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

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

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.

Study Overview

• Status: Completed
• Conditions: Menopause; Vulvovaginal Atrophy; Dyspareunia; Painful Intercourse
• Intervention / Treatment: Drug: Placebo; Drug: Estradiol

• Study Type: Interventional
• Enrollment (Actual): 764
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1S 2L6
    • Clinique RSF Inc.
  • Quebec, Canada, G1W4R4
    • Center for Research Saint-Louis
  • Quebec
    • Montreal, Quebec, Canada, H4N 3C5
      • Diex Research Montreal Inc.
    • Sherbrooke, Quebec, Canada, J1H 1Z1
      • Diex Research Sherbrooke Inc.
    • St-Romuald, Quebec, Canada, G6W 5M6
      • Manna Research Inc
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Medical Affiliated Research Center
    • Montgomery, Alabama, United States, 36117
      • Montogomery Women's Health
  • Arizona
    • Mesa, Arizona, United States, 85209
      • Cactus Clinical Research
    • Phoenix, Arizona, United States, 85032
      • Arizona Wellness Center for Women
    • Scottsdale, Arizona, United States, 85251
      • Radiant Research
    • Tucson, Arizona, United States, 85712
      • Visions Clinical Research - Tucson
  • California
    • Berkeley, California, United States, 94705
      • Sutter East Bay Medical Foundation
    • Lomita, California, United States, 90717
      • Torrance Clinical Research Institute Inc
    • Norwalk, California, United States, 90650
      • Futura Research
    • Sacramento, California, United States, 95821
      • Northern California Research
    • San Diego, California, United States, 92108
      • Medical Center for Clinical Research
    • San Diego, California, United States, 92120
      • San Diego Sexual Medicine
    • San Diego, California, United States, 92123
      • Women's Health Care Research Corp.
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Lynn Institute of the Rockies
    • Denver, Colorado, United States, 80209
      • Downtown Women's Health Care
    • Denver, Colorado, United States, 80220
      • Horizons Clinical Research Center
    • Lakewood, Colorado, United States, 80228
      • Red Rocks OB/Gyn
  • Connecticut
    • Milford, Connecticut, United States, 06460
      • Clinical Research Consulting
    • New London, Connecticut, United States, 06320
      • Coastal Connecticut Research, LLC
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20036
      • James A. Simon, Women's Health & Research Consultants
  • Florida
    • Aventura, Florida, United States, 33180
      • South Florida Medical Research
    • Crystal River, Florida, United States, 34429
      • Nature Coast Clinical Research
    • DeLand, Florida, United States, 32720
      • Avail Clinical Research
    • Fort Myers, Florida, United States, 33916
      • Clinical Physiology Associates
    • Gainesville, Florida, United States, 32606
      • UF Health Physicians Women's & REI Springhill
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research
    • Jacksonville, Florida, United States, 32207
      • UF College of Medicine-Jacksonville, Dept. of Obstetrics and Gynecology
    • Margate, Florida, United States, 33063
      • South Florida Wellness & Clinical Research Institute
    • Miami, Florida, United States, 33186
      • New Age Medical Research Corporation
    • New Port Richey, Florida, United States, 34652
      • Suncoast Clinical Research, Inc.
    • North Miami, Florida, United States, 33161
      • Healthcare Clinical Data
    • North Miami Beach, Florida, United States, 33162
      • Ideal Clinical Research
    • Pinellas Park, Florida, United States, 33781
      • Radiant Research
    • Plantation, Florida, United States, 33324
      • All Women's Healthcare of West Broward
    • Sarasota, Florida, United States, 34239
      • Physician Care Clinical Research
    • West Palm Beach, Florida, United States, 33409
      • Comprehensive Clinical Trials
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Women's Health Associates
    • Augusta, Georgia, United States, 30909
      • Masters of Clinical Research, Inc.
    • Decatur, Georgia, United States, 30034
      • Soapstone Center for Clinical Research
    • Sandy Springs, Georgia, United States, 30328
      • WR-Mount Vernon Clinical Research
    • Savannah, Georgia, United States, 31046
      • Fellows Research Alliance, Inc.
  • Idaho
    • Boise, Idaho, United States, 83642
      • Advanced Clinical Research
    • Idaho Falls, Idaho, United States, 83404
      • Women's Healthcare Associates P.A.
  • Illinois
    • Chicago, Illinois, United States, 60654
      • Radiant Research
  • Indiana
    • Avon, Indiana, United States, 46123
      • American Health Network of Indiana, LLC
    • Lafayette, Indiana, United States, 47905
      • Lafayette Clinical Research Group
  • Kansas
    • Wichita, Kansas, United States, 67226
      • Cypress Medical Research Center
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Central Kentucky Research Associates, Inc.
    • Louisville, Kentucky, United States, 40291
