Study to Evaluate Ospemifene in Patients With Moderate to Severe Vaginal Dryness Due to Menopause

Study Overview
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Brief Summary
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The objective of this study is to evaluate the efficacy and safety of ospemifene 60 mg once daily (QD) compared with placebo in treatment of vulvo-vaginal atrophy (VVA) due to menopause in women with moderate to severe vaginal dryness as the most bothersome symptom (MBS) of VVA.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Ospemifene in Patients With Moderate to Severe Vaginal Dryness, a Symptom of Vulvo-vaginal Atrophy (VVA) Due to Menopause

Conditions
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Vaginal Dryness

Intervention / Treatment
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* Drug: Ospemifene
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is postmenopausal. Subject has moderate to severe vaginal dryness as the self-reported MBS of VVA. Exclusion Criteria: Subject has clinically significant abnormal findings in the physical examination. Subject has a body mass index (BMI) equal to or greater than 38 kg/m^2 Subject has uncontrolled hypertension. Subject has clinically significant abnormal findings in the gynecological examination other than signs of vaginal atrophy. Subject has uterine/vaginal bleeding of unknown origin. Subject has a vaginal infection requiring medication (may be treated and be eligible for study).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ospemifene<br>Participants will take one tablet of ospemifene 60 mg orally, once a day for 12 weeks. | Drug: Ospemifene<br>* 60 mg tablet<br>* Other names: Osphena®;|
| Placebo Comparator: Placebo<br>Participants will take one tablet of matching placebo, orally, once a day for 12 weeks. | Drug: Placebo<br>* Tablet identical to the ospemifene tablet without drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Percentage of Parabasal Cells in the Maturation Index of the Vaginal Smear at Week 12 | Parabasal cells are immature squamous cells in the lining of the vagina. A predominance of parabasal cells indicates absence of estrogenic stimulation and vaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. A decrease in parabasal cells indicates improvement in vaginal atrophy. To calculate least squares (LS) means, a mixed-effects model for repeated measures (MMRM) model was used. | Baseline and Week 12 | 
| Change From Baseline in the Percentage of Superficial Cells in the Maturation Index of the Vaginal Smear at Week 12 | Superficial cells are mature squamous cells in the lining of the vagina that can decrease in number after menopause resulting in vulvovaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. An increase in the number of superficial cells indicates improvement in atrophy. To calculate least squares (LS) means, a mixed-effects model for repeated measures (MMRM) model was used. | Baseline and Week 12 | 
| Change From Baseline in the Vaginal pH at Week 12 | The pH scale ranges from 0 to 14. A pH of 7 is neutral, less than 7 is acidic, and greater than 7 is basic. A typical vaginal pH in women of reproductive age is between 3.5 and 4.5, increasing to > 4.5 after menopause. Vaginal pH was measured by the investigator using a pH indicator strip at the middle third of the vaginal wall. To calculate least squares (LS) means, a mixed-effects model for repeated measures (MMRM) model was used. | Baseline and Week 12 | 
| Change From Baseline in the Severity of Self-reported Most Bothersome Symptom (MBS) of Vaginal Dryness at Week 12 | The severity of the most bothersome symptom of vaginal dryness was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3. | Baseline and Week 12 | 
| Number of Participants With Adverse Events | Treatment-related adverse events (AEs) were defined as AEs that were considered by the investigator to be related to investigational medicinal product, for which causal relationship with the study drug could be reasonably explained. A serious adverse event (SAE) is defined as any AE occurring at any dose that resulted in any of the following outcomes: Death Life-threatening condition Hospitalization or prolongation of existing hospitalization for treatment Persistent or significant disability/incapacity Congenital anomaly/birth defect Other medically important conditions that, based on medical judgment, may jeopardize the participant's health and may require medical intervention to prevent one of the outcomes listed above. | From the first dose of study drug up to 14 days after the last dose; 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Percentage of Parabasal Cells in the Maturation Index of the Vaginal Smear at Weeks 4 and 8 | Parabasal cells are immature squamous cells in the lining of the vagina. A predominance of parabasal cells indicates absence of estrogenic stimulation and vaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. A decrease in parabasal cells indicates improvement in vaginal atrophy. | Baseline and Weeks 4 and 8 | 
