYN	Port Jefferson	New York
United States	Wake Research Associates	Raleigh	North Carolina
United States	National Clinical Research-Richmond, Inc	Richmond	Virginia
United States	Virginia Women's Center, Inc.	Richmond	Virginia
United States	Northern California Research	Sacramento	California
United States	Saginaw Valley Medical Research Group, L.L.C.	Saginaw	Michigan
United States	Stone Oak, LLC dba Discovery Clinical Trials	San Antonio	Texas
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	WR-Mount Vernon Clinical Research	Sandy Springs	Georgia
United States	Physician Care Clinical Research	Sarasota	Florida
United States	Fellows Research Alliance, Inc.	Savannah	Georgia
United States	Radiant Research	Scottsdale	Arizona
United States	Seattle Women's Health, Research, and Gynecology	Seattle	Washington
United States	North Spokane Women's Health	Spokane	Washington
United States	Visions Clinical Research - Tucson	Tucson	Arizona
United States	Tidewater Clinical Research	Virginia Beach	Virginia
United States	James A. Simon, Women's Health & Research Consultants	Washington	District of Columbia
United States	Comprehensive Clinical Trials	West Palm Beach	Florida
United States	Cypress Medical Research Center	Wichita	Kansas
United States	Hawthorne Research	Winston-Salem	North Carolina
United States	Lyndhurst Clinical Research	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
TherapeuticsMD

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety Endpoints - Adverse Events, Vital Signs, Physical Exam Findings, Gynecological Exam Findings, Clinical Lab Tests, Endometrial Biopsies	Adverse events and serious adverse events (SAEs) will be summarized for each treatment group and overall for all active treatment groups with the proportion of subjects reporting each event. Actual values and change from baseline in vital signs, and all laboratory test parameters will be summarized for each treatment group and overall for all active treatment groups with descriptive statistics at each assessment obtained. The incidence rate for endometrial hyperplasia will be calculated for each treatment group.	12 Weeks	Yes
Primary	Co-Primary Efficacy Endpoint - Vaginal Superficial Cells	• Change from baseline to week 12 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo	12 Weeks	No
Primary	Co-Primary Efficacy Endpoint - Vaginal Parabasal Cells	• Change from baseline to week 12 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo	12 Weeks	No
Primary	Co-Primary Efficacy Endpoint - Vaginal pH	• Change from baseline to week 12 in vaginal pH as compared to placebo	12 Weeks	No
Primary	Co-Primary Efficacy Endpoint - Severity of Most Bothersome Symptom (Dyspareunia)	• Change from baseline to week 12 on the severity of the MBS of dyspareunia (vaginal pain associated with sexual activity) associated with VVA as compared to placebo	12 Weeks	No
Secondary	Secondary Efficacy Endpoints - Vaginal Superficial and Parabasal Cells, Vaginal pH and Severity of MBS (dyspareunia)	Change from baseline to weeks 2, 6, and 8 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo; Change from baseline to weeks 2, 6 and 8 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo; Change from baseline to weeks 2, 6 and 8 in vaginal pH as compared to placebo; Change from baseline to weeks 2, 6 and 8 on the severity of the MBS of dyspareunia (vaginal pain associated with sexual activity) associated with VVA as compared to placebo	2, 6 and 8 Weeks	No
Secondary	Secondary Efficacy Endpoints - Severity of other VVA symptoms and visual evaluation of vaginal mucosa	Change from baseline to weeks 2, 6, 8 and 12 on the severity of the vaginal dryness and vulvar and/or vaginal itching or irritation associated with VVA as compared to placebo; Change in visual evaluation of the vaginal mucosa from baseline to weeks 2, 6, 8 and 12 compared to placebo	2, 6, 8 and 12 Weeks	No
Secondary	Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI)	• Change from baseline in the FSFI at week 12 compared to placebo	12 Weeks	No
Secondary	Secondary Efficacy Endpoints - Hormone Concentration Assessments (serum estradiol, estrone and estrone conjugates; SHBG) - PK Substudy	Blood samples will be obtained from a subset of subjects at pre-selected sites to characterize PK parameters (AUC, tmax, Cmin, Cmax) and to measure SHBG	Pre-treatment, Day 1, Weeks 2 and 12	No