      • Bluegrass Clinical Research, Inc.
  • Louisiana
    • Eunice, Louisiana, United States, 70535
      • Horizon Research Group of Opelousas
  • Maryland
    • Frederick, Maryland, United States, 21702
      • Capital Women's Care
    • Lutherville, Maryland, United States, 21093
      • Maryland Center for Sexual Health
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • ClinSite, LLC
    • Kalamazoo, Michigan, United States, 49009
      • Beyer Research
    • Saginaw, Michigan, United States, 48604
      • Saginaw Valley Medical Research Group, L.L.C.
  • Montana
    • Billings, Montana, United States, 59102
      • Montana Health
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Women's Clinic of Lincoln
  • Nevada
    • Las Vegas, Nevada, United States, 89113
      • Office of Edmond E. Pack, MD
    • Las Vegas, Nevada, United States, 89128
      • Office of R. Garn Mabey, MD
  • New Jersey
    • Lawrenceville, New Jersey, United States, 08648
      • Lawrence Ob-Gyn Clinical Research, LLC
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers-Robert Wood Johnson Medical School
    • Plainsboro, New Jersey, United States, 08536
      • Women's Health Research Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Bosque Women's Care
    • Albuquerque, New Mexico, United States, 87109
      • Southwest Clinical Research
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Port Jefferson, New York, United States, 08536
      • Suffolk OB/GYN
  • North Carolina
    • Durham, North Carolina, United States, 27713
      • Women's Wellness Clinic
    • High Point, North Carolina, United States, 27262
      • Pinewest Ob-Gyn, Inc.
    • Raleigh, North Carolina, United States, 27612
      • Wake Research Associates
    • Winston-Salem, North Carolina, United States, 27103
      • Lyndhurst Clinical Research
    • Winston-Salem, North Carolina, United States, 27103
      • Hawthorne Research
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Lillestol Research
  • Ohio
    • Akron, Ohio, United States, 44311
      • Radiant Research
    • Cincinnati, Ohio, United States, 45267-0457
      • University of Cincinnati Physicians Company
    • Cleveland, Ohio, United States, 44122
      • Rapid Medical Research
    • Columbus, Ohio, United States, 43213
      • Columbus Center for Women's Health Research
    • Englewood, Ohio, United States, 45322
      • HWC Women's Research Center
    • Mayfield Heights, Ohio, United States, 44124
      • Landerbrook Health Center
  • Oregon
    • Medford, Oregon, United States, 97504
      • Sunstone Medical Research
  • Pennsylvania
    • Jenkintown, Pennsylvania, United States, 19046
      • The Clinical Trial Center
    • Philadelphia, Pennsylvania, United States, 19114
      • Clinical Research of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15206
      • Clinical Trials Research Services
  • South Carolina
    • Bluffton, South Carolina, United States, 29910
      • Fellows Research Alliance, Inc.
    • Columbia, South Carolina, United States, 29201
      • Vista Clinical Research
    • Mount Pleasant, South Carolina, United States, 29464
      • Coastal Carolina Research Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Medical Research
  • Texas
    • Corpus Christi, Texas, United States, 78414
      • Advanced Research Associates
    • Dallas, Texas, United States, 75234
      • Research Across America
    • Dallas, Texas, United States, 75390-9032
      • UT southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Advances in Health
    • Houston, Texas, United States, 77054
      • TMC Life Research
    • Houston, Texas, United States, 77054
      • Hwca, Pllc
    • San Antonio, Texas, United States, 78258
      • Stone Oak, LLC dba Discovery Clinical Trials
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • National Clinical Research-Norfolk
    • Norfolk, Virginia, United States, 23507
      • Clinical Research Center, EVMS
    • Richmond, Virginia, United States, 23294
      • National Clinical Research-Richmond, Inc
    • Richmond, Virginia, United States, 23233
      • Virginia Women's Center, Inc.
    • Virginia Beach, Virginia, United States, 23456
      • Tidewater Clinical Research
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Women's Health, Research, and Gynecology
    • Spokane, Washington, United States, 99207
      • North Spokane Women's Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Estradiol 4mcg Vaginal Softgel Capsule	Drug: Estradiol
EXPERIMENTAL: Estradiol 10mcg Vaginal Softgel Capsule	Drug: Estradiol
EXPERIMENTAL: Estradiol 25mcg Vaginal Softgel Capsule	Drug: Estradiol
PLACEBO_COMPARATOR: Placebo Vaginal Softgel Capsule	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Baseline and 12 Weeks
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	Baseline and 12 Weeks
Co-Primary Efficacy Endpoint - Vaginal pH	• Change from Baseline to Week 12 in vaginal pH as compared to placebo	Baseline and 12 Weeks
