Efficacy/Safety Study of Brisdelle™ (Formerly Known as Mesafem) in the Treatment of Vasomotor Symptoms (VMS) (N30-003)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Noven Therapeutics
ClinicalTrials.gov Identifier:
NCT01361308
First received: May 24, 2011
Last updated: April 22, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Postmenopausal Symptoms
Drug: Brisdelle (paroxetine mesylate)
Drug: Placebo capsules
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Noven Therapeutics:

Primary Outcome Measures:
  • Mean Change in Frequency of Moderate to Severe VMS From Baseline at Week 4 and Week 12. [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.

  • Mean Change From Baseline in Hot Flash Severity at Week 4 and Week 12 [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Clinical Meaningfulness Anchored to Patient Global Improvement (PGI-I) (%) [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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


  • Change From Baseline in Total Number of Awakenings Due to Hot Flashes, Median [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • Change in Frequency of Moderate to Severe Hot Flashes Frequency From Baseline (BMI <32 kg/m2, Week 4 and Week 12), Median [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • Change in Frequency of Moderate to Severe Hot Flashes Frequency From Baseline (BMI ≥32 kg/m2, Week 4 and Week 12), Median [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • Change in Severity of Moderate to Severe Hot Flashes From Baseline (BMI <32 kg/m2, At Week 4 and Week 12), Median [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • Change in Severity of Moderate to Severe Hot Flashes From Baseline (BMI ≥32 kg/m2, Week 4 and Week 12), Median [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline in Greene Climacteric Scale (GCS) at Week 4 and Week 12, Total Score, Median [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • Percentage of Responders [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Patient Global Improvement (PGI) Scale Responders (%) [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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

    1. = Very much better
    2. = Much better
    3. = A little better
    4. = No change
    5. = A little worse
    6. = Much worse
    7. = Very much worse

  • Percent Daytime and Nighttime Responders, Numerical Rating Scale (NRS) [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline in Arizona Sexual Experience Scale (ASEX, Week 4 and Week 12) Total Score [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • 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) [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • Percent Responders Improvement in VMS From Baseline Using the Clinical Global Impression (CGI) Scale. [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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".


  • Effect of Brisdelle (Paroxetine Mesylate) Capsules on Anxiety and Depression [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.


  • Assessment of Mood [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]
    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.

  • BMI Change From Baseline (kg/m2), Median [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]

    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.



Enrollment: 614
Study Start Date: May 2011
Study Completion Date: February 2012
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Brisdelle (paroxetine mesylate)
Brisdelle (paroxetine mesylate)
Drug: Brisdelle (paroxetine mesylate)
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
Other Names:
  • Former Names: Mesafem Capsules or
  • LDMP (Low-Dose Mesylate salt of Paroxetine)
Placebo Comparator: Placebo Capsules
Placebo Capsules
Drug: Placebo capsules
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
Other Name: Sugar pill

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  1. Known non-responder to previous Selective serotonin reuptake inhibitor (SSRI) or Serotonin norepinephrine reuptake inhibitor (SNRI) treatment for VMS
  2. History of self injurious behavior
  3. History of clinical diagnosis of depression or treatment for depression
  4. History of clinical diagnosis of borderline personality disorder
  5. Use of an investigational study medication within 30 days prior to screening or during the study
  6. Concurrent participation in another clinical trial or previous participation in this trial
  7. Family of investigational-site staff
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01361308

