Efficacy/Safety Study of Brisdelle™ (Formerly Known as Mesafem) in the Treatment of Vasomotor Symptoms (VMS)

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety & efficacy of Brisdelle (paroxetine mesylate) Capsules 7.5 mg for treatment of vasomotor symptoms (VMS) associated with menopause.

Detailed Description
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This is 12-week, multicenter, double-blind, randomized, placebo-controlled study of Brisdelle (paroxetine mesylate) Capsules 7.5 mg and placebo capsules in subjects with moderate to severe postmenopausal VMS, defined as follows: Moderate VMS: Sensation of heat with sweating, able to continue activity Severe VMS: Sensation of heat with sweating, causing cessation of activity The study is comprised of a screening period, a run-in period, a baseline visit, and a double-blind treatment period.

Official Title
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A Phase 3, Twelve-Week, Multicenter, Double-Blind, Randomized, Placebo-Controlled, Efficacy and Safety Study of Mesafem (Paroxetine Mesylate) Capsules in the Treatment of Vasomotor Symptoms Associated With Menopause

Conditions
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Postmenopausal Symptoms

Intervention / Treatment
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* Drug: Brisdelle (paroxetine mesylate)
* Drug: Placebo capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female, ≥ 40 years of age at screening (inclusive) Reported more than 7-8 moderate to severe hot flashes per day (average) or 50-60 moderate to severe hot flashes per week for at least 30 days prior to the screening visit Spontaneous amenorrhea for at least 12 consecutive months or Amenorrhea for at least 6 months and meet the biochemical criteria for menopause or Bilateral salpingo-oophorectomy ≥ 6 weeks with or without hysterectomy Exclusion Criteria: Known non-responder to previous Selective serotonin reuptake inhibitor (SSRI) or Serotonin norepinephrine reuptake inhibitor (SNRI) treatment for VMS History of self injurious behavior History of clinical diagnosis of depression or treatment for depression History of clinical diagnosis of borderline personality disorder Use of an investigational study medication within 30 days prior to screening or during the study Concurrent participation in another clinical trial or previous participation in this trial Family of investigational-site staff

