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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel group, Adaptive, Combined Proof of Concept and Dose-Finding Study to Investigate Efficacy, Safety, Pharmacodynamics and Pharmacokinetics of ASP3652 in the Treatment of Female Subjects with Bladder Pain Syndrome / Interstitial Cystitis

    Summary
    EudraCT number
    		 2011-004555-39
    Trial protocol
    		 BE   NL   CZ   DE   LV   PT   ES   PL   DK   LT  
    Global end of trial date
    18 Mar 2014

    Results information
    Results version number
    		 v1
    This version publication date
    23 May 2016
    First version publication date
    25 Jun 2015
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3652-CL-0018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01613586
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333 BE
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate efficacy of ASP3652 in female subjects with Bladder Pain Syndrome / Interstitial Cystitis (BPS/IC).
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 47
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Poland: 41
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Czech Republic: 45
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Latvia: 24
    Country: Number of subjects enrolled
    Lithuania: 12
    Worldwide total number of subjects
    287
    EEA total number of subjects
    239
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    222
    From 65 to 84 years
    65
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 During the 3-week run-in period, patients were treated with single-blind placebo (3 tablets twice a day). To be eligible for randomization, the mean daily pain (MDP) score had to be at least 4.0 on an 11-point numerical rating scale from 0-10.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Allocation: Randomised 1:1:1:1 for burn-in period of 40 subjects; thereafter Bayesian adaptive allocation based on monthly interim analyses.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects took three matching placebo tablets twice a day for 12 weeks, followed by a 2-week follow-up period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day.

    Arm title
    		 ASP3652 50 mg BID
    Arm description
    		 Subjects took two 25 mg ASP3652 tablets and one placebo tablet twice a day (BID) for 12 weeks, followed by a 2-week follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP3652
    Investigational medicinal product code
    ASP3652
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day.

    Arm title
    		 ASP3652 150 mg BID
    Arm description
    		 Subjects took two 25 mg and one 100 mg ASP3652 tablet twice a day for 12 weeks, followed by a 2-week follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP3652
    Investigational medicinal product code
    ASP3652
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day.

    Arm title
    		 ASP3652 300 mg BID
    Arm description
    		 Subjects took three 100 mg ASP3652 tablets twice a day for 12 weeks, followed by a 2-week follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP3652
    Investigational medicinal product code
    ASP3652
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day.

    Number of subjects in period 1
    		Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Started
    82
    53
    55
    97
    Completed
    69
    46
    48
    83
    Not completed
    13
    7
    7
    14
         Randomized but never received study drug
    -
    -
    -
    1
         Consent withdrawn by subject
    6
    4
    1
    9
         Protocol violation
    4
    2
    1
    1
         Other
    1
    -
    1
    1
         Adverse event
    2
    1
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects took three matching placebo tablets twice a day for 12 weeks, followed by a 2-week follow-up period.

    Reporting group title
    ASP3652 50 mg BID
    Reporting group description
    		 Subjects took two 25 mg ASP3652 tablets and one placebo tablet twice a day (BID) for 12 weeks, followed by a 2-week follow-up period.

    Reporting group title
    ASP3652 150 mg BID
    Reporting group description
    		 Subjects took two 25 mg and one 100 mg ASP3652 tablet twice a day for 12 weeks, followed by a 2-week follow-up period.

    Reporting group title
    ASP3652 300 mg BID
    Reporting group description
    		 Subjects took three 100 mg ASP3652 tablets twice a day for 12 weeks, followed by a 2-week follow-up period.

    Reporting group values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID Total
    Number of subjects
    		 82 53 55 97 287
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.4 ( 15.84 ) 49.6 ( 14.78 ) 53.5 ( 16.56 ) 50.5 ( 16.74 ) -
    Gender categorical
    Units: Subjects
        Female
    		 82 53 55 97 287
        Male
    		 0 0 0 0 0
    Race
    Units: Subjects
        White
    		 82 53 55 97 287
        Other
    		 0 0 0 0 0
    Hunner's lesions present?
    Units: Subjects
        Yes
    		 10 9 16 28 63
        No
    		 39 25 22 36 122
        Unknown
    		 33 19 17 32 101
        Missing
    		 0 0 0 1 1
    Previous or current medication treatment for bladder pain syndrome/Interstitial cystitis (BPS/IC)
    Units: Subjects
        No
    		 42 30 30 50 152
        Yes
    		 40 23 25 47 135
    Time since BPS/IC Diagnosis
    Units: months
        arithmetic mean (standard deviation)
    		 34.4 ( 35.87 ) 34.6 ( 38.43 ) 30.6 ( 33.15 ) 34.7 ( 43.93 ) -
    Duration of BPS/IC Symptoms
    Units: months
        arithmetic mean (standard deviation)
    		 65.3 ( 76.6 ) 61.1 ( 58.82 ) 59.8 ( 61.05 ) 70.1 ( 66.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects took three matching placebo tablets twice a day for 12 weeks, followed by a 2-week follow-up period.

    Reporting group title
    ASP3652 50 mg BID
    Reporting group description
    		 Subjects took two 25 mg ASP3652 tablets and one placebo tablet twice a day (BID) for 12 weeks, followed by a 2-week follow-up period.