  Show 74 Study Locations
Sponsors and Collaborators
Noven Therapeutics
Investigators
Principal Investigator: Corey Jacobs, MD
Principal Investigator: Donna DeSantis, MD
Principal Investigator: Robert Phillips, MD
Principal Investigator: Louise Taber, MD
Principal Investigator: Paige C. Brainard, MD
Principal Investigator: Mark Stripling, MD
Principal Investigator: Gioi Smith-Nguyen, MD
Principal Investigator: Anthony Dulgeroff, MD
Principal Investigator: Elise Kwon, MD
Principal Investigator: Douglas Young, MD
Principal Investigator: William Koltun, MD
Principal Investigator: Dana Shipp, MD
Principal Investigator: Eric Ross, MD
Principal Investigator: Arthur Waldbaum, MD
Principal Investigator: Theodore Cooper, MD
Principal Investigator: J B. Stern, MD
Principal Investigator: Paul DiGrazia, MD
Principal Investigator: Robert Spitz, MD
Principal Investigator: James A Simon, MD
Principal Investigator: Mildred Farmer, MD
Principal Investigator: James Andersen, MD
Principal Investigator: Steven Bowman, MD
Principal Investigator: Rene Casanova, MD
Principal Investigator: Mary Yankaskas, MD
Principal Investigator: Andrew Kaunitz, MD
Principal Investigator: Ronald Surowitz, MD
Principal Investigator: Lisa Cohen, MD
Principal Investigator: Lisa Vendeland, MD
Principal Investigator: Tyrone Malloy, MD
Principal Investigator: Stephen C. Blank, MD
Principal Investigator: Mark Turner, MD
Principal Investigator: Carl R Lang, MD
Principal Investigator: Arthur Donovan, MD
Principal Investigator: Armen Arslanian, MD
Principal Investigator: Shiao-Yu Lee, MD
Principal Investigator: Gayle Moyer, MD
Principal Investigator: Geoffrey Turner, MD
Principal Investigator: Susan L Hendrix, MD
Principal Investigator: Mark Barber, MD
Principal Investigator: Stephen Swanson, MD
Principal Investigator: Timothy Sauter, MD
Principal Investigator: Steven Sussman, MD
Principal Investigator: Elizabeth Bretton, MD
Principal Investigator: Lance A. Rudolph, MD
Principal Investigator: Kenneth Levey, MD
Principal Investigator: Pouru Bhiwandi, MD
Principal Investigator: Richard E. Hedrick, MD
Principal Investigator: Gregory P Tarleton, MD
Principal Investigator: Mira Baron, MD
Principal Investigator: David J Portman, MD
Principal Investigator: Milroy Samuel, MD
Principal Investigator: Stuart Weprin, MD
Principal Investigator: James Liu, MD
Principal Investigator: Angelique Barreto, MD
Principal Investigator: Marvin Kalafer, MD
Principal Investigator: Larry S. Seidman, MD
Principal Investigator: Saul R. Berg, MD
Principal Investigator: Susan Floyd, MD
Principal Investigator: Scott Wilson, MD
Principal Investigator: Cynthia Strout, MD
Principal Investigator: D. S. Harnsberger, MD
Principal Investigator: Janet Dittus, MD
Principal Investigator: Gregg Lucksinger, MD
Principal Investigator: Anna Damian, MD
Principal Investigator: Sandra Hurtado, MD
Principal Investigator: Alfred Poindexter, MD
Principal Investigator: Nancy Campbell, MD
Principal Investigator: William Jennings, MD
Principal Investigator: Jose Ruiz, MD
Principal Investigator: John A. Hoekstra, MD
Principal Investigator: Peter A. Zedler, MD
Principal Investigator: Franklin Morgan, MD
Principal Investigator: Robin Kroll, MD
Principal Investigator: Derrick R Havin, MD
  More Information

Additional Information:
No publications provided by Noven Therapeutics

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Noven Therapeutics
ClinicalTrials.gov Identifier: NCT01361308     History of Changes
Other Study ID Numbers: N30-003
Study First Received: May 24, 2011
Results First Received: July 16, 2013
Last Updated: April 22, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Noven Therapeutics:
Menopause
Vasomotor Symptoms
Hot Flashes Perimenopause
Climacteric Symptoms
Mesafem
Low-Dose Mesylate salt of Paroxetine (LDMP)

Additional relevant MeSH terms:
Paroxetine
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014