| Change From Baseline in the Percentage of Superficial Cells in the Maturation Index of the Vaginal Smear at Weeks 4 and 8 | Superficial cells are mature squamous cells in the lining of the vagina that can decrease in number after menopause resulting in vulvovaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. An increase in the number of superficial cells indicates improvement in atrophy. | Baseline and Weeks 4 and 8 | 
| Change From Baseline in the Vaginal pH | The pH scale ranges from 0 to 14. A pH of 7 is neutral, less than 7 is acidic, and greater than 7 is basic. A typical vaginal pH in women of reproductive age is between 3.5 and 4.5, increasing to > 4.5 after menopause. Vaginal pH was measured by the investigator using a pH indicator strip at the middle third of the vaginal wall. | Baseline and Weeks 4 and 8 | 
| Change From Baseline in the Severity of Self-reported Most Bothersome Symptom (MBS) of Vaginal Dryness at Weeks 4 and 8 | The severity of the most bothersome symptom of vaginal dryness was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3. | Baseline and Weeks 4 and 8 | 
| Change From Baseline in Vaginal and/or Vulvar Irritation or Itching | The severity of vaginal and/or vulvar irritation or itching was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Difficult or Painful Urination | The severity of difficult or painful urination was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Vaginal Pain Associated With Sexual Activity | The severity of vaginal pain associated with sexual activity was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Vaginal Bleeding Associated With Sexual Activity | The severity of vaginal bleeding associated with sexual activity was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Maturation Value | The maturation value is an indicator of the level of maturation attained by the vaginal epithelium. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at the central laboratory by a qualified pathologist. Parabasal cells (P), intermediary cells (I), and superficial cells (S) were counted and results were expressed as the maturation value (MV), whereby superficial cells were assigned a point value of 1.0, intermediate cells were assigned a point value of 0.5, and parabasal cells were assigned a point value of 0. The maturation value (MV) was defined as: (percentage of superficial cells * 1) + (percentage of intermediate cells * 0.5) + (percentage of parabasal calls * 0). Lower MV indicates lower estrogen effect. | Baseline and Weeks 4, 8, and 12 | 
| Percentage of Participants Who Were Responders at Week 4, Week 8, and Week 12 | A participant was defined as a responder if all the following conditions were met:: Increase from baseline in maturation value of at least 10 Decrease from baseline in vaginal pH of at least 0.5 Improvement from baseline (decrease in severity) of at least 1 point in the most bothersome symptom of vaginal dryness | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Vaginal Health Index | The investigator performed an evaluation of the vagina, assessing overall elasticity, fluid secretion, pH, condition of epithelial mucosa, and moisture. The severity of each characteristic was assessed using a 5-grade scale from 1 (worst) to 5 (best). The total score was calculated as the sum of the 5 individual scores and ranges from 5 to 25, where higher scores indicate better vaginal health | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Vulvar Health Index | The investigator performed a visual examination of the vulva, assessing the labia majora, labia minora, clitoris, introitus appearance and elasticity, color, discomfort and pain, and presence of other findings (eg, petechiae, excoriations, ulcers, etc). The severity of each characteristic was assessed on a 4-point scale as 0 = normal, 1 = mild, 2 = moderate, and 3 = severe. The total score was calculated by adding the 7 individual scores and ranges from 0 to 21, where lower scores indicate better vulvar health. A negative change from baseline indicates improvement. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Vulvovaginal Imaging Total Score at Week 12 | Vulvovaginal imaging was performed by trained site personnel following a standard procedure. Photographs were assessed by an Independent Panel Review (IPR) in a blinded fashion. Nine parameters (labia majora, labia minora, clitoris, urethra, introitus and elasticity, color, erythema, moisture, and other findings (petechiae, excoriation, ulceration, etc.)) were evaluated on a scale from 0 (normal/none) to 3 (severe). The total score was calculated from the sum of the 9 individual scores and ranged from 0 to 27 with lower values indicating better vulvovaginal health; a negative change from baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline in Female Sexual Function Index Total Score | The Female Sexual Function Index consists of 19 questions organized into 6 domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) answered by the participant on a 5-point scale from 1 to 5. Where relevant, some questions also include an option of 0 if a question is not applicable due to no sexual activity. Each domain score was calculated by adding the scores of each item in the domain and multiplying by a domain factor. The total score was calculated by summing each domain score and ranges from 2 to 36, with higher values indicating better sexual function. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Female Sexual Function Index Domain Scores at Week 12 | The Female Sexual Function Index consists of 19 questions, organized into 6 domains (desire, arousal, lubrication, orgasm, satisfaction, and pain), answered by the participant on a scale from 1 to 5. Where relevant, some questions also include an option of 0 if not applicable due to no sexual activity. Each domain score was calculated by adding the scores of each item in the domain and multiplying by a domain factor. For all domains, higher values indicate better sexual function, according to the following: Desire (2 questions): domain score ranges from 1.2 to 6; Arousal (4 questions): domain score ranges from 0 to 6; Lubrication (4 questions): domain score ranges from 0 to 6; Orgasm (3 questions): domain score ranges from 0 to 6; Satisfaction (3 questions): domain score ranges from 0.8 to 6; Pain (3 questions): domain score ranges from 0 to 6. | Baseline and Week 12 | 
| Change From Baseline in Urinary Distress Inventory (UDI)-6 Total Score | The presence or absence of urinary symptoms was assessed using the Urinary Distress Inventory (UDI)-6. The symptoms include frequent urination, urine leakage related to the feeling of urgency, urine leakage related to physical activity, coughing, or sneezing, small amounts of urine leakage, difficulty emptying bladder, and pain and discomfort in the lower abdominal or genital area. If a symptom was present, participants were asked to assess the degree to which they were bothered by it on the following 4-point scale: = present but doesn't bother her at all; = present and bothers her slightly; = present and bothers her moderately; = present and bothers her greatly. The total score was calculated by adding the 6 scores together (Absent = 0), and ranges from 0 to 24, with lower values indicating less urinary distress. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline in Bone Sialoprotein at Week 12 | Serum bone sialoprotein (BSP) was measured as a marker of bone resorption. | Baseline and Week 12 | 
| Change From Baseline in Type I Collagen C-Telopeptide (CTX) at Week 12 | Type I collagen C-telopeptide was measured as a marker of bone resorption. | Baseline and Week 12 | 
| Change From Baseline in Deoxypyridinoline at Week 12 | Deoxypyridinoline was measured as a marker of bone resorption. | Baseline and Week 12 | 
| Change From Baseline in Type I Collagen N-Telopeptide (NTX) at Week 12 | Type I collagen N-telopeptide was measured as a marker of bone resorption. | Baseline and Week 12 | 
| Change From Baseline in Tartrate-Resistant Acid Phosphatase 5b at Week 12 | Tartrate-resistant acid phosphatase 5b was measured as a marker of bone resorption. | Baseline and Week 12 | 
| Change From Baseline in Alkaline Phosphatase at Week 12 | Alkaline phosphatase was measured as a marker of bone formation. | Baseline and Week 12 | 
| Change From Baseline in Bone-specific Alkaline Phosphatase at Week 12 | Bone-specific alkaline phosphatase was measured as a marker of bone formation. | Baseline and Week 12 | 
| Change From Baseline in Osteocalcin at Week 12 | Osteocalcin was measured as a marker for bone formation. | Baseline and Week 12 | 
| Change From Baseline in Procollagen 1 N-Terminal Propeptide (P1NP) at Week 12 | Procollagen 1 N-terminal propeptide was measured as a marker of bone formation. | Baseline and Week 12 | 
| Mean Days of Lubricant Use Per Week | The mean number of days/week that lubricant was used as documented by participants in an electronic daily diary. | Week 1 to Week 12 | 
| Mean Days of Intercourse Per Week | The mean number of days/week of intercourse as recorded by participants in an electronic daily diary. | Week 1 to Week 12 | 
| Overall Satisfaction With Treatment at Week 12 | Participants were asked to record their overall satisfaction with treatment in an electronic diary according to the following categories: Very satisfied, Moderately satisfied, About equally satisfied and dissatisfied, Moderately dissatisfied, and Very dissatisfied. | Week 12 | 
| Change From Baseline in Estradiol at Week 12 |  | Baseline and Week 12 | 
| Change From Baseline in Follicle-Stimulating Hormone at Week 12 |  | Baseline and Week 12 | 
| Change From Baseline in Luteinizing Hormone at Week 12 |  | Baseline and Week 12 | 
| Change From Baseline in Sex Hormone-Binding Globulin at Week 12 |  | Baseline and Week 12 | 
| Change From Baseline in Testosterone at Week 12 |  | Baseline and Week 12 | 
| Change From Baseline in Free Testosterone at Week 12 |  | Baseline and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vulvo-vaginal Atrophy, menopause