    Reporting group title
    ASP3652 150 mg BID
    Reporting group description
    		 Subjects took two 25 mg and one 100 mg ASP3652 tablet twice a day for 12 weeks, followed by a 2-week follow-up period.

    Reporting group title
    ASP3652 300 mg BID
    Reporting group description
    		 Subjects took three 100 mg ASP3652 tablets twice a day for 12 weeks, followed by a 2-week follow-up period.

    Primary: Change from Baseline to End of Treatment in Mean Daily Pain (MDP)

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    End point title
    		 Change from Baseline to End of Treatment in Mean Daily Pain (MDP)
    End point description
    The MDP is the mean of the 7 daily consecutive pain measurements, i.e. the mean of the 7 daily consecutive scores of item 4 of the Female GenitoUrinary Pain Index (F-GUPI)-24h, recorded in the last week prior to Baseline and Week 12. The F-GUPI-24h is a validated instrument for evaluating symptoms of BPS/IC. Item 4 in the F-GUPI-24h rates the average pain over the past 24 hours on an 11-point numerical rating scale (NRS) ranging from 0 (no pain) to 10 (pain as bad as you can imagine). This endpoint was analyzed using a Bayesian longitudinal dose-response model. In the table below, the row for "arithmetic mean (standard deviation)" is actually summarizing the posterior mean change from Baseline to end of treatment (EoT) and corresponding standard deviation. For subjects who withdrew due to an adverse event, the change from baseline to EoT in MDP score was set to 0.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    74 [1]
    49 [2]
    52 [3]
    89 [4]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.72 ( 0.266 )
    -1.49 ( 0.292 )
    -1.56 ( 0.265 )
    -1.73 ( 0.225 )
    Notes
    [1] - Full analysis set with available baseline data
    [2] - Full analysis set with available baseline data
    [3] - Full analysis set with available baseline data
    [4] - Full analysis set with available baseline data
    Statistical analysis title
    		 Bayesian Analysis
    Statistical analysis description
    A Bayesian longitudinal dose-response model was used to model changes from baseline to end of treatment in MDP score. The posterior difference versus placebo and 95% credibility interval are presented, along with the posterior probability of the dose group being the maximum effective dose.
    Comparison groups
    Placebo v ASP3652 50 mg BID
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.183 [5]
    Method
    		 Bayesian longitudinal dose-response mode
    Parameter type
    		 Posterior difference versus placebo
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Dispersion value
    0.395
    Notes
    [5] - Posterior probability of maximum effective dose
    Statistical analysis title
    		 Bayesian Analysis
    Statistical analysis description
    A Bayesian longitudinal dose-response model was used to model changes from baseline to end of treatment in MDP score. The posterior difference versus placebo and 95% credibility interval are presented, along with the posterior probability of the dose group being the maximum effective dose.
    Comparison groups
    Placebo v ASP3652 150 mg BID
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.231 [6]
    Method
    		 Bayesian longitudinal dose-response mode
    Parameter type
    		 Posterior difference versus placebo
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 0.9
    Variability estimate
    Standard deviation
    Dispersion value
    0.379
    Notes
    [6] - Posterior probability of maximum effective dose
    Statistical analysis title
    		 Bayesian Analysis
    Statistical analysis description
    A Bayesian longitudinal dose-response model was used to model changes from baseline to end of treatment in MDP score. The posterior difference versus placebo and 95% credibility interval are presented, along with the posterior probability of the dose group being the maximum effective dose.
    Comparison groups
    Placebo v ASP3652 300 mg BID
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.586 [7]
    Method
    		 Bayesian longitudinal dose-response mode
    Parameter type
    		 Posterior difference versus placebo
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.66
    Variability estimate
    Standard deviation
    Dispersion value
    0.349
    Notes
    [7] - Posterior probability of maximum effective dose

