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

Sponsor
TherapeuticsMD (Industry)
Overall Status
Completed
CT.gov ID
NCT02253173
Collaborator
(none)
764
Enrollment
105
Locations
4
Arms
13
Duration (Months)
7.3
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
764 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
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 Start Date :
Sep 1, 2014
Actual Primary Completion Date :
Oct 1, 2015
Actual Study Completion Date :
Oct 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Estradiol 4mcg Vaginal Softgel Capsule

Estradiol 4mcg Vaginal Softgel Capsule

Drug: Estradiol
Experimental: Estradiol 10mcg Vaginal Softgel Capsule

Estradiol 10mcg Vaginal Softgel Capsule

Drug: Estradiol
Experimental: Estradiol 25mcg Vaginal Softgel Capsule

Estradiol 25mcg Vaginal Softgel Capsule

Drug: Estradiol
Placebo Comparator: Placebo Vaginal Softgel Capsule

Placebo Vaginal Softgel Capsule

Drug: Placebo

Outcome Measures

Primary Outcome Measures

  1. 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

  2. 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

  3. Co-Primary Efficacy Endpoint - Vaginal pH [Baseline and 12 Weeks]

    • Change from Baseline to Week 12 in vaginal pH as compared to placebo

  4. 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

  1. Secondary Efficacy Endpoints - Vaginal Superficial Cells [Baseline and Week 2]

    • Change from Baseline to Week 2 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo

  2. 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

  3. 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

  4. Secondary Efficacy Endpoints - Vaginal Parabasal Cells [Baseline and Week 2]

    Change from Baseline to Week 2 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo

  5. Secondary Efficacy Endpoints - Vaginal Parabasal Cells [Baseline and Week 6]

    Change from Baseline to Week 6 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo

  6. 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

  7. Secondary Efficacy Endpoints - Vaginal pH [Baseline and Week 2]

    Change from Baseline to Week 2 in vaginal pH as compared to placebo

  8. Secondary Efficacy Endpoints - Vaginal pH [Baseline and Week 6]

    Change from Baseline to Week 6 in vaginal pH as compared to placebo

  9. Secondary Efficacy Endpoints - Vaginal pH [Baseline and Week 8]

    Change from Baseline to Week 8 in vaginal pH as compared to placebo

  10. Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia) [Baseline and Week 2]

    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

  11. Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia) [Baseline and Week 6]

    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

  12. 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

  13. Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness) [Baseline and Week 2]

    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

  14. Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness) [Baseline and Week 6]

    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

  15. Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness) [Baseline and Week 8]

    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

  16. 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

  17. Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation) [Baseline and Week 2]

    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

  18. Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation) [Baseline and Week 6]

    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

  19. Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation) [Baseline and Week 8]

    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

  20. 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

  21. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color) [Baseline and Week 2]

    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

  22. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color) [Baseline to Week 6]

    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

  23. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color) [Baseline to Week 8]

    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

  24. 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

  25. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity) [Baseline and Week 2]

    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

  26. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity) [Baseline and Week 6]

    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

  27. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity) [Baseline and Week 8]

    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

  28. 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

  29. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness) [Baseline and Week 2]

    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

  30. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness) [Baseline and Week 6]

    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

  31. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness) [Baseline and Week 8]

    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

  32. 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

  33. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions) [Baseline and Week 2]

    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

  34. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions) [Baseline and Week 6]

    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

  35. Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions) [Baseline and Week 8]

    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

  36. 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

  37. 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.

  38. 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.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

Other Outcome Measures

  1. PK Substudy - Hormone Concentration Assessments (Serum Estradiol, Estrone and Estrone Conjugates; SHBG) [Pre-treatment, Day 2, Weeks 2 and 12]

    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

Eligibility Criteria

Criteria

Ages Eligible for Study:
40 Years to 75 Years
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
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.

  1. ≤5% superficial cells on vaginal cytological smear

  2. Vaginal pH > 5.0

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

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

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

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

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

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

  9. 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).

  10. 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:

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

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

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

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

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

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

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

  9. Hypersensitivity to estrogens;

  10. Endometrial hyperplasia;

  11. Undiagnosed vaginal bleeding;

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

  13. Thrombophlebitis, thrombosis or thromboembolic disorders;

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

  15. Myocardial infarction or ischemic heart disease;

  16. 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;

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

  18. Recent history of known alcohol or drug abuse.

  19. 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.

