Clinical trial NCT02253173: Estradiol Vaginal Softgel Capsules in Treating Symptoms of Vulvar and Vaginal Atrophy in Postmenopausal Women
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Vulvovaginal Atrophy
Menopause
Dyspareunia
Painful Intercourse
Keywords: VVA
Painful Sex
Postmenopausal
Lead sponsor: TherapeuticsMD
Sponsor class: INDUSTRY
First posted: 2014-10-01
Enrollment: 764
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Co-Primary Efficacy Endpoint - Vaginal Superficial Cells
timeFrame: Baseline and 12 Weeks
measure: Co-Primary Efficacy Endpoint - Vaginal Parabasal Cells
timeFrame: Baseline and 12 Weeks
measure: Co-Primary Efficacy Endpoint - Vaginal pH
timeFrame: Baseline and 12 Weeks
measure: Co-Primary Efficacy Endpoint - Severity of Most Bothersome Symptom (Dyspareunia)
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Secondary Efficacy Endpoints - Vaginal Superficial Cells
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints- Vaginal Superficial Cells
timeFrame: Baseline and Week 6
measure: Secondary Efficacy Endpoints - Vaginal Superficial Cells
timeFrame: Baseline and Week 8
measure: Secondary Efficacy Endpoints - Vaginal Parabasal Cells
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints - Vaginal Parabasal Cells
timeFrame: Baseline and Week 6
measure: Secondary Efficacy Endpoints - Vaginal Parabasal Cells
timeFrame: Baseline and Week 8
measure: Secondary Efficacy Endpoints - Vaginal pH
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints - Vaginal pH
timeFrame: Baseline and Week 6
measure: Secondary Efficacy Endpoints - Vaginal pH
timeFrame: Baseline and Week 8
measure: Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)
timeFrame: Baseline and Week 6
measure: Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)
timeFrame: Baseline and Week 8
measure: Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)
timeFrame: Baseline and Week 6
measure: Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)
timeFrame: Baseline and Week 8
measure: Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)
timeFrame: Baseline and Week 6
measure: Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)
timeFrame: Baseline and Week 8
measure: Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)
timeFrame: Baseline to Week 6
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)
timeFrame: Baseline to Week 8
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)
timeFrame: Baseline and Week 6
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)
timeFrame: Baseline and Week 8
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)
timeFrame: Baseline and Week 6
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)
timeFrame: Baseline and Week 8
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)
timeFrame: Baseline and Week 2
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)
timeFrame: Baseline and Week 6
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)
timeFrame: Baseline and Week 8
measure: Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) - Total Score
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Arousal
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Desire
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Lubrication
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Orgasm
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Pain
timeFrame: Baseline and Week 12
measure: Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Satisfaction
timeFrame: Baseline and Week 12
Other outcomes:
measure: PK Substudy - Hormone Concentration Assessments (Serum Estradiol, Estrone and Estrone Conjugates; SHBG)
timeFrame: Pre-treatment, Day 2, Weeks 2 and 12
Locations:
city: Huntsville
country: United States
facility: Medical Affiliated Research Center
state: Alabama
city: Montgomery
country: United States
facility: Montogomery Women's Health
state: Alabama
city: Mesa
country: United States
facility: Cactus Clinical Research
state: Arizona
city: Phoenix
country: United States
facility: Arizona Wellness Center for Women
state: Arizona
city: Scottsdale
country: United States
facility: Radiant Research
state: Arizona
city: Tucson
country: United States
facility: Visions Clinical Research - Tucson
state: Arizona
city: Berkeley
country: United States
facility: Sutter East Bay Medical Foundation
state: California
city: Lomita
country: United States
facility: Torrance Clinical Research Institute Inc
state: California
city: Norwalk
country: United States
facility: Futura Research
state: California
city: Sacramento
country: United States
facility: Northern California Research
state: California
city: San Diego
country: United States
facility: Medical Center for Clinical Research
state: California
city: San Diego
country: United States
facility: San Diego Sexual Medicine
state: California
city: San Diego
country: United States
facility: Women's Health Care Research Corp.
state: California
city: Colorado Springs
country: United States
facility: Lynn Institute of the Rockies
state: Colorado
city: Denver
country: United States
facility: Downtown Women's Health Care
state: Colorado
city: Denver
country: United States
facility: Horizons Clinical Research Center
state: Colorado
city: Lakewood
country: United States
facility: Red Rocks OB/Gyn
state: Colorado
city: Milford
country: United States
facility: Clinical Research Consulting
state: Connecticut
city: New London
country: United States
facility: Coastal Connecticut Research, LLC
state: Connecticut
city: Washington, D.C.
country: United States
facility: James A. Simon, Women's Health & Research Consultants
state: District of Columbia
city: Aventura
country: United States
facility: South Florida Medical Research
state: Florida
city: Crystal River
country: United States
facility: Nature Coast Clinical Research
state: Florida
city: DeLand
country: United States
facility: Avail Clinical Research
state: Florida
city: Fort Myers
country: United States
facility: Clinical Physiology Associates
state: Florida
city: Gainesville
country: United States
facility: UF Health Physicians Women's & REI Springhill
state: Florida
city: Jacksonville
country: United States
facility: UF College of Medicine-Jacksonville, Dept. of Obstetrics and Gynecology
state: Florida
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Margate
country: United States
facility: South Florida Wellness & Clinical Research Institute
state: Florida
city: Miami
country: United States
facility: New Age Medical Research Corporation
state: Florida
city: New Port Richey
country: United States
facility: Suncoast Clinical Research, Inc.
state: Florida
city: North Miami Beach
country: United States
facility: Ideal Clinical Research
state: Florida
city: North Miami
country: United States
facility: Healthcare Clinical Data
state: Florida
city: Pinellas Park
country: United States
facility: Radiant Research
state: Florida
city: Plantation
country: United States
facility: All Women's Healthcare of West Broward
state: Florida
city: Sarasota
country: United States
facility: Physician Care Clinical Research
state: Florida
city: West Palm Beach
country: United States
facility: Comprehensive Clinical Trials
state: Florida
city: Atlanta
country: United States
facility: Women's Health Associates
state: Georgia
city: Augusta
country: United States
facility: Masters of Clinical Research, Inc.
state: Georgia
city: Decatur
country: United States
facility: Soapstone Center for Clinical Research
state: Georgia
city: Sandy Springs
country: United States
facility: WR-Mount Vernon Clinical Research
state: Georgia
city: Savannah
country: United States
facility: Fellows Research Alliance, Inc.
state: Georgia
city: Boise
country: United States
facility: Advanced Clinical Research
state: Idaho
city: Idaho Falls
country: United States
facility: Women's Healthcare Associates P.A.
state: Idaho
city: Chicago
country: United States
facility: Radiant Research
state: Illinois
city: Avon
country: United States
facility: American Health Network of Indiana, LLC
state: Indiana
city: Lafayette
country: United States
facility: Lafayette Clinical Research Group
state: Indiana
city: Wichita
country: United States
facility: Cypress Medical Research Center
state: Kansas
city: Lexington
country: United States
facility: Central Kentucky Research Associates, Inc.
state: Kentucky
city: Louisville
country: United States
facility: Bluegrass Clinical Research, Inc.
state: Kentucky
city: Eunice
country: United States
facility: Horizon Research Group of Opelousas
state: Louisiana
city: Frederick
country: United States
facility: Capital Women's Care
state: Maryland
city: Lutherville
country: United States
facility: Maryland Center for Sexual Health
state: Maryland
city: Ann Arbor
country: United States
facility: ClinSite, LLC
state: Michigan
city: Kalamazoo
country: United States
facility: Beyer Research
state: Michigan
city: Saginaw
country: United States
facility: Saginaw Valley Medical Research Group, L.L.C.
