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

A Phase 3, Twenty-Four 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

To assess the safety and efficacy of Brisdelle (paroxetine mesylate) Capsules 7.5 mg for treatment of vasomotor symptoms (VMS) associated with menopause

Study Overview

• Status: Completed
• Conditions: Hot Flashes
• Intervention / Treatment: Drug: Brisdelle (paroxetine mesylate); Drug: Placebo capsules

Detailed Description

The study is a 24-week, multicenter, double-blind, randomized, placebo-controlled study of Brisdelle (paroxetine mesylate) Capsules 7.5 mg in subjects with moderate to severe postmenopausal VMS, defined as follows:

1. Moderate VMS: Sensation of heat with sweating, able to continue activity
2. 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.

• Study Type: Interventional
• Enrollment (Actual): 570
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Montgomery, Alabama, United States, 36116
      • Montgomery Women's Health Associates, PC
  • Arizona
    • Chandler, Arizona, United States, 85224
      • East Valley Family Physicians PLC
  • California
    • San Diego, California, United States, 92103
      • Genesis Center for Clinical Research
    • Santa Ana, California, United States, 92705
      • Apex Research Institute
  • Colorado
    • Denver, Colorado, United States, 80218
      • Downtown Women's Health Care
  • Connecticut
    • Waterbury, Connecticut, United States, 06708
      • Chase Medical Research, LLC
  • Florida
    • Boynton Beach, Florida, United States, 33472
      • Visions Clinical Research
    • Brooksville, Florida, United States, 34601
      • Meridien Research
    • Clearwater, Florida, United States, 33759
      • Women's Medical Research Group, LLC
    • Lake Worth, Florida, United States, 33461
      • Altus Research
    • Naples, Florida, United States, 34102
      • Anchor Research Center
    • West Palm Beach, Florida, United States, 33409
      • Comprehensive Clinical Trials, Llc
  • Georgia
    • Decatur, Georgia, United States, 30034
      • Soapstone Center for Clinical Research
    • Sandy Springs, Georgia, United States, 30328
      • Mount Vernon Clinical Research, LLC
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Women's Clinic of Lincoln, PC
  • New Jersey
    • Moorestown, New Jersey, United States, 08057
      • Phoenix OB-GYN Associates, LLC
  • New York
    • Rochester, New York, United States, 14609
      • Rochester Clinical Research
  • North Carolina
    • Greensboro, North Carolina, United States, 27408
      • Hawthorne Research
    • Winston-Salem, North Carolina, United States, 27103
      • Hawthorne Medical Research, Inc.
  • Ohio
    • Columbus, Ohio, United States, 43213
      • Columbus Center for Women's Health Research
  • Pennsylvania
    • Jenkintown, Pennsylvania, United States, 19046
      • The Clinical Trial Center, LLC
    • Philadelphia, Pennsylvania, United States, 19114
      • Philadelphia Clinical Research
    • Pittsburgh, Pennsylvania, United States, 15206
      • Clinical Trials Research Services, LLC
  • South Carolina
    • Columbia, South Carolina, United States, 29201
      • SC Clinical Research Center, LLC
    • Mt. Pleasant, South Carolina, United States, 29464
      • Coastal Carolina Research Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Medical Research, Llc
    • Nashville, Tennessee, United States, 37203
      • Clinical Research Associates, Inc.
  • Texas
    • Houston, Texas, United States, 77054
      • The Woman's Hospital of Texas Clinical Research Center
  • Virginia
    • Richmond, Virginia, United States, 23294
      • National Clinical Research, Inc.
    • Richmond, Virginia, United States, 23233
      • Virginia Women's Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Women's Clinical Research Center
    • Spokane, Washington, United States, 99207
      • North Spokane Women's Clinic Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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. BMI ≥ 40 kg/m²
2. Known non-responder to previous Selective serotonin reuptake inhibitor (SSRI) or Serotonin norepinephrine reuptake inhibitor (SNRI) treatment for VMS
3. History of self-injurious behavior
4. History of clinical diagnosis of depression; or treatment for depression
5. History of clinical diagnosis of borderline personality disorder
6. Use of an investigational study medication within 30 days prior to screening or during the study
7. Concurrent participation in another clinical trial or previous participation in this trial
8. Family of investigational-site staff

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Brisdelle (paroxetine mesylate)	Drug: Brisdelle (paroxetine mesylate); Eligible subjects will be randomized to receive either Brisdelle (paroxetine mesylate) Capsules 7.5 mg or placebo capsules in a 1:1 ratio.; Other Names: Former Names: Mesafem Capsules or; LDMP (Low-Dose Mesylate salt of Paroxetine)
Placebo Comparator: Placebo capsules; Sugar pill	Drug: Placebo capsules; Eligible subjects will be randomized to receive either Brisdelle (paroxetine mesylate) Capsules 7.5 mg or placebo capsules in a 1:1 ratio.; Other Names: Sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Hot Flash Frequency 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	Week 4 and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Percent Persistence of Benefit, Statistically Significant Difference in Having 50% or More Reduction Compared to Baseline at Week 24.	Persistence of treatment benefit to 24 weeks post treatment was assessed by using the following responder analysis. Responders were defined as those subjects who achieved ≥ 50% reduction from baseline in moderate to severe hot-flash frequency at Week 24; the percent change in hot flash frequency is calculated using the formula: Percent reduction at week 24 = [(number of moderate to severe hot flash frequency at baseline - number of moderate to severe hot flash frequency at week 24) / number of moderate to severe hot flash frequency at baseline ]*100%.	Week 24
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). Responders: Subjects with NRS Score of 5 Or Less. Non-Responders: Subjects With NRS Score of Greater than Or Equal to 6.	Week 4 and Week 12
Change From Baseline in Arizona Sexual Experience Scale (ASEX, Week 4 and Week 12) Total Score, Median	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.	Week 4 and Week 12

Collaborators and Investigators

• Sponsor: Noven Therapeutics
• Investigators: Principal Investigator: Robin Kroll, MD, Women's Clinical Research Center, Seattle, WA 98105; Principal Investigator: Ashley Tunkle, MD, Anchor Research Center, Naples, FL 34102; Principal Investigator: Derrick R Havin, MD, North Spokane Women's Clinic Research, Spokane, WA 99207; Principal Investigator: Richard E Hedrick, MD, Hawthorne Medical Research, Inc., Winston-Salem, NC 27103; Principal Investigator: Samuel N Lederman, MD, Altus Research, Lake Worth, FL 33461; Principal Investigator: Larry S Seidman, DO, Philadelphia Clinical Research, LLC, Philadelphia, PA 19114; Principal Investigator: James E Tomblin, MD, Hawthorne Medical Research, Inc., Greensboro, NC 27408; Principal Investigator: Peter A Zedler, MD, Virginia Women's Center, Richmond, VA 23233; Principal Investigator: D S Harnsberger, MD, Chattanooga Medical Research, LLC, Chattanooga, TN 37404; Principal Investigator: John A Hoekstra, MD, National Clinical Research, Inc., Richmond, VA 23294; Principal Investigator: Matthew Davis, MD, Rochester Clinical Research, Rochester, NY 14609; Principal Investigator: Donna DeSantis, MD, East Valley Family Physicians PLC, Chandler, AZ 85224; Principal Investigator: Steven Drosman, Genesis Center For Clinical Research, San Diego, CA 92103; Principal Investigator: Mildred Farmer, MD, Meridien Research, Brooksville, FL 34601; Principal Investigator: Sandra Hurtado, MD, The Woman's Hospital of Texas Clinical Research Center, Houston, TX 77054; Principal Investigator: Bruce Levine, MD, Phoenix Ob-Gyn Associates, LLC, Moorestown, NJ 08057; Principal Investigator: Tyrone Malloy, MD, Soapstone Center for Clinical Research, Decatur, GA 30034; Principal Investigator: Eric Ross, MD, Apex Research Institute, Santa Ana, CA 92705; Principal Investigator: Cynthia Strout, MD, Coastal Carolina Research Center, Mt. Pleasant, SC 29464; Principal Investigator: Arthur Waldbaum, MD, Downtown Women's Health Care, Denver, CO, 80218; Principal Investigator: Edward Zbella, MD, Women's Medical Research Group, LLC, Clearwater, FL 33759; Principal Investigator: James R Dockery, MD, Montgomery Women's Health Associates, PC, Montgomery, AL 36116; Principal Investigator: Stephen C Blank, MD, Mount Vernon Clinical Research, LLC, Sandy Springs, GA 30328; Principal Investigator: Keith Aqua, MD, Visions Clinical Research, Boynton Beach, FL 33472; Principal Investigator: Saul R Berg, MD, Clinical Trials Research Services, LLC, Pittsburgh, PA 15206; Principal Investigator: Marvin Kalafer, MD, The Clinical Trial Center, LLC, Jenkintown, PA 19046; Principal Investigator: David J Portman, MD, Columbus Center for Women's Health Research, Columbus, Ohio 43213; Principal Investigator: Stephen Swanson, MD, Women's Clinic of Lincoln, PC, Lincoln, NE 68510; Principal Investigator: Joseph Soufer, MD, Chase Medical Research, LLC, Waterbury, CT 06708; Principal Investigator: ShaH R Scott, MD, Clinical Research Associates, Inc., Nashville, TN 37203; Principal Investigator: Mary K Neuffer, MD, SC Clinical Research Center, LLC, Columbia, SC 29201; Principal Investigator: Ronald Ackerman, MD, Comprehensive Clinical Trials, LLC, West Palm Beach, FL 33409

