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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

Serum bone sialoprotein (BSP) was measured as a marker of bone resorption.

Type I collagen C-telopeptide was measured as a marker of bone resorption.

Deoxypyridinoline was measured as a marker of bone resorption.

Type I collagen N-telopeptide was measured as a marker of bone resorption.

Tartrate-resistant acid phosphatase 5b was measured as a marker of bone resorption.

Alkaline phosphatase was measured as a marker of bone formation.

Bone-specific alkaline phosphatase was measured as a marker of bone formation.

Osteocalcin was measured as a marker for bone formation.

Procollagen 1 N-terminal propeptide was measured as a marker of bone formation.

The mean number of days/week that lubricant was used as documented by participants in an electronic daily diary.

The mean number of days/week of intercourse as recorded by participants in an electronic daily diary.

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.