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 VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 12	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Efficacy Endpoints - Vaginal Superficial Cells	• Change from Baseline to Week 2 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo	Baseline and Week 2
Secondary Efficacy Endpoints- Vaginal Superficial Cells	Change from Baseline to Week 6 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo	Baseline and Week 6
Secondary Efficacy Endpoints - Vaginal Superficial Cells	Change from Baseline to Week 8 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo	Baseline and Week 8
Secondary Efficacy Endpoints - Vaginal Parabasal Cells	Change from Baseline to Week 2 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo	Baseline and Week 2
Secondary Efficacy Endpoints - Vaginal Parabasal Cells	Change from Baseline to Week 6 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo	Baseline and Week 6
Secondary Efficacy Endpoints - Vaginal Parabasal Cells	Change from Baseline to Week 8 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo	Baseline and Week 8
Secondary Efficacy Endpoints - Vaginal pH	Change from Baseline to Week 2 in vaginal pH as compared to placebo	Baseline and Week 2
Secondary Efficacy Endpoints - Vaginal pH	Change from Baseline to Week 6 in vaginal pH as compared to placebo	Baseline and Week 6
Secondary Efficacy Endpoints - Vaginal pH	Change from Baseline to Week 8 in vaginal pH as compared to placebo	Baseline and Week 8
Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)	Change from Baseline to Week 2 on the severity of the MBS of dyspareunia (vaginal pain associated with sexual activity) associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 2	Baseline and Week 2
Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)	Change from Baseline to Week 6 on the severity of the MBS of dyspareunia (vaginal pain associated with sexual activity) associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 6	Baseline and Week 6
Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)	Change from Baseline to Week 8 on the severity of the MBS of dyspareunia (vaginal pain associated with sexual activity) associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 8	Baseline and Week 8
Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)	Change from Baseline to Week 2 on the severity of vaginal dryness associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 2	Baseline and Week 2
Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)	Change from Baseline to Week 6 on the severity of vaginal dryness associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 6	Baseline and Week 6
Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)	Change from Baseline to Week 8 on the severity of vaginal dryness associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 8	Baseline and Week 8
Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)	Change from Baseline to Week 12 on the severity of vaginal dryness associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 12	Baseline and Week 12
Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)	Change from Baseline to Week 2 on the severity of vulvar and/or vaginal itching or irritation associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 2	Baseline and Week 2
Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)	Change from Baseline to Week 6 on the severity of vulvar and/or vaginal itching or irritation associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 6	Baseline and Week 6
Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)	Change from Baseline to Week 8 on the severity of vulvar and/or vaginal itching or irritation associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 8	Baseline and Week 8
Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)	Change from Baseline to Week 12 on the severity of vulvar and/or vaginal itching or irritation associated with VVA as compared to placebo VVA Symptoms Self-Assessment Questionnaire Severity Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Subjects assessed severity at Baseline and Week 12	Baseline and Week 12
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)	Change from Baseline to Week 2 in Vaginal Color as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Color: No atrophy (pink) = 0; Mild (lighter in color) = 1; Moderate(pale in color) = 2; Severe (transparent/no color or inflamed) = 3 Severity was assessed by the Investigator at Baseline and Week 2	Baseline and Week 2
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)	Change from Baseline to Week 6 in Vaginal Color as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Color: No atrophy (pink) = 0; Mild (lighter in color) = 1; Moderate(pale in color) = 2; Severe (transparent/no color or inflamed) = 3 Severity was assessed by the Investigator at Baseline and Week 6	Baseline to Week 6
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)	Change from Baseline to Week 8 in Vaginal Color as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Color: No atrophy (pink) = 0; Mild (lighter in color) = 1; Moderate(pale in color) = 2; Severe (transparent/no color or inflamed) = 3 Severity was assessed by the Investigator at Baseline and Week 8	Baseline to Week 8