    Secondary: Change from Baseline to End of Treatment in F-GUPI Total Score

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    End point title
    		 Change from Baseline to End of Treatment in F-GUPI Total Score
    End point description
    The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess symptoms in women with genitourinary pain complaints. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of one week: - Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity; - Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms; - Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact. The F-GUPI Total score ranges from 0 to 45 with higher scores indicating increasing disease activity. This endpoint was analyzed using a Bayesian longitudinal dose-response model. In the table below, the data are summarizing the posterior mean change from Baseline to EoT and corresponding standard deviation. For subjects who withdrew due to an adverse event, the change from baseline to EoT was set to 0.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    74 [8]
    49 [9]
    50 [10]
    89 [11]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -7.5 ( 1.07 )
    -6.6 ( 0.94 )
    -6.5 ( 0.84 )
    -7.1 ( 0.79 )
    Notes
    [8] - Full analysis set with available baseline data
    [9] - Full analysis set with available baseline data
    [10] - Full analysis set with available baseline data
    [11] - Full analysis set with available baseline data
    Statistical analysis title
    		 Bayesian Analysis
    Statistical analysis description
    A Bayesian longitudinal dose-response model was used to model changes from baseline to end of treatment in F-GUPI total score. The posterior difference versus placebo and 95% credibility interval are presented, along with the posterior probability of the dose group being the maximum effective dose.
    Comparison groups
    Placebo v ASP3652 50 mg BID
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.28
    Method
    		 Bayesian longitudinal dose-response mode
    Parameter type
    		 Posterior difference versus placebo
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 3.8
    Variability estimate
    Standard deviation
    Dispersion value
    1.43
    Statistical analysis title
    		 Bayesian Analysis
    Statistical analysis description
    A Bayesian longitudinal dose-response model was used to model changes from baseline to end of treatment in F-GUPI total score. The posterior difference versus placebo and 95% credibility interval are presented, along with the posterior probability of the dose group being the maximum effective dose.
    Comparison groups
    Placebo v ASP3652 150 mg BID
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.143
    Method
    		 Bayesian longitudinal dose-response mode
    Parameter type
    		 Posterior difference versus placebo
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 3.8
    Variability estimate
    Standard deviation
    Dispersion value
    1.38
    Statistical analysis title
    		 Bayesian Analysis
    Statistical analysis description
    A Bayesian longitudinal dose-response model was used to model changes from baseline to end of treatment in F-GUPI total score. The posterior difference versus placebo and 95% credibility interval are presented, along with the posterior probability of the dose group being the maximum effective dose.
    Comparison groups
    Placebo v ASP3652 300 mg BID
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.577
    Method
    		 Bayesian longitudinal dose-response mode
    Parameter type
    		 Posterior difference versus placebo
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 3
    Variability estimate
    Standard deviation
    Dispersion value
    1.29

    Secondary: Change from Baseline to End of Treatment in F-GUPI Pain Domain Score

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    End point title
    		 Change from Baseline to End of Treatment in F-GUPI Pain Domain Score
    End point description
    The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess the degree of symptoms in women with genitourinary pain complaints. The pain subscale comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity, with a recall period of one week. The pain subscale score ranges from 0 to 23 where higher scores indicate increasing pain. Least squares (LS) means were generated from an analysis of covariance (ANCOVA) model with treatment group and country as factors and the Baseline value as a covariate. Last observation carried forward (LOCF) imputation was used; for subjects who withdrew due to an adverse event, change from baseline to EoT was set to 0.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    74 [12]
    49 [13]
    50 [14]
    89 [15]
    Units: units on a scale
        least squares mean (standard error)
    -3.8 ( 0.49 )
    -3.8 ( 0.61 )
    -3.1 ( 0.6 )
    -4.1 ( 0.45 )
    Notes
    [12] - Full analysis set with available baseline data
    [13] - Full analysis set with available baseline data
    [14] - Full analysis set with available baseline data
    [15] - Full analysis set with available baseline data
    Statistical analysis title
    		 Frequentist Analysis
    Statistical analysis description
    The F-GUPI pain domain score was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
    Comparison groups
    Placebo v ASP3652 50 mg BID
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference vs placebo
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.79
    Statistical analysis title
    		 Frequentist Analysis
    Statistical analysis description
    The F-GUPI pain domain score was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
    Comparison groups
    Placebo v ASP3652 150 mg BID
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference vs placebo
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 2.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78
    Statistical analysis title
    		 Frequentist Analysis
    Statistical analysis description
    The F-GUPI pain domain score was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
    Comparison groups
    Placebo v ASP3652 300 mg BID
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference vs placebo
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.67

    Secondary: Change from Baseline to End of Treatment in Mean Number of Micturitions per 24 Hours

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    End point title
    		 Change from Baseline to End of Treatment in Mean Number of Micturitions per 24 Hours
    End point description
    The average number of micturitions (urinations) per 24 hours was derived from the number of times a subject urinated (excluding incontinence only episodes) per day as recorded by the subject in a micturition diary for 3 days prior to the Baseline and Week 12 clinic visits. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    71 [16]
    44 [17]
    49 [18]
    87 [19]
    Units: micturitions
        least squares mean (standard error)
    -1.92 ( 0.642 )
    0.16 ( 0.818 )
    -1.56 ( 0.775 )
    -1.09 ( 0.583 )
    Notes
    [16] - Full analysis set with available Baseline data
    [17] - Full analysis set with available Baseline data
    [18] - Full analysis set with available Baseline data
    [19] - Full analysis set with available Baseline data
    Statistical analysis title
    		 Frequentist Analysis
    Statistical analysis description
    The change from baseline in the number of micturitions per 24 hours was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
    Comparison groups
    Placebo v ASP3652 50 mg BID
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean difference vs placebo
    Point estimate
    2.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 4.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.046
    Statistical analysis title
    		 Frequentist Analysis
    Statistical analysis description
    The change from baseline in the number of micturitions per 24 hours was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
    Comparison groups
    Placebo v ASP3652 150 mg BID
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean difference vs placebo
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.62
         upper limit
    		 2.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.007
    Statistical analysis title
    		 Frequentist Analysis
    Statistical analysis description
    The change from baseline in the number of micturitions per 24 hours was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
    Comparison groups
    Placebo v ASP3652 300 mg BID
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean difference vs placebo
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.89
         upper limit
    		 2.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.873

    Secondary: Change from Baseline in MDP Scores at Weeks 4, 8, 12 and at Follow-up

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    End point title
    		 Change from Baseline in MDP Scores at Weeks 4, 8, 12 and at Follow-up
    End point description
    The MDP is the mean of the 7 daily consecutive pain measurements, i.e. the mean of the 7 daily consecutive scores of item 4 of the Female GenitoUrinary Pain Index (F-GUPI)-24h, recorded in the last week prior to Baseline and Week 12. The F-GUPI-24h is a validated instrument for evaluating symptoms of BPS/IC. Item 4 in the F-GUPI-24h rates the average pain over the past 24 hours on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). This endpoint was analysed using the full analysis set with no imputation for missing data. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: units on a scale
    least squares mean (standard error)
        Week 4 (n=67, 44, 49, 82)
    -0.7 ( 0.184 )
    -0.82 ( 0.227 )
    -0.76 ( 0.214 )
    -0.97 ( 0.166 )
        Week 8 (n=68, 46, 51, 84)
    -1.25 ( 0.223 )
    -1.13 ( 0.271 )
    -1.43 ( 0.257 )
    -1.28 ( 0.2 )
        Week 12 (n=65, 45, 46, 82)
    -1.81 ( 0.262 )
    -1.61 ( 0.316 )
    -1.45 ( 0.312 )
    -1.79 ( 0.234 )
        Follow-Up (n=55, 40, 42, 66)
    -1.76 ( 0.277 )
    -1.48 ( 0.328 )
    -1.45 ( 0.317 )
    -1.84 ( 0.255 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in F-GUPI Total Score at Weeks 4, 8, 12 and Follow-up

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    End point title
    		 Change from Baseline in F-GUPI Total Score at Weeks 4, 8, 12 and Follow-up
    End point description
    The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess symptoms in women with genitourinary pain complaints. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of one week: - Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity; - Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms; - Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact. The F-GUPI Total score ranges from 0 to 45 with higher scores indicating increasing disease activity. This endpoint was analysed using the full analysis set with no imputation for missing data. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and Follow-up (2 weeks after end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: units on a scale
    least squares mean (standard error)
        Week 4 (n=73, 49, 48, 89)
    -3.9 ( 0.76 )
    -3.3 ( 0.93 )
    -2.8 ( 0.94 )
    -4.7 ( 0.69 )
        Week 8 (n=67, 45, 48, 85)
    -5.5 ( 0.93 )
    -4.2 ( 1.14 )
    -6 ( 1.1 )
    -5.9 ( 0.83 )
        Week 12 (n=66, 44, 45, 81)
    -7.7 ( 1.08 )
    -8.3 ( 1.32 )
    -5.8 ( 1.31 )
    -7.6 ( 0.98 )
        Follow-Up (n=56, 41, 39, 62)
    -7.7 ( 1.26 )
    -7.3 ( 1.49 )
    -8.1 ( 1.52 )
    -8.7 ( 1.21 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in F-GUPI Pain Domain Score at Weeks 4, 8, 12 and Follow-Up

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    End point title
    		 Change from Baseline in F-GUPI Pain Domain Score at Weeks 4, 8, 12 and Follow-Up
    End point description
    The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess the degree of symptoms in women with genitourinary pain complaints. The pain subscale comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity, with a recall period of one week. The pain subscale score ranges from 0 to 23 where higher scores indicate increasing pain. This endpoint was analysed using the full analysis set with no imputation for missing data. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: units on a scale
    least squares mean (standard error)
        Week 4 (n=73, 49, 48, 89)
    -2.1 ( 0.39 )
    -1.7 ( 0.48 )
    -1.6 ( 0.48 )
    -2.5 ( 0.35 )
        Week 8 (n=67, 45, 48, 85)
    -3 ( 0.46 )
    -2.4 ( 0.56 )
    -3.2 ( 0.54 )
    -3.3 ( 0.41 )
        Week 12 (n=66, 44, 45, 81)
    -4 ( 0.53 )
    -4.3 ( 0.64 )
    -3.1 ( 0.64 )
    -4.3 ( 0.48 )
        Follow-Up (n=56, 41, 39, 62)
    -3.8 ( 0.62 )
    -4.1 ( 0.73 )
    -3.9 ( 0.75 )
    -4.9 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Visit in F-GUPI Urinary Symptoms Score

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    End point title
    		 Change from Baseline to Each Visit in F-GUPI Urinary Symptoms Score
    End point description
    The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess the degree of symptoms in women with genitourinary pain complaints. The voiding problems/urinary subscale comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms with a recall period of one week. The urinary subscale score ranges from 0 to 10, where 10 indicates worse symptoms. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: units on a scale
    least squares mean (standard error)
        Week 4 (n=73, 49, 48, 89)
    -0.68 ( 0.233 )
    -0.73 ( 0.285 )
    -0.44 ( 0.287 )
    -1.04 ( 0.212 )
        Week 8 (n=67, 45, 48, 85)
    -1.12 ( 0.269 )
    -1.01 ( 0.329 )
    -1.16 ( 0.318 )
    -1.08 ( 0.239 )
        Week 12 (n=66, 44, 45, 81)
    -1.74 ( 0.282 )
    -1.74 ( 0.346 )
    -1.02 ( 0.343 )
    -1.37 ( 0.257 )
        End of Treatment (n=74, 49, 50, 89)
    -1.68 ( 0.275 )
    -1.57 ( 0.339 )
    -1.26 ( 0.335 )
    -1.37 ( 0.251 )
        Follow-Up (n=75, 49, 54, 90)
    -1.66 ( 0.315 )
    -1.31 ( 0.372 )
    -1.93 ( 0.38 )
    -1.62 ( 0.303 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Visit in F-GUPI Quality of Life Impact Score

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    End point title
    		 Change from Baseline to Each Visit in F-GUPI Quality of Life Impact Score
    End point description
    The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess the degree of symptoms in women with genitourinary pain complaints. The effects on the quality of life (QoL) subscale comprises 3 questions (Items 7 to 9) on impact with a recall period of one week. The quality of life impact subscale score ranges from 0 to 12, where 12 indicates more impact on quality of life. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: units on a scale
    least squares mean (standard error)
        Week 4 (n=73, 49, 48, 89)
    -1.04 ( 0.269 )
    -0.79 ( 0.329 )
    -0.72 ( 0.331 )
    -1.19 ( 0.244 )
        Week 8 (n=67, 45, 48, 85)
    -1.38 ( 0.324 )
    -0.86 ( 0.396 )
    -1.69 ( 0.383 )
    -1.53 ( 0.288 )
        Week 12 (n=66, 44, 45, 81)
    -1.94 ( 0.369 )
    -2.27 ( 0.453 )
    -1.73 ( 0.449 )
    -1.96 ( 0.335 )
        End of Treatment (n=74, 49, 50, 89)
    -1.91 ( 0.35 )
    -2.09 ( 0.432 )
    -1.98 ( 0.426 )
    -1.94 ( 0.32 )
        Follow-Up (n=56, 41, 39, 62)
    -2.21 ( 0.431 )
    -1.95 ( 0.508 )
    -2.3 ( 0.518 )
    -2.22 ( 0.412 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Visit in Severity of Pain

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    End point title
    		 Change from Baseline to Each Visit in Severity of Pain
    End point description
    Severity of pain was assessed by item 4 of the F-GUPI. The F-GUPI is a validated instrument for evaluating symptoms of BPS/IC. Item 4 in the F-GUPI rates the average pain over the past week on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: units on a scale
    least squares mean (standard error)
        Week 4 (n=73, 49, 48, 89)
    -1.03 ( 0.185 )
    -0.77 ( 0.227 )
    -0.77 ( 0.228 )
    -1.04 ( 0.169 )
        Week 8 (n=67, 45, 48, 85)
    -1.43 ( 0.23 )
    -1.2 ( 0.281 )
    -1.65 ( 0.271 )
    -1.46 ( 0.206 )
        Week 12 (n=66, 44, 45, 81)
    -2.02 ( 0.259 )
    -1.99 ( 0.318 )
    -1.56 ( 0.315 )
    -2.02 ( 0.237 )
        End of Treatment (n=74, 49, 50, 89)
    -1.89 ( 0.248 )
    -1.76 ( 0.305 )
    -1.66 ( 0.301 )
    -1.95 ( 0.227 )
        Follow-Up (n=56, 41, 39, 62)
    -1.99 ( 0.301 )
    -1.9 ( 0.356 )
    -1.74 ( 0.364 )
    -2.19 ( 0.29 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with at Least 4 Points Decrease in F-GUPI Total Score at Each Visit

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    End point title
    		 Percentage of Subjects with at Least 4 Points Decrease in F-GUPI Total Score at Each Visit
    End point description
    The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess symptoms in women with genitourinary pain complaints. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of one week: - Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity; - Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms; - Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact. The F-GUPI Total score ranges from 0 to 45 with higher scores indicating increasing disease activity. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used. For subjects who withdrew due to an AE, change from Baseline to EoT value is set equal to 0.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: percentage of subjects
    number (not applicable)
        Week 4 (n=73, 49, 48, 89)
    49.3
    36.7
    37.5
    46.1
        Week 8 (n=67, 45, 48, 85)
    55.2
    44.4
    54.2
    55.3
        Week 12 (n=66, 44, 45, 81)
    65.2
    61.4
    46.7
    65.4
        End of Treatment (n=74, 49, 50, 89)
    60.8
    55.1
    48
    62.9
        Follow-Up (n=56, 41, 39, 62)
    62.5
    53.7
    61.5
    71
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with at Least 7 Points Decrease in F-GUPI Total Score at Each Visit

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    End point title
    		 Percentage of Subjects with at Least 7 Points Decrease in F-GUPI Total Score at Each Visit
    End point description
    The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess symptoms in women with genitourinary pain complaints. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of one week: - Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity; - Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms; - Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact. The F-GUPI Total score ranges from 0 to 45 with higher scores indicating increasing disease activity. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used. For subjects who withdrew due to an AE, change from Baseline to EoT value is set equal to 0.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: percentage of subjects
    number (not applicable)
        Week 4 (n=73, 49, 48, 89)
    30.1
    22.4
    25
    33.7
        Week 8 (n=67, 45, 48, 85)
    40.3
    33.3
    41.7
    41.2
        Week 12 (n=66, 44, 45, 81)
    47
    43.2
    35.6
    50.6
        End of Treatment (n=74, 49, 50, 89)
    43.2
    38.8
    36
    48.3
        Follow-Up (n=56, 41, 39, 62)
    48.2
    41.5
    43.6
    58.1
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Visit in Mean Daily F-GUPI-24h Total Score

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    End point title
    		 Change from Baseline to Each Visit in Mean Daily F-GUPI-24h Total Score
    End point description
    The Female GenitoUrinary Pain Index-24 hour (F-GUPI-24h) is a validated instrument used to assess symptoms in women with genitourinary pain complaints over the past 24 hours. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of 24 hours: - Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity; - Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms; - Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact. The F-GUPI-24h total score ranges from 0 to 45 with higher scores indicating increasing disease activity. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: units on a scale
    least squares mean (standard error)
        Week 4 (n=67, 44, 49, 82)
    -2.4 ( 0.74 )
    1.2 ( 0.92 )
    -2.1 ( 0.87 )
    -4.3 ( 0.67 )
        Week 8 (n=68, 46, 51, 84)
    -4.8 ( 0.91 )
    -3.6 ( 1.1 )
    -4.9 ( 1.04 )
    -5.2 ( 0.81 )
        Week 12 (n=65, 45, 46, 82)
    -6.8 ( 1.07 )
    -5.9 ( 1.29 )
    -5.5 ( 1.28 )
    -6.5 ( 0.96 )
        End of Treatment (n=74, 49, 52, 89)
    -6.3 ( 1.01 )
    -5.6 ( 1.24 )
    -5.9 ( 1.2 )
    -6.6 ( 0.92 )
        Follow-Up (n=55, 40, 42, 66)
    -7.5 ( 1.19 )
    -5.9 ( 1.41 )
    -5.6 ( 1.36 )
    -6.8 ( 1.09 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with a Successful Global Response Assessment Response at Each Visit

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    End point title
    		 Percentage of Subjects with a Successful Global Response Assessment Response at Each Visit
    End point description
    Patient-assessed treatment effect was measured using a global response assessment (GRA). A self-reported 7 grade GRA was used to evaluate a patient’s clinical condition relative to Baseline (grades: markedly worse, moderately worse, slightly worse, no change, slightly improved, moderately improved or markedly improved). Successful GRA response was defined as the scores moderately improved or markedly improved disease on the patient-rated 7-point scale. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: percentage of subjects
    number (not applicable)
        Week 4 (n=73, 49, 48, 89)
    27.4
    14.3
    31.3
    29.2
        Week 8 (n=67, 45, 48, 85)
    44.8
    28.9
    31.3
    35.3
        Week 12 (n=66, 44, 45, 81)
    47
    45.5
    33.3
    55.6
        End of Treatment (n=74, 49, 50, 89)
    45.9
    40.8
    36
    52.8
        Follow-Up (n=56, 41, 39, 62)
    50
    31.7
    33.3
    51.6
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in Bladder Pain/Interstitial Cystitis Symptom Scale (BPIC-SS) Total Score

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    End point title
    		 Change from Baseline to End of Treatment in Bladder Pain/Interstitial Cystitis Symptom Scale (BPIC-SS) Total Score
    End point description
    The BPIC-SS questionnaire consists of eight questions concerning bladder pain over the previous seven days. Items 1 to 5 address pain and are rated from 0 (never) to 4 (always), Items 6 and 7 address the impact of bladder pain, rated from 0 (not at all) to 4 (a great deal) and Item 8 is an 11-point NRS describing the worst bladder pain experienced in the previous seven days ranging from 0 (no bladder pain) to 10 (worst possible bladder pain). The BPIC-SS Total score ranges from 0 up to 38, with higher scores indicative of worse pain. A total score of 19 or more is taken to indicate moderate/severe disease. This endpoint was analysed using the full analysis set; LOCF imputation was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    68
    44
    45
    81
    Units: units on a scale
        least squares mean (standard error)
    -8.7 ( 0.96 )
    -9.3 ( 1.2 )
    -7.9 ( 1.19 )
    -8.7 ( 0.89 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in BPIC-SS Worst Bladder Pain Score

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    End point title
    		 Change from Baseline to End of Treatment in BPIC-SS Worst Bladder Pain Score
    End point description
    Item 8 of the BPIC-SS is an 11-point NRS describing the worst bladder pain experienced in the previous seven days. The response for this question ranges from 0 (no bladder pain) to 10 (worst possible bladder pain). This endpoint was analysed using the full analysis set; LOCF imputation was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    68
    44
    45
    81
    Units: units on a scale
        least squares mean (standard error)
    -2.1 ( 0.28 )
    -2.3 ( 0.35 )
    -2.1 ( 0.35 )
    -2.4 ( 0.26 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in Interstitial Cystitis Symptom Index (ICSI) Total Score

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    End point title
    		 Change from Baseline to End of Treatment in Interstitial Cystitis Symptom Index (ICSI) Total Score
    End point description
    The Interstitial Cystitis Symptom Index (ICSI) consists of 4 questions which are all rated from 0 (not at all/none) to 5 (almost always): - Frequency of strong need to urinate with little or no warning - Needing to urinate again within two hours of urinating - Frequency of having to get up to urinate at night - Experience of pain or burning in the bladder The ICSI Total score ranges from 0 to 20 and can be categorized to indicate mild (0 to 6), moderate (7 to 14), or severe (15 to 20) symptoms. This endpoint was analysed using the full analysis set; LOCF imputation was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    68
    44
    45
    81
    Units: units on a scale
        least squares mean (standard error)
    -2.8 ( 0.5 )
    -3.6 ( 0.62 )
    -2.4 ( 0.62 )
    -3 ( 0.46 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in Interstitial Cystitis Problem Index (ICPI) Total Score

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    End point title
    		 Change from Baseline to End of Treatment in Interstitial Cystitis Problem Index (ICPI) Total Score
    End point description
    The Interstitial Cystitis Problem Index (ICPI) consists of 4 questions which ask if symptoms of IC have been a problem. Responses are rated from 0 (no problem) to 4 (big problem): - Frequency of urination - Getting up at night to urinate - Needing to urinate with little warning - Burning pain, discomfort or pressure in the bladder The ICPI Total score ranges from 0 to 16, with higher scores indicating more severe symptoms. This endpoint was analysed using the full analysis set; LOCF imputation was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    68
    44
    45
    81
    Units: Units on a scale
        least squares mean (standard error)
    -2.7 ( 0.48 )
    -3.5 ( 0.6 )
    -2.1 ( 0.59 )
    -2.9 ( 0.44 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in Short Form of the McGill Pain Questionnaire (SF-MPQ) Total Score

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    End point title
    		 Change from Baseline to End of Treatment in Short Form of the McGill Pain Questionnaire (SF-MPQ) Total Score
    End point description
    The short form of the McGill pain questionnaire (SF-MPQ) asks about the sensory, affective and evaluative dimensions of pain experience. Higher scores on the SF-MPQ are indicative of more severe disease. The sensory and affective dimensions of the SF-MPQ ask the respondent how each of a set of different adjectives describe their pain over the previous week. Responses to each question range from 0 (None) to 3 (Severe). The sum of the responses within each dimension give the SF-MPQ Sensory score (ranging from 0 to 33) and the SF-MPQ Affective score (ranging from 0 to 12). These sum of these two scores gives the SF-MPQ Total score. This endpoint was analysed using the full analysis set; LOCF imputation was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    68
    44
    45
    81
    Units: units on a scale
        least squares mean (standard error)
    -6.9 ( 1.12 )
    -8.8 ( 1.41 )
    -5 ( 1.39 )
    -8 ( 1.04 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in Female Sexual Function Index (FSFI) Total Score

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    End point title
    		 Change from Baseline to End of Treatment in Female Sexual Function Index (FSFI) Total Score
    End point description
    Sexual functioning was assessed using the FSFI, a validated 19-item, self-administered questionnaire from which scores for assessing six key domains of sexual function and satisfaction can be derived. Each of the 19 items ranges from 0 or 1 (a score of 0 in some questions indicates that no sexual activity occurred in the previous month) up to a maximum of 5. The sum of the responses within each domain are added together and multiplied by a domain factor to give a domain score which can vary up to a maximum value of 6. The FSFI Total score is then calculated as the sum of the six separate domains and ranges from 2 to 36. A FSFI total score of less than or equal to 26.55 has been classified as “Female sexual Dysfunction”. This endpoint was analysed using the full analysis set; LOCF imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    68
    44
    44
    81
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.69 ( 7.616 )
    3.06 ( 6.279 )
    -0.08 ( 8.73 )
    2.1 ( 7.794 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Number of Micturitions per 24 Hours at Weeks 4, 8, 12 and Follow-up

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    End point title
    		 Change from Baseline in Mean Number of Micturitions per 24 Hours at Weeks 4, 8, 12 and Follow-up
    End point description
    The average number of micturitions (urinations) per 24 hours was derived from the number of times a subject urinated (excluding incontinence only episodes) per day as recorded by the subject in a micturition diary for 3 days prior to each visit. This endpoint was analysed using the full analysis set with no imputation for missing data. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: micturitions
    least squares mean (standard error)
        Week 4 (n=65, 41, 47, 78)
    -1.29 ( 0.504 )
    0.83 ( 0.638 )
    -0.42 ( 0.594 )
    -1.29 ( 0.46 )
        Week 8 (n=64, 41, 48, 81)
    -1.37 ( 0.756 )
    0.53 ( 0.951 )
    -0.01 ( 0.877 )
    -0.57 ( 0.676 )
        Week 12 (n=62, 41, 43, 78)
    -1.98 ( 0.708 )
    0.17 ( 0.876 )
    -1.24 ( 0.858 )
    -1.17 ( 0.637 )
        Follow-Up (n=61, 39, 41, 74)
    -3.13 ( 0.743 )
    0.94 ( 0.938 )
    -0.59 ( 0.919 )
    -0.86 ( 0.682 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Visit in Mean Number of Nocturia Episodes per 24 Hours

