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

Phase 3

Completed

Conditions: Dyspareunia
Vulvovaginal Atrophy
Menopause
Painful Intercourse

Interventions: Drug: Estradiol
Drug: Placebo

Registration Number: NCT02253173

Lead Sponsor: TherapeuticsMD

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 764

Inclusion Criteria

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.
≤5% superficial cells on vaginal cytological smear
Vaginal pH > 5.0
Moderate to severe symptom of vaginal pain associated with sexual activity considered the most bothersome vaginal symptom by the subject at screening visit 1A.
Moderate to severe symptom of vaginal pain associated with sexual activity at screening visit 1B.
Onset of moderate to severe dyspareunia in the postmenopausal years.
Subjects should be sexually active (i.e. have sexual activity with vaginal penetration within approximately 1 month of screening visit 1A).
Subjects should anticipate having sexual activity (with vaginal penetration) during the conduct of the trial.
For subjects with an intact uterus: Subjects must have an acceptable result from an evaluable screening endometrial biopsy.
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).
In the opinion of the investigator, the subject will comply with the protocol and has a high probability of completing the study.

Exclusion Criteria

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.
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).
Recent history of known alcohol or drug abuse.
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.
Current history of Heavy smoking (more than 15 cigarettes per day) or use of e-cigarettes.
Use of an intrauterine device within 12 weeks before screening visit 1A.
Use of an investigational drug within 60 days before screening visit 1A.
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)
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.
Current use of marijuana.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Estradiol 4mcg Vaginal Softgel Capsule	Estradiol	Estradiol 4mcg Vaginal Softgel Capsule
Estradiol 25mcg Vaginal Softgel Capsule	Estradiol	Estradiol 25mcg Vaginal Softgel Capsule
Placebo Vaginal Softgel Capsule	Placebo	Placebo Vaginal Softgel Capsule
Estradiol 10mcg Vaginal Softgel Capsule	Estradiol	Estradiol 10mcg Vaginal Softgel Capsule

Primary Outcome Measures

Name	Time	Method
Co-Primary Efficacy Endpoint - Vaginal pH	Baseline and 12 Weeks	• Change from Baseline to Week 12 in vaginal pH as compared to placebo
Co-Primary Efficacy Endpoint - Vaginal Superficial Cells	Baseline and 12 Weeks	• Change from Baseline to Week 12 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo
Co-Primary Efficacy Endpoint - Vaginal Parabasal Cells	Baseline and 12 Weeks	• Change from Baseline to Week 12 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo
Co-Primary Efficacy Endpoint - Severity of Most Bothersome Symptom (Dyspareunia)	Baseline and Week 12	• 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

Secondary Outcome Measures

Name	Time	Method
Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)	Baseline and Week 8	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
Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)	Baseline and Week 12	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
Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)	Baseline and Week 12	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
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)	Baseline and Week 12	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
Secondary Efficacy Endpoints - Vaginal Superficial Cells	Baseline and Week 8	Change from Baseline to Week 8 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo
Secondary Efficacy Endpoints - Vaginal pH	Baseline and Week 8	Change from Baseline to Week 8 in vaginal pH as compared to placebo
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) - Total Score	Baseline and Week 12	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.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Lubrication	Baseline and Week 12	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.
Secondary Efficacy Endpoints- Vaginal Superficial Cells	Baseline and Week 6	Change from Baseline to Week 6 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo
Secondary Efficacy Endpoints - Vaginal Parabasal Cells	Baseline and Week 8	Change from Baseline to Week 8 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)	Baseline and Week 12	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
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Orgasm	Baseline and Week 12	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.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)	Baseline and Week 12	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
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Arousal	Baseline and Week 12	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.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Satisfaction	Baseline and Week 12	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.
Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)	Baseline and Week 12	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
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Desire	Baseline and Week 12	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.
Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Pain	Baseline and Week 12	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.

Trial Locations

Locations (101): 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
🇺🇸
Akron, Ohio, 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
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Medical Affiliated Research Center
🇺🇸Huntsville, Alabama, United States