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)	Change from Baseline to Week 12 in Vaginal Color as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Color: No atrophy (pink) = 0; Mild (lighter in color) = 1; Moderate(pale in color) = 2; Severe (transparent/no color or inflamed) = 3 Severity was assessed by the Investigator at Baseline and Week 12	Baseline and Week 12
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)	Change from Baseline to Week 2 in Vaginal Epithelial Integrity as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Integrity: No atrophy (normal) = 0; Mild (vaginal surface bleeds with scraping) = 1; Moderate (vaginal surface bleeds with light contact) = 2; Severe (vaginal surface has petechiae before contact and bleeds with light contact) = 3 Severity was assessed by the Investigator at Baseline and Week 2	Baseline and Week 2
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)	Change from Baseline to Week 6 in Vaginal Epithelial Integrity as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Integrity: No atrophy (normal) = 0; Mild (vaginal surface bleeds with scraping) = 1; Moderate (vaginal surface bleeds with light contact) = 2; Severe (vaginal surface has petechiae before contact and bleeds with light contact) = 3 Severity was assessed by the Investigator at Baseline and Week 6	Baseline and Week 6
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)	Change from Baseline to Week 8 in Vaginal Epithelial Integrity as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Integrity: No atrophy (normal) = 0; Mild (vaginal surface bleeds with scraping) = 1; Moderate (vaginal surface bleeds with light contact) = 2; Severe (vaginal surface has petechiae before contact and bleeds with light contact) = 3 Severity was assessed by the Investigator at Baseline and Week 8	Baseline and Week 8
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)	Change from Baseline to Week 12 in Vaginal Epithelial Integrity as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Integrity: No atrophy (normal) = 0; Mild (vaginal surface bleeds with scraping) = 1; Moderate (vaginal surface bleeds with light contact) = 2; Severe (vaginal surface has petechiae before contact and bleeds with light contact) = 3 Severity was assessed by the Investigator at Baseline and Week 12	Baseline and Week 12
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)	Change from Baseline to Week 2 in Vaginal Epithelial Surface Thickness as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Surface Thickness: No atrophy (rogation and elasticity of vault) = 0; Mild (poor rogation with some elasticity noted of vaginal vault) = 1; Moderate (smooth, some elasticity of vaginal vault) = 2; Severe [smooth, no elasticity, constriction of the upper one third of vagina or loss of vaginal tone (cystocele and rectocele)] = 3 Severity was assessed by the Investigator at Baseline and Week 2	Baseline and Week 2
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)	Change from Baseline to Week 6 in Vaginal Epithelial Surface Thickness as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Surface Thickness: No atrophy (rogation and elasticity of vault) = 0; Mild (poor rogation with some elasticity noted of vaginal vault) = 1; Moderate (smooth, some elasticity of vaginal vault) = 2; Severe [smooth, no elasticity, constriction of the upper one third of vagina or loss of vaginal tone (cystocele and rectocele)] = 3 Severity was assessed by the Investigator at Baseline and Week 6	Baseline and Week 6
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)	Change from Baseline to Week 8 in Vaginal Epithelial Surface Thickness as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Surface Thickness: No atrophy (rogation and elasticity of vault) = 0; Mild (poor rogation with some elasticity noted of vaginal vault) = 1; Moderate (smooth, some elasticity of vaginal vault) = 2; Severe [smooth, no elasticity, constriction of the upper one third of vagina or loss of vaginal tone (cystocele and rectocele)] = 3 Severity was assessed by the Investigator at Baseline and Week 8	Baseline and Week 8
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)	Change from Baseline to Week 12 in Vaginal Epithelial Surface Thickness as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Epithelial Surface Thickness: No atrophy (rogation and elasticity of vault) = 0; Mild (poor rogation with some elasticity noted of vaginal vault) = 1; Moderate (smooth, some elasticity of vaginal vault) = 2; Severe [smooth, no elasticity, constriction of the upper one third of vagina or loss of vaginal tone (cystocele and rectocele)] = 3 Severity was assessed by the Investigator at Baseline and Week 12	Baseline and Week 12
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)	Change from Baseline to Week 2 in Vaginal Secretions as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Secretions: No atrophy (normal clear secretions noted on vaginal walls) = 0; Mild (superficial coating of secretions, difficulty with speculum insertion) = 1; Moderate (scant not covering the entire vaginal vault, may need lubrication with speculum insertion to prevent pain) = 2; Severe (none, inflamed, ulceration noted, need lubrication with speculum insertion to prevent pain) = 3 Severity was assessed by the Investigator at Baseline and Week 2	Baseline and Week 2
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)	Change from Baseline to Week 6 in Vaginal Secretions as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Secretions: No atrophy (normal clear secretions noted on vaginal walls) = 0; Mild (superficial coating of secretions, difficulty with speculum insertion) = 1; Moderate (scant not covering the entire vaginal vault, may need lubrication with speculum insertion to prevent pain) = 2; Severe (none, inflamed, ulceration noted, need lubrication with speculum insertion to prevent pain] = 3 Severity was assessed by the Investigator at Baseline and Week 6	Baseline and Week 6
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)	Change from Baseline to Week 8 in Vaginal Secretions as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Secretions: No atrophy (normal clear secretions noted on vaginal walls) = 0; Mild (superficial coating of secretions, difficulty with speculum insertion) = 1; Moderate (scant not covering the entire vaginal vault, may need lubrication with speculum insertion to prevent pain) = 2; Severe (none, inflamed, ulceration noted, need lubrication with speculum insertion to prevent pain] = 3 Severity was assessed by the Investigator at Baseline and Week 8	Baseline and Week 8
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)	Change from Baseline to Week 12 in Vaginal Secretions as compared to placebo Vaginal Mucosa Assessment Scale - Vaginal Secretions: No atrophy (normal clear secretions noted on vaginal walls) = 0; Mild (superficial coating of secretions, difficulty with speculum insertion) = 1; Moderate (scant not covering the entire vaginal vault, may need lubrication with speculum insertion to prevent pain) = 2; Severe (none, inflamed, ulceration noted, need lubrication with speculum insertion to prevent pain] = 3 Severity was assessed by the Investigator at Baseline and Week 12	Baseline and Week 12
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) - Total Score	Change from Baseline to Week 12 in FSFI Total Score as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.	Baseline and Week 12
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Arousal	Change from Baseline to Week 12 in FSFI Domain Score (Arousal) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.	Baseline and Week 12
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Desire	Change from Baseline to Week 12 in FSFI Domain Score (Desire) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.	Baseline and Week 12
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Lubrication	Change from Baseline to Week 12 in FSFI Domain Score (Lubrication) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.	Baseline and Week 12
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Orgasm	Change from Baseline to Week 12 in FSFI Domain Score (Orgasm) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.	Baseline and Week 12
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Pain	Change from Baseline to Week 12 in FSFI Domain Score (Pain) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.	Baseline and Week 12
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Satisfaction	Change from Baseline to Week 12 in FSFI Domain Score (Satisfaction) as compared to placebo The FSFI is a brief, multidimensional questionnaire for assessing sexual function in women (Rosen et al., 2000). The questionnaire consists of 19 items that assess sexual function over the past 4 weeks and yield domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI questionnaire has a minimum total score of 2.0, a maximum score of 36.0 points and was administered at Baseline and Week 12.	Baseline and Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK Substudy - Hormone Concentration Assessments (Serum Estradiol, Estrone and Estrone Conjugates; SHBG)	Blood samples will be obtained from a subset of subjects at pre-selected sites to characterize PK parameters (AUC, tmax, Cmin, Cmax, Cavg) and to measure SHBG	Pre-treatment, Day 2, Weeks 2 and 12

Collaborators and Investigators

• Sponsor: TherapeuticsMD

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): October 1, 2015

Study Registration Dates

• First Submitted: September 26, 2014
• First Submitted That Met QC Criteria: September 30, 2014
• First Posted (ESTIMATE): October 1, 2014

Study Record Updates

• Last Update Posted (ACTUAL): May 25, 2017
• Last Update Submitted That Met QC Criteria: April 20, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Postmenopausal; VVA; Painful Sex
• Additional Relevant MeSH Terms: Mental Disorders; Pathological Conditions, Anatomical; Sexual Dysfunctions, Psychological; Sexual Dysfunction, Physiological; Atrophy; Dyspareunia; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Estradiol
• Other Study ID Numbers: TXV14-01