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

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

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

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

  24. 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.

  1. 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);

  2. 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);

  3. 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;

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

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

  3. Painful genital warts or localized areas of ulceration;

  4. A history of active, chronic pelvic pain;

  5. Interstitial cystitis;

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

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

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

  9. 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;

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

  11. 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.

  12. Current use of marijuana.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Medical Affiliated Research Center Huntsville Alabama United States 35801
2 Montogomery Women's Health Montgomery Alabama United States 36117
3 Cactus Clinical Research Mesa Arizona United States 85209
4 Arizona Wellness Center for Women Phoenix Arizona United States 85032
5 Radiant Research Scottsdale Arizona United States 85251
6 Visions Clinical Research - Tucson Tucson Arizona United States 85712
7 Sutter East Bay Medical Foundation Berkeley California United States 94705
8 Torrance Clinical Research Institute Inc Lomita California United States 90717
9 Futura Research Norwalk California United States 90650
10 Northern California Research Sacramento California United States 95821
11 Medical Center for Clinical Research San Diego California United States 92108
12 San Diego Sexual Medicine San Diego California United States 92120
13 Women's Health Care Research Corp. San Diego California United States 92123
14 Lynn Institute of the Rockies Colorado Springs Colorado United States 80909
15 Downtown Women's Health Care Denver Colorado United States 80209
16 Horizons Clinical Research Center Denver Colorado United States 80220
17 Red Rocks OB/Gyn Lakewood Colorado United States 80228
18 Clinical Research Consulting Milford Connecticut United States 06460
19 Coastal Connecticut Research, LLC New London Connecticut United States 06320
20 James A. Simon, Women's Health & Research Consultants Washington, D.C. District of Columbia United States 20036
21 South Florida Medical Research Aventura Florida United States 33180
22 Nature Coast Clinical Research Crystal River Florida United States 34429
23 Avail Clinical Research DeLand Florida United States 32720
24 Clinical Physiology Associates Fort Myers Florida United States 33916
25 UF Health Physicians Women's & REI Springhill Gainesville Florida United States 32606
26 UF College of Medicine-Jacksonville, Dept. of Obstetrics and Gynecology Jacksonville Florida United States 32207
27 Jacksonville Center for Clinical Research Jacksonville Florida United States 32216
28 South Florida Wellness & Clinical Research Institute Margate Florida United States 33063
29 New Age Medical Research Corporation Miami Florida United States 33186
30 Suncoast Clinical Research, Inc. New Port Richey Florida United States 34652
31 Ideal Clinical Research North Miami Beach Florida United States 33162
32 Healthcare Clinical Data North Miami Florida United States 33161
33 Radiant Research Pinellas Park Florida United States 33781
34 All Women's Healthcare of West Broward Plantation Florida United States 33324
35 Physician Care Clinical Research Sarasota Florida United States 34239
36 Comprehensive Clinical Trials West Palm Beach Florida United States 33409
37 Women's Health Associates Atlanta Georgia United States 30342
38 Masters of Clinical Research, Inc. Augusta Georgia United States 30909
39 Soapstone Center for Clinical Research Decatur Georgia United States 30034
40 WR-Mount Vernon Clinical Research Sandy Springs Georgia United States 30328
41 Fellows Research Alliance, Inc. Savannah Georgia United States 31046
42 Advanced Clinical Research Boise Idaho United States 83642
43 Women's Healthcare Associates P.A. Idaho Falls Idaho United States 83404
44 Radiant Research Chicago Illinois United States 60654
45 American Health Network of Indiana, LLC Avon Indiana United States 46123
46 Lafayette Clinical Research Group Lafayette Indiana United States 47905