state: Michigan
city: Billings
country: United States
facility: Montana Health
state: Montana
city: Lincoln
country: United States
facility: Women's Clinic of Lincoln
state: Nebraska
city: Las Vegas
country: United States
facility: Office of Edmond E. Pack, MD
state: Nevada
city: Las Vegas
country: United States
facility: Office of R. Garn Mabey, MD
state: Nevada
city: Lawrenceville
country: United States
facility: Lawrence OB-GYN Clinical Research, LLC
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers-Robert Wood Johnson Medical School
state: New Jersey
city: Plainsboro
country: United States
facility: Women's Health Research Center
state: New Jersey
city: Albuquerque
country: United States
facility: Bosque Women's Care
state: New Mexico
city: Albuquerque
country: United States
facility: Southwest Clinical Research
state: New Mexico
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Port Jefferson
country: United States
facility: Suffolk OB/GYN
state: New York
city: Durham
country: United States
facility: Women's Wellness Clinic
state: North Carolina
city: High Point
country: United States
facility: Pinewest OB-GYN, Inc.
state: North Carolina
city: Raleigh
country: United States
facility: Wake Research Associates
state: North Carolina
city: Winston-Salem
country: United States
facility: Hawthorne Research
state: North Carolina
city: Winston-Salem
country: United States
facility: Lyndhurst Clinical Research
state: North Carolina
city: Fargo
country: United States
facility: Lillestol Research
state: North Dakota
city: Akron
country: United States
facility: Radiant Research
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Physicians Company
state: Ohio
city: Cleveland
country: United States
facility: Rapid Medical Research
state: Ohio
city: Columbus
country: United States
facility: Columbus Center for Women's Health Research
state: Ohio
city: Englewood
country: United States
facility: HWC Women's Research Center
state: Ohio
city: Mayfield Heights
country: United States
facility: Landerbrook Health Center
state: Ohio
city: Medford
country: United States
facility: Sunstone Medical Research
state: Oregon
city: Jenkintown
country: United States
facility: The Clinical Trial Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Clinical Research of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Clinical Trials Research Services
state: Pennsylvania
city: Bluffton
country: United States
facility: Fellows Research Alliance, Inc.
state: South Carolina
city: Columbia
country: United States
facility: Vista Clinical Research
state: South Carolina
city: Mount Pleasant
country: United States
facility: Coastal Carolina Research Center
state: South Carolina
city: Chattanooga
country: United States
facility: Chattanooga Medical Research
state: Tennessee
city: Corpus Christi
country: United States
facility: Advanced Research Associates
state: Texas
city: Dallas
country: United States
facility: Research Across America
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Advances in Health
state: Texas
city: Houston
country: United States
facility: Hwca, Pllc
state: Texas
city: Houston
country: United States
facility: TMC Life Research
state: Texas
city: San Antonio
country: United States
facility: Stone Oak, LLC dba Discovery Clinical Trials
state: Texas
city: Norfolk
country: United States
facility: National Clinical Research-Norfolk
state: Virginia
city: Norfolk
country: United States
facility: Clinical Research Center, EVMS
state: Virginia
city: Richmond
country: United States
facility: Virginia Women's Center, Inc.
state: Virginia
city: Richmond
country: United States
facility: National Clinical Research-Richmond, Inc
state: Virginia
city: Virginia Beach
country: United States
facility: Tidewater Clinical Research
state: Virginia
city: Seattle
country: United States
facility: Seattle Women's Health, Research, and Gynecology
state: Washington
city: Spokane
country: United States
facility: North Spokane Women's Health
state: Washington
city: Montreal
country: Canada
facility: Diex Research Montreal Inc.
state: Quebec
city: Sherbrooke
country: Canada
facility: Diex Research Sherbrooke Inc.
state: Quebec
city: St-Romuald
country: Canada
facility: Manna Research Inc
state: Quebec
city: Quebec
country: Canada
facility: Clinique RSF Inc.
city: Quebec
country: Canada
facility: Center for Research Saint-Louis
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.