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

• ClinicalTrials.gov Identifier: NCT02253173
• Recruitment Status: Completed
• First Posted: October 1, 2014
• Results First Posted: May 25, 2017
• Last Update Posted: May 25, 2017
• Sponsor: TherapeuticsMD
• Information provided by (Responsible Party): TherapeuticsMD

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
Vulvovaginal Atrophy; Menopause; Dyspareunia; Painful Intercourse	Drug: Estradiol; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• 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: September 2014
• Actual Primary Completion Date: October 2015
• Actual Study Completion Date: October 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline and Week 2 ]
   Change from Baseline to Week 2 in vaginal pH as compared to placebo
8. Secondary Efficacy Endpoints - Vaginal pH [ Time Frame: Baseline and Week 6 ]
   Change from Baseline to Week 6 in vaginal pH as compared to placebo
9. Secondary Efficacy Endpoints - Vaginal pH [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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

• Ages Eligible for Study: 40 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Postmenopausal female subjects between the ages of 40 and 75 years (at the time of randomization) with at least:

   • 12 months of spontaneous amenorrhea (women <55 years of age with a history of hysterectomy without bilateral oophorectomy prior to natural menopause must have follicle stimulating hormone (FSH) levels > 40 mIU/mL), OR
   • 6 months of spontaneous amenorrhea with follicle stimulating hormone (FSH) levels > 40mlU/mL OR
   • At least 6 weeks postsurgical bilateral oophorectomy.
2. ≤5% superficial cells on vaginal cytological smear
3. Vaginal pH > 5.0
4. Moderate to severe symptom of vaginal pain associated with sexual activity considered the most bothersome vaginal symptom by the subject at screening visit 1A.
5. Moderate to severe symptom of vaginal pain associated with sexual activity at screening visit 1B.
6. Onset of moderate to severe dyspareunia in the postmenopausal years.
7. Subjects should be sexually active (i.e. have sexual activity with vaginal penetration within approximately 1 month of screening visit 1A).
8. Subjects should anticipate having sexual activity (with vaginal penetration) during the conduct of the trial.
9. For subjects with an intact uterus: Subjects must have an acceptable result from an evaluable screening endometrial biopsy.
10. Subjects who have a Body Mass Index (BMI) less than or equal to 38 kg/m2. BMI values should be rounded to the nearest integer (ex. 32.4 rounds down to 32, while 26.5 rounds up to 27).
11. In the opinion of the investigator, the subject will comply with the protocol and has a high probability of completing the study.

Exclusion Criteria:

1. Use of the following:

   1. Oral estrogen-, progestin-, androgen-, or SERM-containing drug products within 8 weeks before screening visit 1A (can enter washout);
   2. Use of transdermal hormone products within 4 weeks before screening visit 1A (can enter washout);
   3. Use of vaginal hormone products (rings, creams, gels) within 4 weeks before screening visit1A (can enter washout);
   4. Use of intrauterine progestins within 8 weeks before screening visit 1A (can enter washout);
   5. Use of progestin implants/injectables or estrogen pellets/injectables within 6 months before screening visit 1A (cannot enter washout);
   6. Use of vaginal lubricants or moisturizers within 7 days before the screening visit 1B vaginal pH assessment.

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

   1. Hypersensitivity to estrogens;
   2. Endometrial hyperplasia;
   3. Undiagnosed vaginal bleeding;
   4. Have a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis C or chronic renal failure);
   5. Thrombophlebitis, thrombosis or thromboembolic disorders;
   6. Cerebrovascular accident, stroke, or transient ischemic attack;
   7. Myocardial infarction or ischemic heart disease;
   8. Malignancy or treatment for malignancy, within the previous 5 years, with the exception of basal cell carcinoma of the skin or squamous cell carcinoma of the skin. A history of estrogen dependent neoplasia, breast cancer, melanoma or any gynecologic cancer, at any time, excludes the subject;
   9. Endocrine disease (except for controlled hypothyroidism or controlled non-insulin dependent diabetes mellitus).
3. Recent history of known alcohol or drug abuse.
4. History of sexual abuse or spousal abuse that, in the opinion of the PI, may interfere with the subject's assessment of vaginal pain with sexual activity.
5. Current history of Heavy smoking (more than 15 cigarettes per day) or use of e-cigarettes.
6. Use of an intrauterine device within 12 weeks before screening visit 1A.
7. Use of an investigational drug within 60 days before screening visit 1A.

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

   1. Unresolved cervical cytologic smear report of atypical glandular cells of undetermined significance (AGUS) or atypical squamous cells of undetermined significance (ASCUS).