47 Cypress Medical Research Center Wichita Kansas United States 67226
48 Central Kentucky Research Associates, Inc. Lexington Kentucky United States 40509
49 Bluegrass Clinical Research, Inc. Louisville Kentucky United States 40291
50 Horizon Research Group of Opelousas Eunice Louisiana United States 70535
51 Capital Women's Care Frederick Maryland United States 21702
52 Maryland Center for Sexual Health Lutherville Maryland United States 21093
53 ClinSite, LLC Ann Arbor Michigan United States 48106
54 Beyer Research Kalamazoo Michigan United States 49009
55 Saginaw Valley Medical Research Group, L.L.C. Saginaw Michigan United States 48604
56 Montana Health Billings Montana United States 59102
57 Women's Clinic of Lincoln Lincoln Nebraska United States 68510
58 Office of Edmond E. Pack, MD Las Vegas Nevada United States 89113
59 Office of R. Garn Mabey, MD Las Vegas Nevada United States 89128
60 Lawrence OB-GYN Clinical Research, LLC Lawrenceville New Jersey United States 08648
61 Rutgers-Robert Wood Johnson Medical School New Brunswick New Jersey United States 08901
62 Women's Health Research Center Plainsboro New Jersey United States 08536
63 Bosque Women's Care Albuquerque New Mexico United States 87109
64 Southwest Clinical Research Albuquerque New Mexico United States 87109
65 Columbia University Medical Center New York New York United States 10032
66 Suffolk OB/GYN Port Jefferson New York United States 08536
67 Women's Wellness Clinic Durham North Carolina United States 27713
68 Pinewest OB-GYN, Inc. High Point North Carolina United States 27262
69 Wake Research Associates Raleigh North Carolina United States 27612
70 Hawthorne Research Winston-Salem North Carolina United States 27103
71 Lyndhurst Clinical Research Winston-Salem North Carolina United States 27103
72 Lillestol Research Fargo North Dakota United States 58103
73 Radiant Research Akron Ohio United States 44311
74 University of Cincinnati Physicians Company Cincinnati Ohio United States 45267-0457
75 Rapid Medical Research Cleveland Ohio United States 44122
76 Columbus Center for Women's Health Research Columbus Ohio United States 43213
77 HWC Women's Research Center Englewood Ohio United States 45322
78 Landerbrook Health Center Mayfield Heights Ohio United States 44124
79 Sunstone Medical Research Medford Oregon United States 97504
80 The Clinical Trial Center Jenkintown Pennsylvania United States 19046
81 Clinical Research of Philadelphia Philadelphia Pennsylvania United States 19114
82 Clinical Trials Research Services Pittsburgh Pennsylvania United States 15206
83 Fellows Research Alliance, Inc. Bluffton South Carolina United States 29910
84 Vista Clinical Research Columbia South Carolina United States 29201
85 Coastal Carolina Research Center Mount Pleasant South Carolina United States 29464
86 Chattanooga Medical Research Chattanooga Tennessee United States 37404
87 Advanced Research Associates Corpus Christi Texas United States 78414
88 Research Across America Dallas Texas United States 75234
89 UT Southwestern Medical Center Dallas Texas United States 75390-9032
90 Advances in Health Houston Texas United States 77030
91 Hwca, Pllc Houston Texas United States 77054
92 TMC Life Research Houston Texas United States 77054
93 Stone Oak, LLC dba Discovery Clinical Trials San Antonio Texas United States 78258
94 National Clinical Research-Norfolk Norfolk Virginia United States 23502
95 Clinical Research Center, EVMS Norfolk Virginia United States 23507
96 Virginia Women's Center, Inc. Richmond Virginia United States 23233
97 National Clinical Research-Richmond, Inc Richmond Virginia United States 23294
98 Tidewater Clinical Research Virginia Beach Virginia United States 23456
99 Seattle Women's Health, Research, and Gynecology Seattle Washington United States 98105
100 North Spokane Women's Health Spokane Washington United States 99207
101 Diex Research Montreal Inc. Montreal Quebec Canada H4N 3C5
102 Diex Research Sherbrooke Inc. Sherbrooke Quebec Canada J1H 1Z1
103 Manna Research Inc St-Romuald Quebec Canada G6W 5M6
104 Clinique RSF Inc. Quebec Canada G1S 2L6
105 Center for Research Saint-Louis Quebec Canada G1W4R4

Sponsors and Collaborators

  • TherapeuticsMD

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
TherapeuticsMD
ClinicalTrials.gov Identifier:
NCT02253173
Other Study ID Numbers:
  • TXV14-01
First Posted:
Oct 1, 2014
Last Update Posted:
May 25, 2017
Last Verified:
Apr 1, 2017
Keywords provided by TherapeuticsMD
VVA
Painful Sex
Postmenopausal
Additional relevant MeSH terms:
Dyspareunia
Atrophy
Estradiol