Publications and helpful links

General Publications

• Pinkerton JV, Joffe H, Kazempour K, Mekonnen H, Bhaskar S, Lippman J. Low-dose paroxetine (7.5 mg) improves sleep in women with vasomotor symptoms associated with menopause. Menopause. 2015 Jan;22(1):50-8. doi: 10.1097/GME.0000000000000311.
• Portman DJ, Kaunitz AM, Kazempour K, Mekonnen H, Bhaskar S, Lippman J. Effects of low-dose paroxetine 7.5 mg on weight and sexual function during treatment of vasomotor symptoms associated with menopause. Menopause. 2014 Oct;21(10):1082-90. doi: 10.1097/GME.0000000000000210.
• Simon JA, Portman DJ, Kaunitz AM, Mekonnen H, Kazempour K, Bhaskar S, Lippman J. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause. 2013 Oct;20(10):1027-35. doi: 10.1097/GME.0b013e3182a66aa7.
• Fugate SE, Church CO. Nonestrogen treatment modalities for vasomotor symptoms associated with menopause. Ann Pharmacother. 2004 Sep;38(9):1482-99. doi: 10.1345/aph.1D610. Epub 2004 Aug 3.
• 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.
• 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.
• Greene JG. A factor analytic study of climacteric symptoms. J Psychosom Res. 1976;20(5):425-30. doi: 10.1016/0022-3999(76)90005-2. No abstract available.

Helpful Links

• Sponsor

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): November 1, 2011

Study Registration Dates

• First Submitted: April 8, 2010
• First Submitted That Met QC Criteria: April 9, 2010
• First Posted (Estimate): April 12, 2010

Study Record Updates

• Last Update Posted (Estimate): October 15, 2015
• Last Update Submitted That Met QC Criteria: October 14, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Menopause; Vasomotor Symptoms; Mesafem; Low-Dose Mesylate salt of Paroxetine (LDMP); Perimenopause; Hot Flashes; Climacteric symptoms; Nonhormonal therapies
• Additional Relevant MeSH Terms: Hot Flashes; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Paroxetine
• Other Study ID Numbers: N30-004