      Cervical cytologic smear report of low-grade squamous intraepithelial lesion (SIL) or greater, CIN1 or greater, or any reported dysplasia; Subjects with ASCUS are eligible only if high risk human papilloma virus (HPV) result is negative.

   2. Unresolved findings suspicious for malignancy on the breast exam; incomplete mammogram result (BI-RADS 0) or unresolved findings suggestive of malignant changes or findings requiring short interval follow-up on the prestudy mammogram (subjects must have mammography result of BI-RADS 1 or 2 to enroll.) Mammogram may be performed within 9 months prior to Visit 2 (randomization) with documentation available. (The site must obtain a copy of the official report for the subject's study file, and it must be verified that the mammogram itself is available if needed for additional assessment);
   3. In subjects with intact uterus: have a screening endometrial biopsy sample that is found by both primary pathologists to have endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified. (With the approval of the Medical Monitor, the screening endometrial biopsy may be repeated once);

   4. In subjects with intact uterus: an endometrial biopsy report by one central pathologist at screening with one of the following:

      • Endometrial hyperplasia endometrial cancer, proliferative endometrium, weakly proliferative endometrium, disordered proliferative pattern; OR
      • Endometrial polyps with hyperplasia, glandular atypia of any degree (e.g., atypical nuclei) or cancer;
   5. Vulvar or vaginal inflammatory condition such as a contact or allergic dermatitis, lichen sclerosis or other pathological findings;
   6. Presence of suspicious vulvar or vaginal lesions for dysplasia, malignancy or other pathology other than atrophy;
   7. Painful genital warts or localized areas of ulceration;
   8. A history of active, chronic pelvic pain;
   9. Interstitial cystitis;
   10. Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal for the laboratory used;
   11. Fasting total cholesterol greater than 300 mg/dL (7.77 mmol/L) or triglycerides greater than 300 mg/dL (3.39 mmol/L);
   12. Fasting blood glucose greater than 125 mg/dL (6.94 mmol/L) with a hemoglobin A1C of greater than or equal to 6.5%;
   13. Uncontrolled hypertension; subjects with elevated sitting blood pressure, greater than 140 mm Hg systolic or greater than 90 mm Hg diastolic and may not be using more than 2 antihypertensive medications for the treatment of hypertension;
   14. Clinically significant abnormal 12-lead ECG (such as myocardial infarction or other findings suggestive of ischemia)
9. Be known to be pregnant or have a positive urine pregnancy test. (Note: A pregnancy test is not required for subjects who have had bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or are 55 years old or greater and have experienced cessation of menses for at least 1 year.
10. Current use of marijuana.

Contacts and Locations

Locations

United States, Alabama

Medical Affiliated Research Center

Huntsville, Alabama, United States, 35801

Montogomery Women's Health

Montgomery, Alabama, United States, 36117

United States, Arizona

Cactus Clinical Research

Mesa, Arizona, United States, 85209

Arizona Wellness Center for Women

Phoenix, Arizona, United States, 85032

Radiant Research

Scottsdale, Arizona, United States, 85251

Visions Clinical Research - Tucson

Tucson, Arizona, United States, 85712

United States, California

Sutter East Bay Medical Foundation

Berkeley, California, United States, 94705

Torrance Clinical Research Institute Inc

Lomita, California, United States, 90717

Futura Research

Norwalk, California, United States, 90650

Northern California Research

Sacramento, California, United States, 95821

Medical Center for Clinical Research

San Diego, California, United States, 92108

San Diego Sexual Medicine

San Diego, California, United States, 92120

Women's Health Care Research Corp.

San Diego, California, United States, 92123

United States, Colorado

Lynn Institute of the Rockies

Colorado Springs, Colorado, United States, 80909

Downtown Women's Health Care

Denver, Colorado, United States, 80209

Horizons Clinical Research Center

Denver, Colorado, United States, 80220

Red Rocks OB/Gyn

Lakewood, Colorado, United States, 80228

United States, Connecticut

Clinical Research Consulting

Milford, Connecticut, United States, 06460

Coastal Connecticut Research, LLC

New London, Connecticut, United States, 06320

United States, District of Columbia

James A. Simon, Women's Health & Research Consultants

Washington, D.C., District of Columbia, United States, 20036

United States, Florida

South Florida Medical Research

Aventura, Florida, United States, 33180

Nature Coast Clinical Research

Crystal River, Florida, United States, 34429

Avail Clinical Research

DeLand, Florida, United States, 32720

Clinical Physiology Associates

Fort Myers, Florida, United States, 33916

UF Health Physicians Women's & REI Springhill

Gainesville, Florida, United States, 32606

UF College of Medicine-Jacksonville, Dept. of Obstetrics and Gynecology

Jacksonville, Florida, United States, 32207

Jacksonville Center for Clinical Research

Jacksonville, Florida, United States, 32216

South Florida Wellness & Clinical Research Institute

Margate, Florida, United States, 33063

New Age Medical Research Corporation

Miami, Florida, United States, 33186

Suncoast Clinical Research, Inc.