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Period Title: Overall Study
STARTED 191 191 190 192
COMPLETED 175 174 177 178
NOT COMPLETED 16 17 13 14

Baseline Characteristics

Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule Total
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo Total of all reporting groups
Overall Participants 191 191 190 192 764
Age (Count of Participants)
<=18 years
0
0%
0
0%
0
0%
0
0%
0
0%
Between 18 and 65 years
148
77.5%
162
84.8%
156
82.1%
151
78.6%
617
80.8%
>=65 years
43
22.5%
29
15.2%
34
17.9%
41
21.4%
147
19.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
59.8
(5.90)
58.5
(6.29)
58.9
(6.26)
59.3
(6.07)
59.1
(6.14)
Sex: Female, Male (Count of Participants)
Female
191
100%
191
100%
190
100%
192
100%
764
100%
Male
0
0%
0
0%
0
0%
0
0%
0
0%
Region of Enrollment (participants) [Number]
Canada
13
6.8%
10
5.2%
15
7.9%
12
6.3%
50
6.5%
United States
178
93.2%
181
94.8%
175
92.1%
180
93.8%
714
93.5%
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]
162.7
(6.86)
162.9
(6.93)
162.3
(6.37)
162.2
(6.30)
162.5
(6.62)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]
70.4
(14.26)
71.1
(13.49)
70.6
(13.7)
70.4
(13.6)
70.6
(13.74)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]
26.5
(4.87)
26.8
(4.68)
26.7
(4.79)
26.7
(4.59)
26.7
(4.73)

Outcome Measures

1. Primary Outcome
Title Co-Primary Efficacy Endpoint - Vaginal Superficial Cells
Description • Change from Baseline to Week 12 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo
Time Frame Baseline and 12 Weeks

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo
Arm/Group Description Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Measure Participants 170 171 174 172
Least Squares Mean (Standard Error) [percentage of vaginal superficial cells]
17.50
(1.542)
16.72
(1.540)
23.20
(1.529)
5.63
(1.537)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
2. Primary Outcome
Title Co-Primary Efficacy Endpoint - Vaginal Parabasal Cells
Description • Change from Baseline to Week 12 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo
Time Frame Baseline and 12 Weeks

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo
Arm/Group Description Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Measure Participants 170 171 174 172
Least Squares Mean (Standard Error) [percentage of vaginal parabasal cells]
-40.63
(1.755)
-44.07
(1.751)
-45.55
(1.745)
-6.73
(1.750)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
3. Primary Outcome
Title Co-Primary Efficacy Endpoint - Vaginal pH
Description • Change from Baseline to Week 12 in vaginal pH as compared to placebo
Time Frame Baseline and 12 Weeks

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo
Arm/Group Description Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Measure Participants 170 171 174 174
Least Squares Mean (Standard Error) [pH units]
-1.32
(0.066)
-1.42
(0.066)
-1.34
(0.066)
-0.28
(0.066)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
4. Primary Outcome
Title Co-Primary Efficacy Endpoint - Severity of Most Bothersome Symptom (Dyspareunia)
Description • 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
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo
Arm/Group Description Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
Measure Participants 151 154 159 163
Least Squares Mean (Standard Error) [units on a scale]
-1.52
(0.071)
-1.69
(0.071)
-1.69
(0.071)
-1.28
(0.070)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0149
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
5. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Superficial Cells
Description • Change from Baseline to Week 2 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 186 188 184 185
Least Squares Mean (Standard Error) [percentage of vaginal superficial cells]
31.35
(1.496)
31.93
(1.488)
38.85
(1.500)
6.05
(1.498)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
6. Secondary Outcome
Title Secondary Efficacy Endpoints- Vaginal Superficial Cells
Description Change from Baseline to Week 6 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo
Time Frame Baseline and Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 172 170 173 176
Least Squares Mean (Standard Error) [percentage of vaginal superficial cells]
18.41
(1.536)
16.88
(1.543)
22.65
(1.532)
5.43
(1.525)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
7. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Superficial Cells
Description Change from Baseline to Week 8 in the percentage of vaginal superficial cells (by vaginal cytologic smear) compared to placebo
Time Frame Baseline and Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 164 165 166 167
Least Squares Mean (Standard Error) [percentage of vaginal superficial cells]
19.04
(1.561)
17.41
(1.558)
23.88
(1.554)
5.98
(1.551)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
8. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Parabasal Cells
Description Change from Baseline to Week 2 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 186 188 184 185
Least Squares Mean (Standard Error) [percentage of vaginal parabasal cells]
-40.23
(1.720)
-44.42
(1.710)
-45.60
(1.723)
-7.00
(1.720)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
9. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Parabasal Cells
Description Change from Baseline to Week 6 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo
Time Frame Baseline and Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 172 170 173 176
Least Squares Mean (Standard Error) [percentage of vaginal parabasal cells]
-39.36
(1.750)
-43.55
(1.752)
-45.61
(1.746)
-9.23
(1.741)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
10. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Parabasal Cells
Description Change from Baseline to Week 8 in the percentage of vaginal parabasal cells (by vaginal cytologic smear) compared to placebo
Time Frame Baseline and Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 164 165 166 167
Least Squares Mean (Standard Error) [percentage of vaginal parabasal cells]
-41.87
(1.768)
-43.78
(1.764)
-45.08
(1.762)
-7.86
(1.760)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
11. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal pH
Description Change from Baseline to Week 2 in vaginal pH as compared to placebo
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 186 188 184 186
Least Squares Mean (Standard Error) [pH units]
-1.23
(0.064)
-1.37
(0.064)
-1.30
(0.065)
-0.28
(0.064)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
12. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal pH
Description Change from Baseline to Week 6 in vaginal pH as compared to placebo
Time Frame Baseline and Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 172 170 173 176
Least Squares Mean (Standard Error) [pH units]
-1.32
(0.066)
-1.40
(0.066)
-1.48
(0.066)
-0.30
(0.065)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
13. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal pH
Description Change from Baseline to Week 8 in vaginal pH as compared to placebo
Time Frame Baseline and Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 164 165 166 167
Least Squares Mean (Standard Error) [pH units]
-1.35
(0.067)
-1.46
(0.067)
-1.45
(0.066)
-0.38
(0.066)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
14. Secondary Outcome
Title Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)
Description 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
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 145 147 140 141
Least Squares Mean (Standard Error) [units on a scale]
-0.99
(0.072)
-1.08
(0.072)
-1.02
(0.073)
-0.76
(0.072)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0260
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0019
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0105
Comments
Method Mixed Models Analysis
Comments
15. Secondary Outcome
Title Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)
Description 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
Time Frame Baseline and Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 148 150 150 159
Least Squares Mean (Standard Error) [units on a scale]
-1.30
(0.072)
-1.37
(0.072)
-1.48
(0.072)
-1.03
(0.070)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0069
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0009
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
16. Secondary Outcome
Title Secondary Efficacy Endpoints - Severity of Most Bothersome Symptom (Dyspareunia)
Description 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
Time Frame Baseline and Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 140 136 129 143
Least Squares Mean (Standard Error) [units on a scale]
-1.52
(0.073)
-1.64
(0.074)
-1.62
(0.075)
-1.15
(0.072)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0003
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
17. Secondary Outcome
Title Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)
Description 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
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 186 188 184 185
Least Squares Mean (Standard Error) [units on a scale]
-0.86
(0.066)
-1.01
(0.065)
-0.96
(0.066)
-0.72
(0.066)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1269
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0019
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0082
Comments
Method Mixed Models Analysis
Comments
18. Secondary Outcome
Title Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)
Description 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
Time Frame Baseline and Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 172 170 172 176
Least Squares Mean (Standard Error) [units on a scale]
-1.14
(0.067)
-1.27
(0.068)
-1.23
(0.067)
-0.90
(0.067)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0094
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0005
Comments
Method Mixed Models Analysis
Comments
19. Secondary Outcome
Title Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)
Description 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
Time Frame Baseline and Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 163 165 165 167
Least Squares Mean (Standard Error) [units on a scale]
-1.25