Ages Eligible for Study
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Minimum Age: 40 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: Brisdelle (paroxetine mesylate)<br>Brisdelle (paroxetine mesylate) | Drug: Brisdelle (paroxetine mesylate)<br>* Subjects will be randomized to receive either Brisdelle (paroxetine mesylate) Capsules 7.5 mg or placebo in a 1:1 ratio, administered once daily at bedtime beginning on Day 1 and continuing up to Day 84<br>* Other names: LDMP (Low-Dose Mesylate salt of Paroxetine);|
| Placebo Comparator: Placebo Capsules<br>Placebo Capsules | Drug: Placebo capsules<br>* Subjects will be randomized to receive either Brisdelle (paroxetine mesylate) Capsules 7.5 mg or placebo in a 1:1 ratio, administered once daily at bedtime beginning on Day 1 and continuing up to Day 84<br>* Other names: Sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Frequency of Moderate to Severe VMS From Baseline at Week 4 and Week 12. | Subjects recorded the number of hot flashes per week using an electronic diary. The results reported are not hot flashes per week. The results reported are: Mean Baseline frequency of moderate to severe VMS Mean change in frequency of moderate to severe VMS from baseline to Week 4 Mean change in frequency of moderate to severe VMS from baseline to Week 12. | Week 4 and Week 12 | 
| Mean Change From Baseline in Hot Flash Severity at Week 4 and Week 12 | Subjects recorded the number of hot flashes per week using an electronic diary. Severity score for hot flashes for each subject was calculated as the sum of 2 times the number of moderate hot flashes, plus 3 times the number of severe hot flashes, divided by the total number of moderate and severe hot flashes. Weekly Severity Score = (2•Fm +3•FS)/(Fm + FS) Daily Severity Score = {(2•F) m +3•FS)/(Fm + FS)}/7 Where, Fm= Frequency of Moderate Hot Flashes Fs = Frequency of Severe Hot Flashes The calculated severity score is reported below. | Week 4 and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Meaningfulness Anchored to Patient Global Improvement (PGI-I) (%) | A patient improvement scale questionnaire was used during participant visits. The clinical meaningfulness of the observed treatment effect was demonstrated by performing the following analysis: Subjects were categorized in to 2 groups (satisfied and unsatisfied). Based on a 7 point patient global impression (PGI) questionnaire which assesses the subject improvement in VMS. Subjects were considered satisfied with their treatment if their response to the question Compared to before starting the study medication, how would you describe your hot flushes now? is 'Very much better' (1) or 'Much better' (2) or 'A little better' (3) and will be considered unsatisfied if their response to the same question is 'No change' (4) or 'A little worse' (5) or 'Much worse' (6) or 'Very much worse' (7). Receiver Operator Curve (ROC) analysis was performed on the combined data. Subjects who were satisfied with their treatment were considered to have a treatment effect with clinical meaningfulness | Week 4 and Week 12 | 
| Change From Baseline in Total Number of Awakenings Due to Hot Flashes, Median | Participants completed a electronic diary to report nightime awakenings. Subjects took study drug once daily at bedtime and they were instructed to complete daily hot flash and sleep diaries to record the number of hot flashes daily, the severity of each episode of hot flash and total number of awakenings due to hot flashes. The diary data was used to evaluate and compare the treatment groups, on the change from baseline to Week 4 and Week 12, in the total number of awakenings due to hot flashes. The total number of awakenings due to hot flashes in the run-in period was used as baseline. | Week 4 and Week 12 | 
| Change in Frequency of Moderate to Severe Hot Flashes Frequency From Baseline (BMI <32 kg/m2, Week 4 and Week 12), Median | Subjects were weighed at each clinic visit and reported the number of hot flashes using an electronic diary. For the BMI <32 kg/m2 subgroup, the mean weekly reduction in frequency of moderate to severe hot flashes from Baseline was calculated for Week 4 and Week 12. | Week 4 and Week 12 | 
| Change in Frequency of Moderate to Severe Hot Flashes Frequency From Baseline (BMI ≥32 kg/m2, Week 4 and Week 12), Median | Subjects were weighed at each clinic visit and reported the number of hot flashes using an electronic diary. For the BMI ≥32 kg/m2 subgroup, the mean weekly reduction in frequency of moderate to severe hot flashes from Baseline was calculated for Week 4 and Week 12. | Week 4 and Week 12 | 
| Change in Severity of Moderate to Severe Hot Flashes From Baseline (BMI <32 kg/m2, At Week 4 and Week 12), Median | Subjects were weighed at each clinic visit and reported the number of hot flashes using an electronic diary. For the BMI <32 kg/m2 subgroup, the mean weekly reduction in the severity of moderate to severe hot flashes from Baseline was calculated at Week 4 and Week 12. Subjects recorded the number of hot flashes per week using an electronic diary. Severity score for hot flashes for each subject was calculated as the sum of 2 times the number of moderate hot flashes, plus 3 times the number of severe hot flashes, divided by the total number of moderate and severe hot flashes. Weekly Severity Score = (2•Fm +3•FS)/(Fm + FS) Daily Severity Score = {(2•F) m +3•FS)/(Fm + FS)}/7 Where, Fm= Frequency of Moderate Hot Flashes Fs = Frequency of Severe Hot Flashes The calculated severity score is reported below. | Week 4 and Week 12 | 
| Change in Severity of Moderate to Severe Hot Flashes From Baseline (BMI ≥32 kg/m2, Week 4 and Week 12), Median | Subjects were weighed at each clinic visit and reported the number of hot flashes using an electronic diary. For the BMI ≥32 kg/m2 subgroup, the mean weekly reduction in the severity of moderate to severe hot flashes from Baseline was calculated at Week 4 and Week 12. Subjects recorded the number of hot flashes per week using an electronic diary. Severity score for hot flashes for each subject was calculated as the sum of 2 times the number of moderate hot flashes, plus 3 times the number of severe hot flashes, divided by the total number of moderate and severe hot flashes. Weekly Severity Score = (2•Fm +3•FS)/(Fm + FS) Daily Severity Score = {(2•F) m +3•FS)/(Fm + FS)}/7 Where, Fm= Frequency of Moderate Hot Flashes Fs = Frequency of Severe Hot Flashes The calculated severity score is reported below. | Week 4 and Week 12 | 