New Port Richey, Florida, United States, 34652

Ideal Clinical Research

North Miami Beach, Florida, United States, 33162

Healthcare Clinical Data

North Miami, Florida, United States, 33161

Radiant Research

Pinellas Park, Florida, United States, 33781

All Women's Healthcare of West Broward

Plantation, Florida, United States, 33324

Physician Care Clinical Research

Sarasota, Florida, United States, 34239

Comprehensive Clinical Trials

West Palm Beach, Florida, United States, 33409

United States, Georgia

Women's Health Associates

Atlanta, Georgia, United States, 30342

Masters of Clinical Research, Inc.

Augusta, Georgia, United States, 30909

Soapstone Center for Clinical Research

Decatur, Georgia, United States, 30034

WR-Mount Vernon Clinical Research

Sandy Springs, Georgia, United States, 30328

Fellows Research Alliance, Inc.

Savannah, Georgia, United States, 31046

United States, Idaho

Advanced Clinical Research

Boise, Idaho, United States, 83642

Women's Healthcare Associates P.A.

Idaho Falls, Idaho, United States, 83404

United States, Illinois

Radiant Research

Chicago, Illinois, United States, 60654

United States, Indiana

American Health Network of Indiana, LLC

Avon, Indiana, United States, 46123

Lafayette Clinical Research Group

Lafayette, Indiana, United States, 47905

United States, Kansas

Cypress Medical Research Center

Wichita, Kansas, United States, 67226

United States, Kentucky

Central Kentucky Research Associates, Inc.

Lexington, Kentucky, United States, 40509

Bluegrass Clinical Research, Inc.

Louisville, Kentucky, United States, 40291

United States, Louisiana

Horizon Research Group of Opelousas

Eunice, Louisiana, United States, 70535

United States, Maryland

Capital Women's Care

Frederick, Maryland, United States, 21702

Maryland Center for Sexual Health

Lutherville, Maryland, United States, 21093

United States, Michigan

ClinSite, LLC

Ann Arbor, Michigan, United States, 48106

Beyer Research

Kalamazoo, Michigan, United States, 49009

Saginaw Valley Medical Research Group, L.L.C.

Saginaw, Michigan, United States, 48604

United States, Montana

Montana Health

Billings, Montana, United States, 59102

United States, Nebraska

Women's Clinic of Lincoln

Lincoln, Nebraska, United States, 68510

United States, Nevada

Office of Edmond E. Pack, MD

Las Vegas, Nevada, United States, 89113

Office of R. Garn Mabey, MD

Las Vegas, Nevada, United States, 89128

United States, New Jersey

Lawrence OB-GYN Clinical Research, LLC

Lawrenceville, New Jersey, United States, 08648

Rutgers-Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States, 08901

Women's Health Research Center

Plainsboro, New Jersey, United States, 08536

United States, New Mexico

Bosque Women's Care

Albuquerque, New Mexico, United States, 87109

Southwest Clinical Research

Albuquerque, New Mexico, United States, 87109

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

Suffolk OB/GYN

Port Jefferson, New York, United States, 08536

United States, North Carolina

Women's Wellness Clinic

Durham, North Carolina, United States, 27713

Pinewest OB-GYN, Inc.

High Point, North Carolina, United States, 27262

Wake Research Associates

Raleigh, North Carolina, United States, 27612

Hawthorne Research

Winston-Salem, North Carolina, United States, 27103

Lyndhurst Clinical Research

Winston-Salem, North Carolina, United States, 27103

United States, North Dakota

Lillestol Research

Fargo, North Dakota, United States, 58103

United States, Ohio

Radiant Research

Akron, Ohio, United States, 44311

University of Cincinnati Physicians Company

Cincinnati, Ohio, United States, 45267-0457

Rapid Medical Research

Cleveland, Ohio, United States, 44122

Columbus Center for Women's Health Research

Columbus, Ohio, United States, 43213

HWC Women's Research Center

Englewood, Ohio, United States, 45322

Landerbrook Health Center

Mayfield Heights, Ohio, United States, 44124

United States, Oregon

Sunstone Medical Research

Medford, Oregon, United States, 97504

United States, Pennsylvania

The Clinical Trial Center

Jenkintown, Pennsylvania, United States, 19046

Clinical Research of Philadelphia

Philadelphia, Pennsylvania, United States, 19114

Clinical Trials Research Services

Pittsburgh, Pennsylvania, United States, 15206

United States, South Carolina

Fellows Research Alliance, Inc.