(0.069)
-1.44
(0.068)
-1.34
(0.068)
-1.01
(0.068)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0128
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0008
Comments
Method Mixed Models Analysis
Comments
20. Secondary Outcome
Title Secondary Efficacy Endpoints - Severity of Other VVA Symptoms (Vaginal Dryness)
Description 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
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 171 173 176 174
Least Squares Mean (Standard Error) [units on a scale]
-1.27
(0.068)
-1.47
(0.067)
-1.47
(0.067)
-0.97
(0.067)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0014
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
21. Secondary Outcome
Title Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)
Description 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
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 186 188 184 185
Least Squares Mean (Standard Error) [units on a scale]
-0.47
(0.054)
-0.56
(0.053)
-0.51
(0.054)
-0.47
(0.054)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9616
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.2439
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.6518
Comments
Method Mixed Models Analysis
Comments
22. Secondary Outcome
Title Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)
Description 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
Time Frame Baseline and Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 172 170 172 176
Least Squares Mean (Standard Error) [units on a scale]
-0.57
(0.055)
-0.64
(0.055)
-0.61
(0.055)
-0.55
(0.055)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.7829
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.2328
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.4118
Comments
Method Mixed Models Analysis
Comments
23. Secondary Outcome
Title Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)
Description 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
Time Frame Baseline and Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 163 165 165 167
Least Squares Mean (Standard Error) [units on a scale]
-0.74
(0.056)
-0.76
(0.056)
-0.73
(0.056)
-0.59
(0.056)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0639
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0356
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0914
Comments
Method Mixed Models Analysis
Comments
24. Secondary Outcome
Title Secondary Efficacy Endpoints - Other VVA Symptoms (Vulvar and/or Vaginal Itching or Irritation)
Description 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
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 171 173 176 174
Least Squares Mean (Standard Error) [units on a scale]
-0.75
(0.055)
-0.81
(0.055)
-0.77
(0.055)
-0.60
(0.055)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0503
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0055
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0263
Comments
Method Mixed Models Analysis
Comments
25. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)
Description 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
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 185 187 184 187
Least Squares Mean (Standard Error) [units on a scale]
-0.69
(0.048)
-0.77
(0.047)
-0.78
(0.048)
-0.40
(0.047)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
26. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)
Description 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
Time Frame Baseline to Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 172 170 173 176
Least Squares Mean (Standard Error) [units on a scale]
-0.82
(0.049)
-0.93
(0.049)
-0.89
(0.049)
-0.50
(0.048)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
27. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)
Description 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
Time Frame Baseline to Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 164 165 166 167
Least Squares Mean (Standard Error) [units on a scale]
-0.98
(0.050)
-1.04
(0.050)
-0.99
(0.049)
-0.50
(0.049)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
28. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Color)
Description 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
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 171 173 175 175
Least Squares Mean (Standard Error) [units on a scale]
-0.97
(0.049)
-1.06
(0.049)
-0.96
(0.049)
-0.60
(0.049)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
29. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)
Description 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
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 185 187 184 186
Least Squares Mean (Standard Error) [units on a scale]
-0.85
(0.049)
-0.87
(0.049)
-0.93
(0.049)
-0.53
(0.049)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
30. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)
Description 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
Time Frame Baseline and Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 172 170 173 176
Least Squares Mean (Standard Error) [units on a scale]
-0.97
(0.051)
-1.02
(0.051)
-1.01
(0.051)
-0.61
(0.050)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
31. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)
Description 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
Time Frame Baseline and Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 164 165 166 167
Least Squares Mean (Standard Error) [units on a scale]
-1.03
(0.052)
-1.08
(0.051)
-1.08
(0.051)
-0.66
(0.051)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
32. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Integrity)
Description 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
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 171 173 175 175
Least Squares Mean (Standard Error) [units on a scale]
-0.97
(0.051)
-1.07
(0.051)
-1.01
(0.050)
-0.60
(0.050)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
33. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)
Description 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
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 185 187 184 186
Least Squares Mean (Standard Error) [units on a scale]
-0.76
(0.049)
-0.76
(0.049)
-0.76
(0.049)
-0.40
(0.049)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
34. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)
Description 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
Time Frame Baseline and Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 172 170 173 176
Least Squares Mean (Standard Error) [units on a scale]
-0.85
(0.051)
-0.93
(0.051)
-0.90
(0.050)
-0.53
(0.050)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
35. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)
Description 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
Time Frame Baseline and Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 164 165 166 167
Least Squares Mean (Standard Error) [units on a scale]
-0.96
(0.051)
-1.04
(0.051)
-0.99
(0.051)
-0.59
(0.051)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
36. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Epithelial Surface Thickness)
Description 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
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 171 173 175 175
Least Squares Mean (Standard Error) [units on a scale]
-0.98
(0.051)
-1.03
(0.051)
-0.94
(0.050)
-0.61
(0.050)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
37. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)
Description 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
Time Frame Baseline and Week 2

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 2 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 185 187 184 186
Least Squares Mean (Standard Error) [units on a scale]
-0.79
(0.050)
-0.83
(0.050)
-0.86
(0.050)
-0.54
(0.050)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0004
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
38. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)
Description 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
Time Frame Baseline and Week 6

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 6 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 172 170 173 176
Least Squares Mean (Standard Error) [units on a scale]
-0.90
(0.051)
-0.95
(0.051)
-0.97
(0.051)
-0.60
(0.051)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
39. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)
Description 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
Time Frame Baseline and Week 8

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 8 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 164 165 166 167
Least Squares Mean (Standard Error) [units on a scale]
-1.00
(0.052)
-1.04
(0.052)
-1.06
(0.052)
-0.63
(0.052)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
40. Secondary Outcome
Title Secondary Efficacy Endpoints - Vaginal Mucosa Assessment (Vaginal Secretions)
Description 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
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 171 173 175 175
Least Squares Mean (Standard Error) [units on a scale]
-1.01
(0.051)
-1.06
(0.051)
-1.04
(0.051)
-0.64
(0.051)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Mixed Models Analysis
Comments
41. Secondary Outcome
Title Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) - Total Score
Description 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.
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 153 152 156 158
Least Squares Mean (95% Confidence Interval) [units on a scale]
7.909
9.431
10.283
7.458
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9075
Comments
Method ANCOVA
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0492
Comments
Method ANCOVA
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0019
Comments
Method ANCOVA
Comments
42. Secondary Outcome
Title Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Arousal
Description 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.
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 154 152 157 159
Least Squares Mean (95% Confidence Interval) [units on a scale]
0.875
1.287
1.392
0.93
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9719
Comments
Method ANCOVA
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0614
Comments
Method ANCOVA
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0085
Comments
Method ANCOVA
Comments
43. Secondary Outcome
Title Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Desire
Description 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.
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 154 152 157 159
Least Squares Mean (95% Confidence Interval) [units on a scale]
0.625
0.800
0.848
0.630
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9999
Comments
Method ANCOVA
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.2855
Comments
Method ANCOVA
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1189
Comments
Method ANCOVA
Comments
44. Secondary Outcome
Title Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Lubrication
Description 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.
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 153 152 156 159
Least Squares Mean (95% Confidence Interval) [units on a scale]
1.834
2.242
2.299
1.595
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.4162
Comments
Method ANCOVA
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0013
Comments
Method ANCOVA
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0003
Comments
Method ANCOVA
Comments
45. Secondary Outcome
Title Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Orgasm
Description 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.
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 153 152 156 159
Least Squares Mean (95% Confidence Interval) [units on a scale]
1.162
1.274
1.591
1.202
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9929
Comments
Method ANCOVA
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9634
Comments
Method ANCOVA
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0898
Comments
Method ANCOVA
Comments
46. Secondary Outcome
Title Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Pain
Description 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.
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 154 152 156 159
Least Squares Mean (95% Confidence Interval) [units on a scale]
2.173
2.548
2.514
1.930
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.5146
Comments
Method ANCOVA
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0099
Comments
Method ANCOVA
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0150
Comments
Method ANCOVA
Comments
47. Secondary Outcome
Title Secondary Efficacy Endpoints - Female Sexual Function Index (FSFI) Domain Score - Satisfaction
Description 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.
Time Frame Baseline and Week 12

Outcome Measure Data

Analysis Population Description
For the statistical test utilized (MMRM), the number of subjects analyzed varied based on if they had both Baseline and Week 12 data so it would not necessarily match the overall number of subjects in the MITT Population at Baseline.
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo Vaginal Softgel Capsule
Arm/Group Description Estradiol 4mcg Vaginal Softgel Capsule Estradiol Estradiol 10mcg Vaginal Softgel Capsule Estradiol Estradiol 25mcg Vaginal Softgel Capsule Estradiol Placebo Vaginal Softgel Capsule Placebo
Measure Participants 154 152 157 158
Least Squares Mean (95% Confidence Interval) [units on a scale]
1.257
1.384
1.629
1.174
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol 4mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9039
Comments
Method ANCOVA
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Estradiol 10mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.3751
Comments
Method ANCOVA
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Estradiol 25mcg Vaginal Softgel Capsule, Placebo
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0073
Comments
Method ANCOVA
Comments
48. Other Pre-specified Outcome
Title PK Substudy - Hormone Concentration Assessments (Serum Estradiol, Estrone and Estrone Conjugates; SHBG)
Description 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
Time Frame Pre-treatment, Day 2, Weeks 2 and 12

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description

Adverse Events

Time Frame
Adverse Event Reporting Description
Arm/Group Title Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo
Arm/Group Description Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks. Postmenopausal women self-administered intravaginally one capsule daily for 14 days and then bi-weekly for 10 weeks.
All Cause Mortality
Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN) / (NaN)
Serious Adverse Events
Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/191 (0%) 3/191 (1.6%) 4/190 (2.1%) 1/192 (0.5%)
Cardiac disorders
Atrial fibrillation 0/191 (0%) 0/191 (0%) 1/190 (0.5%) 0/192 (0%)
Sinus node dysfunction 0/191 (0%) 1/191 (0.5%) 0/190 (0%) 0/192 (0%)
Gastrointestinal disorders
Appendicitis 0/191 (0%) 0/191 (0%) 1/190 (0.5%) 0/192 (0%)
Infections and infestations
Endophthalmitis 0/191 (0%) 0/191 (0%) 1/190 (0.5%) 0/192 (0%)
Injury, poisoning and procedural complications
Ankle fracture 0/191 (0%) 1/191 (0.5%) 0/190 (0%) 0/192 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/191 (0%) 1/191 (0.5%) 0/190 (0%) 0/192 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma 0/191 (0%) 1/191 (0.5%) 0/190 (0%) 0/192 (0%)
Nervous system disorders
Cervical myelopathy 0/191 (0%) 0/191 (0%) 0/190 (0%) 1/192 (0.5%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease 0/191 (0%) 0/191 (0%) 1/190 (0.5%) 0/192 (0%)
Other (Not Including Serious) Adverse Events
Estradiol 4mcg Vaginal Softgel Capsule Estradiol 10mcg Vaginal Softgel Capsule Estradiol 25mcg Vaginal Softgel Capsule Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 46/191 (24.1%) 41/191 (21.5%) 45/190 (23.7%) 66/192 (34.4%)
Infections and infestations
Nasopharyngitis 5/191 (2.6%) 6/191 (3.1%) 7/190 (3.7%) 10/192 (5.2%)
Upper respiratory infection 5/191 (2.6%) 6/191 (3.1%) 3/190 (1.6%) 5/192 (2.6%)
Urinary tract infection 5/191 (2.6%) 5/191 (2.6%) 8/190 (4.2%) 4/192 (2.1%)
Musculoskeletal and connective tissue disorders
Back pain 9/191 (4.7%) 1/191 (0.5%) 4/190 (2.1%) 8/192 (4.2%)
Nervous system disorders
Headache 12/191 (6.3%) 14/191 (7.3%) 6/190 (3.2%) 15/192 (7.8%)
Reproductive system and breast disorders
Vaginal discharge 5/191 (2.6%) 6/191 (3.1%) 4/190 (2.1%) 13/192 (6.8%)
Vulvovaginal pruritus 4/191 (2.1%) 3/191 (1.6%) 7/190 (3.7%) 10/192 (5.2%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain 1/191 (0.5%) 0/191 (0%) 6/190 (3.2%) 1/192 (0.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results Point of Contact

Name/Title Sebastian Mirkin, MD, Chief Medical Officer
Organization TherapeuticsMD
Phone 561-961-1900 ext 1952
Email sebastian.mirkin@therapeuticsmd.com
Responsible Party:
TherapeuticsMD
ClinicalTrials.gov Identifier:
NCT02253173
Other Study ID Numbers:
  • TXV14-01
First Posted:
Oct 1, 2014
Last Update Posted:
May 25, 2017
Last Verified:
Apr 1, 2017