| Change From Baseline in Greene Climacteric Scale (GCS) at Week 4 and Week 12, Total Score, Median | The Greene Climacteric Scale (GCS) was used for this measurement. The scale has 21 questions and measures symptoms in 4 areas; these are psychological (anxiety and depression), physical, vasomotor, and libido. The severity of the symptom was scored as: 0=none, 1=mild, 2=moderate, and 3=severe. Anxiety was determined by using the sum of scores 1 to 6, and depression was determined by using the sum of scores 7 to 11. Physical aspects were determined by using the sum of scores 12 to 18; vasomotor aspects were determined by using the sum of scores 19 to 20; and libido was determined by using the score for question 21. The total GCS score ranges from 0 to 63 which is the sum of all the scores for the 21-symptom assessment questions in this scale. Each subject's total GCS score at baseline and at Week 4 and Week 12 were used to calculate change from baseline in these symptoms. The change from baseline is reported below. | Week 4 and Week 12 | 
| Percentage of Responders | Participants reported the number of hot flashes using an electronic diary. Participants who hd a ≥50% reduction in hot flash frequency were defined as responders. The percent of responders is presented below. | Week 4 and Week 12 | 
| Percentage of Patient Global Improvement (PGI) Scale Responders (%) | Percentage of PGI Responders: Subject's overall improvement in VMS from baseline assessed using the Patient Global Improvement (PGI) scale. Responders: Subjects Achieving a Score of Very Much Better Or Much Better Or A Little Better. Non Responders: Subjects with a Score of No Change Or A Little Worse Or Much Worse Or Very Much Worse. Patient Global Improvement (PGI) scale is described below: Compared to before starting study medication, how would you describe your hot flushes now? 0 = Not assessed = Very much better = Much better = A little better = No change = A little worse = Much worse = Very much worse | Week 4 and Week 12 | 
| Percent Daytime and Nighttime Responders, Numerical Rating Scale (NRS) | Subject's overall improvement in VMS from Baseline assessed using the Numerical Rating Scale (NRS) The NRS is measured on a scale of 0 to 10 on how bothered the subject was by her VMS (0=not bothered at all and 10=very much bothered). The measure being reported below is percentage of responders who had an improvement in NRSscore at Week 4 and Week 12 compared to baseline. A responder is defined as a subject who had an improvement in the NRS score. An improvement is defined as a score ≤5 on each question. | Week 4 and Week 12 | 
| Change From Baseline in Arizona Sexual Experience Scale (ASEX, Week 4 and Week 12) Total Score | The Arizona Sexual Experiences Scale (ASEX) is a 5-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Possible total scores range from 5 to 30, with the higher scores indicating more sexual dysfunction. The sum of the scores for all 5 items was calculated at Week 4 and Week 12. The results presented below are change from baseline at Week 4 and Week 12. | Week 4 and Week 12 | 
| Effect of Paroxetine Mesylate Capsules on Percent Improvement of Hot Flash Interference From Baseline at Week 4 and Week 12, Hot Flash Related Daily Interference Scale (HFRDIS) | Interference of hot flashes was measured by using the hot flash-related daily interference scale (HFRDIS). The HFRDIS is a 10-item scale that measures the degree to which hot flashes interfere with 9 daily activities and the tenth item measures the degree to which hot flashes interfere with each of the other items. Subjects can score for each item on a scale from 0 to 10 where 0 = Do not interfere and a score of 10 = Completely interferes. The measure being reported below is percentage of responders who had an improvement in HFRDIS score at Week 4 and Week 12 compared to baseline. A responder is defined as a subject who had an improvement in the HFRDIS score. An improvement is defined as a score ≤3 on each question. | Week 4 and Week 12 | 
| Percent Responders Improvement in VMS From Baseline Using the Clinical Global Impression (CGI) Scale. | Proportion of NRS Responders: Subject's overall improvement in VMS from Baseline was assessed using the Numerical Rating Scale (NRS) The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. Responders: Subjects Achieving a Score of Very Much Improved Or Much Improved Or Minimally Improved. Non Responders: Subjects with a Score of No Change Or Minimally Worse Or Much Worse Or Very Much Worse. | Week 4 and Week 12 | 
| Effect of Brisdelle (Paroxetine Mesylate) Capsules on Anxiety and Depression | Depression & anxiety were measured by using the Hospital Anxiety & Depression Scale (HADS). The HADS was developed to assess anxiety & depression. It is meant to differentiate symptoms of depression with those of anxiety. Number of items: 14 (7 questions relating to anxiety; 7 questions relating to depression). Responses are based on the relative frequency of symptoms over the past week, using a four point scale ranging from 0 (not at all) to 3 (very often indeed). Responses are summed to provide separate scores for anxiety and depression symptomology with possible scores ranging from 0 to 21 for each scale. The results presented below are the percentage of participants with abnormal HADS Scores for both Abnormal Anxiety & Abnormal Depression at Week 4 and Week 12. | Week 4 and Week 12 | 
| Assessment of Mood | Mood was measured by using the Profile of Mood States (POMS) questionnaire. The Profile of Moods States (POMS) is a 65-item multi-dimensional measure that provides a method of assessing transient, fluctuating active mood states. Key areas that are measured include: tension-anxiety, anger-hostility, fatigue-inertia, depression-dejection, vigor-activity, confusion-bewilderment. Responses to questions are scored with the following numerical values: Not at all = 1, A little = 2, Moderate = 3, Quite a bit = 4, Extremely = 5. A total score for a domain was obtained by summing the responses of individual items in the domain. The total POMS score can range from 65 to 325. Each subject's total POMS score at baseline and at Week 4 and Week 12 were used to calculate the percent of participants with less disturbance in mood at Week 4 and Week 12 compared to baseline. The percent of participants with less disturbance in mood is reported below. | Week 4 and Week 12 | 
| BMI Change From Baseline (kg/m2), Median | Subjects were weighed at each clinic visit and reported the number of hot flashes using an electronic diary. Assessment of the effect of Brisdelle compared with placebo on body mass index. | Week 4 and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Menopause, Vasomotor Symptoms, Hot Flashes Perimenopause, Climacteric Symptoms, Mesafem, Low-Dose Mesylate salt of Paroxetine (LDMP)