Bluffton, South Carolina, United States, 29910

Vista Clinical Research

Columbia, South Carolina, United States, 29201

Coastal Carolina Research Center

Mount Pleasant, South Carolina, United States, 29464

United States, Tennessee

Chattanooga Medical Research

Chattanooga, Tennessee, United States, 37404

United States, Texas

Advanced Research Associates

Corpus Christi, Texas, United States, 78414

Research Across America

Dallas, Texas, United States, 75234

UT Southwestern Medical Center

Dallas, Texas, United States, 75390-9032

Advances in Health

Houston, Texas, United States, 77030

Hwca, Pllc

Houston, Texas, United States, 77054

TMC Life Research

Houston, Texas, United States, 77054

Stone Oak, LLC dba Discovery Clinical Trials

San Antonio, Texas, United States, 78258

United States, Virginia

National Clinical Research-Norfolk

Norfolk, Virginia, United States, 23502

Clinical Research Center, EVMS

Norfolk, Virginia, United States, 23507

Virginia Women's Center, Inc.

Richmond, Virginia, United States, 23233

National Clinical Research-Richmond, Inc

Richmond, Virginia, United States, 23294

Tidewater Clinical Research

Virginia Beach, Virginia, United States, 23456

United States, Washington

Seattle Women's Health, Research, and Gynecology

Seattle, Washington, United States, 98105

North Spokane Women's Health

Spokane, Washington, United States, 99207

Canada, Quebec

Diex Research Montreal Inc.

Montreal, Quebec, Canada, H4N 3C5

Diex Research Sherbrooke Inc.

Sherbrooke, Quebec, Canada, J1H 1Z1

Manna Research Inc

St-Romuald, Quebec, Canada, G6W 5M6

Canada

Clinique RSF Inc.

Quebec, Canada, G1S 2L6

Center for Research Saint-Louis

Quebec, Canada, G1W4R4

Sponsors and Collaborators

TherapeuticsMD

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mirkin S, Simon JA, Liu JH, Archer DF, Castro PD, Graham S, Bernick B, Komm B. Evaluation of endometrial progesterone receptor expression after 12 weeks of exposure to a low-dose vaginal estradiol insert. Menopause. 2021 May 28;28(9):998-1003. doi: 10.1097/GME.0000000000001801.

Constantine G, Millheiser LS, Kaunitz AM, Parish SJ, Graham S, Bernick B, Mirkin S. Early onset of action with a 17beta-estradiol, softgel, vaginal insert for treating vulvar and vaginal atrophy and moderate to severe dyspareunia. Menopause. 2019 Nov;26(11):1259-1264. doi: 10.1097/GME.0000000000001394.

Constantine GD, Simon JA, Pickar JH, Archer DF, Bernick B, Graham S, Mirkin S. Estradiol vaginal inserts (4 microg and 10 microg) for treating moderate to severe vulvar and vaginal atrophy: a review of phase 3 safety, efficacy and pharmacokinetic data. Curr Med Res Opin. 2018 Dec;34(12):2131-2136. doi: 10.1080/03007995.2018.1527578. Epub 2018 Sep 28.

Constantine GD, Bouchard C, Pickar JH, Archer DF, Graham S, Bernick B, Mirkin S. Consistency of Effect with a Low-Dose, Estradiol Vaginal Capsule (TX-004HR): Evaluating Improvement in Vaginal Physiology and Moderate-to-Severe Dyspareunia in Subgroups of Postmenopausal Women. J Womens Health (Larchmt). 2017 Jun;26(6):616-623. doi: 10.1089/jwh.2016.6187. Epub 2017 Mar 29.

• Responsible Party: TherapeuticsMD
• ClinicalTrials.gov Identifier: NCT02253173
• Other Study ID Numbers: TXV14-01
• First Posted: October 1, 2014
• Results First Posted: May 25, 2017
• Last Update Posted: May 25, 2017
• Last Verified: April 2017

Keywords provided by TherapeuticsMD:

VVA; Painful Sex; Postmenopausal

Additional relevant MeSH terms:

Dyspareunia; Atrophy; Pathological Conditions, Anatomical; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Mental Disorders; Estradiol; Estrogens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs