Eight-Week Efficacy & Safety Study of Brisdelle™ (Formerly Known as Mesafem) in the Treatment of Vasomotor Symptoms Associated With Menopause

Eligible subjects will be entered into a 1-week observation period followed by a 1-week run-in period. Following completion of the run-in period, eligible subjects will be randomized to receive either Brisdelle (paroxetine mesylate) Capsules 7.5 mg or placebo in a 1:1 ratio. Study drug will be administered once daily at bedtime. Symptom assessment questionnaires will be administered at baseline and at Day 28 and Day 57 visits.

• Brisdelle (paroxetine mesylate) (Drug), also known as Former Names: Mesafem capsules 7.5 mg or, LDMP (Low-Dose Mesylate salt of Paroxetine): Eligible subjects will be randomized to receive Brisdelle™ (paroxetine mesylate) Capsules 7.5 mg.
• Sugar pill (Drug): Subjects will receive a sugar pill.

Primary outcomes

• Mean Change From Baseline in Hot Flash Frequency at Week 4 and Week 8 [Week 4 and Week 8]: The number of hot flashes reported in the result table are: * 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 8. They are both measured as hot flashes per week.
• Mean Change From Baseline in Hot Flash Severity at Week 4 and Week 8 [Week 4 and Week 8]: A scale was not used to measure severity scores. Severity scores of hot flashes were calculated for each subject. The following formula was used to calculate severity. SS = (2•Fm + 3•Fs) ÷ (Fm + Fs) Where: SS = severity score Fm = frequency of moderate hot flashes Fs = frequency of severe hot flashes The mean number of moderate and severe hot flashes that was recorded in the Run-In Period was used to calculate the baseline severity score.

Secondary outcomes

• Change From Baseline in Climacteric Symptoms at Week 8 [Week 8]: 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 8 were used to calculate change from baseline in these symptoms. The change from baseline is reported below.
• Change From Baseline in Hot Flash Composite Score at Week 4 and Week 8 [Week 4 and Week 8]: A scale was not used for this measurement. Composite scores of hot flashes were calculated by using the following formula: CS = (2 • Fm + 3 • Fs) Where: CS = composite score Fm = frequency of moderate hot flashes Fs = frequency of severe hot flashes The mean number of moderate and severe hot flashes recorded in the Run-In Period was used to calculate the baseline composite score.
• Effect of Brisdelle (Paroxetine Mesylate) Capsules on Depression and Anxiety at Week 8 [Week 8]: Depression \& anxiety were measured using the Hospital Anxiety \& Depression Scale (HADS). The HADS is a scale developed to assess anxiety \& depression. The HADS Scale consists of 14 Questions (7 relating to anxiety; 7 relating to depression) with possible scores ranging from 0 to 21. The results presented below are the number of participants with abnormal HADS Scores for both Abnormal Anxiety \& Abnormal Depression combined at Week 8.
• Effect of Brisdelle (Paroxetine Mesylate) Capsules on Mood at Week 4 [Week 4]: Mood was measured 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 "335." The percentage of participants who had a change from baseline in the total score at Week 4 is reported below.
• Effect of Brisdelle (Paroxetine Mesylate) Capsules on Improvement of Hot Flash Interference at Week 4 [Week 4]: 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 compared to baseline. A responder is defined as a subject who had an improvement in the HFRDIS score. An improvement is define as a score ≤3 on each question.
• Proportion of Clinical Global Impression (CGI) Responders at Week 4 and Week 8 [Week 4 and Week 8]: The Clinical Global Impression Scale (CGIS) was completed by the investigator and was used to measure the severity of the VMS at any given time and the improvement from baseline. Responders were defined as subjects who achieved a score of 1 to 3 where 1 = very much improved, 2 = much improved, and 3 = minimally improved. Non-responders were defined as subjects who achieved a score of 4 to 7 where 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
• Asses the Effect of Brisdelle (Paroxetine Mesylate) Capsules on the Interference on Sexual Functioning at Week 8 [Week 8]: 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.
• Proportion of Numerical Rating Scale (NRS) True Responders at Week 4 and Week 8 [Week 4 and Week 8]: The Subject Impression Numerical Rating Scale (NRS) is an 11-point scale was used to measure how bothered a subject was by hot flashes both during the day and the night. The measure being reported below is percentage of responders who had an improvement in NRS score at Week 4 compared to baseline. A responder is defined as a subject who had an improvement in the NRS score. An improvement is define as a score ≤3 on each question.
• Effect of Brisdelle (Paroxetine Mesylate) Capsules on BMI at Week 4 and Week 8 [Week 4 and Week 8]: Body Mass Index (BMI) was calculated by using height in centimeters and weight in kilograms.

Sex: Female, ages: 41 Years to any

Inclusion Criteria:

1. Female, >40 years of age
2. 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
3. Spontaneous amenorrhea for at least 12 consecutive months
4. Amenorrhea for at least 6 months and meet the biochemical criteria for menopause
5. Bilateral salpingo-oophorectomy >6 weeks with or without hysterectomy

Exclusion Criteria:

1. History of hypersensitivity or adverse reaction to paroxetine mesylate
2. Use of an investigational study medication within 30 days prior to screening or during the study
3. Concurrent participation in another clinical trial or previous participation in this trial
4. Family of investigational-site staff

Participant flow

Outcome results

• Mean Change From Baseline in Hot Flash Frequency at Week 4 and Week 8 (Primary), Mean, Hot flashes: Brisdelle (Paroxetine Mesylate) Capsules 82.44 (0 to 0); Placebo - Sugar Pill 83.18 (0 to 0) (p 0.0177)
• Mean Change From Baseline in Hot Flash Severity at Week 4 and Week 8 (Primary), Mean, Severity score: Brisdelle (Paroxetine Mesylate) Capsules 2.570 +/- 0.044; Placebo - Sugar Pill 2.539 +/- 0.035 (p 0.0644)
• Change From Baseline in Climacteric Symptoms at Week 8 (Secondary), Mean, units on a scale: Brisdelle (Paroxetine Mesylate) Capsules 16.63 +/- 1.55; Placebo - Sugar Pill 17.33 +/- 1.32
• Change From Baseline in Hot Flash Composite Score at Week 4 and Week 8 (Secondary), Mean, Composite score: Brisdelle (Paroxetine Mesylate) Capsules 211.9 +/- 8.85; Placebo - Sugar Pill 213.0 +/- 11.34
• Effect of Brisdelle (Paroxetine Mesylate) Capsules on Depression and Anxiety at Week 8 (Secondary), Number, participants: Brisdelle (Paroxetine Mesylate) Capsules 2; Placebo - Sugar Pill 1
• Effect of Brisdelle (Paroxetine Mesylate) Capsules on Mood at Week 4 (Secondary), Number, percentage of participants: Brisdelle (Paroxetine Mesylate) Capsules 21; Placebo - Sugar Pill 18
• Effect of Brisdelle (Paroxetine Mesylate) Capsules on Improvement of Hot Flash Interference at Week 4 (Secondary), Number, percentage of responders: Brisdelle (Paroxetine Mesylate) Capsules 12; Placebo - Sugar Pill 11
• Proportion of Clinical Global Impression (CGI) Responders at Week 4 and Week 8 (Secondary), Number, Percentage of participants: Brisdelle (Paroxetine Mesylate) Capsules 73.91; Placebo - Sugar Pill 60.00
• Asses the Effect of Brisdelle (Paroxetine Mesylate) Capsules on the Interference on Sexual Functioning at Week 8 (Secondary), Mean, units on a scale: Brisdelle (Paroxetine Mesylate) Capsules 17.98 +/- 0.67; Placebo - Sugar Pill 17.33 +/- 0.72
• Proportion of Numerical Rating Scale (NRS) True Responders at Week 4 and Week 8 (Secondary), Number, Percentage of true responders: Brisdelle (Paroxetine Mesylate) Capsules 33.33; Placebo - Sugar Pill 16.67
• Effect of Brisdelle (Paroxetine Mesylate) Capsules on BMI at Week 4 and Week 8 (Secondary), Mean, BMI Kg/m2: Brisdelle (Paroxetine Mesylate) Capsules 27.85 +/- 1.0; Placebo - Sugar Pill 27.69 +/- 0.081

Adverse events

Time frame: 56 days

Serious adverse events by term

Other adverse events by term

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• Kritz-Silverstein D, Goldani Von Muhlen D, Barrett-Connor E. Prevalence and clustering of menopausal symptoms in older women by hysterectomy and oophorectomy status. J Womens Health Gend Based Med. 2000 Sep;9(7):747-55. doi: 10.1089/15246090050147727. PMID 11025867
• Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, Nicolaidis C, Walker M, Humphrey L. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006 May 3;295(17):2057-71. doi: 10.1001/jama.295.17.2057. PMID 16670414
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• Patrick F. Freuen, MD, Principal investigator, North Spokane Women's Clinic, Spokane, WA 99207
• Richard E. Hedrick, MD, Principal investigator, Hawthorne Medical Research, Inc., Winston-Salem, NC 27103
• Samuel N. Lederman, MD, Principal investigator, Altus Research, Lake Worth, FL 33461
• Larry S. Seidman, DO, Principal investigator, Philadelphia Clinical Research, LLC, Philadelphia, PA 19114
• James E. Tomblin, MD, Principal investigator, Hawthorne Medical Research, Inc., Greensboro, NC 27408
• Peter A. Zedler, MD, Principal investigator, Virginia Women's Center, Richmond, VA 23233
• D. S. Harnsberger, MD, Principal investigator, Chattanooga Medical Research, LLC, Chattanooga, TN 37404
• John A. Hoekstra, MD, Principal investigator, National Clinical Research, Inc., Richmond, VA 23294
• Robin Kroll, MD, Principal investigator, Women's Clinical Research Center, Seattle, WA 98105
• Ashley Tunkle, MD, Principal investigator, Anchor Research Center, Naples, FL 34102