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    End point title
    		 Change from Baseline to Each Visit in Mean Number of Nocturia Episodes per 24 Hours
    End point description
    Nocturia is defined as waking at night one or more times to void (i.e. any voiding associated with sleep disturbance between the time the subject goes to bed with the intention to sleep until the time the subjects gets up in the morning with the intention to stay awake). A “night time” episode of incontinence only was not considered a nocturia episode. The number of nocturia episodes per 24 hours was derived from the average number of times a subject urinated during sleeping time in the 3 day prior to each visit as recorded in the micturition diary. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: nocturia episodes
    arithmetic mean (standard error)
        Week 4 (n=65, 41, 47, 78)
    -1 ( 1 )
    -0.4 ( 1.35 )
    0.6 ( 0.55 )
    -0.5 ( 0.44 )
        Week 8 (n=64, 41, 48, 81)
    -1.1 ( 0.86 )
    -0.3 ( 1.31 )
    -1 ( 0.66 )
    -1 ( 0.48 )
        Week 12 (n=62, 41, 43, 78)
    -1.5 ( 0.89 )
    0.2 ( 1.12 )
    -0.6 ( 0.71 )
    -1.1 ( 0.46 )
        End of Treatment (n=71, 44, 49, 87)
    -1.7 ( 0.81 )
    0.1 ( 1.05 )
    -1 ( 0.64 )
    -0.9 ( 0.42 )
        Follow-Up (n=61, 39, 41, 74)
    -3 ( 0.94 )
    0.8 ( 1.36 )
    -1.1 ( 0.64 )
    -0.9 ( 0.53 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Visit in Mean Number of Urgency Episodes per 24 Hours

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    End point title
    		 Change from Baseline to Each Visit in Mean Number of Urgency Episodes per 24 Hours
    End point description
    Urgency is defined as the complaint of a sudden, compelling desire to pass urine, which is difficult to defer. Each episode was graded using the following 5 point scale based on Patient Perception of Intensity of Urgency Scale (PPIUS): 0 = No urgency; 1 = Mild urgency, could postpone voiding as long as necessary; 2 = Moderate urgency, could postpone voiding for a short time; 3 = Severe urgency, could not postpone voiding, had to rush to the toilet; 4 = Urge incontinence, leaked before arriving to the toilet. The mean number of urgency episodes per 24 hours was derived from the average number of times a subject recorded an urgency episode of severity of 3 or 4 per day during the 3-day micturition diary period. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: urgency episodes
    least squares mean (standard error)
        Week 4 (n=65, 41, 47, 78)
    -2.36 ( 0.492 )
    -0.15 ( 0.622 )
    -0.71 ( 0.582 )
    -1.29 ( 0.45 )
        Week 8 (n=64, 41, 48, 81)
    -2.95 ( 0.585 )
    -1.23 ( 0.734 )
    -1.51 ( 0.68 )
    -1.6 ( 0.523 )
        Week 12 (62, 41, 43, 78)
    -2.8 ( 0.569 )
    -0.58 ( 0.701 )
    -2.26 ( 0.691 )
    -2.4 ( 0.511 )
        End of Treatment (n=71, 44, 49, 87)
    -2.57 ( 0.516 )
    -0.57 ( 0.656 )
    -2.15 ( 0.624 )
    -2.42 ( 0.468 )
        Follow-Up (n=61, 39, 41, 74)
    -3.68 ( 0.612 )
    0.28 ( 0.771 )
    -1.99 ( 0.758 )
    -2.31 ( 0.561 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Visit in Mean Level of Urgency per Micturition

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    End point title
    		 Change from Baseline to Each Visit in Mean Level of Urgency per Micturition
    End point description
    Each episode was graded using the following 5 point scale based on Patient Perception of Intensity of Urgency Scale (PPIUS): 0 = No urgency; 1 = Mild urgency, could postpone voiding as long as necessary; 2 = Moderate urgency, could postpone voiding for a short while; 3 = Severe urgency, could not postpone voiding, but had to rush to the toilet in order not to wet myself; 4 = Urge incontinence, leaked before arriving to the toilet. The mean level of urgency was derived from the average severity grade recorded by the subject for each micturition, with or without incontinence, during the 3-day micturition diary period. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: units on a scale
    least squares mean (standard error)
        Week 4 (n=65, 41, 47, 78)
    -0.2 ( 0.058 )
    -0.1 ( 0.074 )
    -0.03 ( 0.069 )
    -0.2 ( 0.053 )
        Week 8 (n=64, 41, 48, 81)
    -0.33 ( 0.067 )
    -0.21 ( 0.084 )
    -1.19 ( 0.078 )
    -0.29 ( 0.06 )
        Week 12 (n=62, 41, 43, 78)
    -0.35 ( 0.074 )
    -0.17 ( 0.091 )
    -0.2 ( 0.09 )
    -0.28 ( 0.066 )
        End of Treatment (n=71, 44, 49, 87)
    -0.31 ( 0.071 )
    -0.14 ( 0.091 )
    -0.18 ( 0.086 )
    -0.35 ( 0.065 )
        Follow-Up (n=61, 39, 41, 74)
    -0.4 ( 0.076 )
    -0.19 ( 0.096 )
    -0.25 ( 0.094 )
    -0.32 ( 0.07 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Visit in Total Urgency Score (TUS) per 24 Hours

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    End point title
    		 Change from Baseline to Each Visit in Total Urgency Score (TUS) per 24 Hours
    End point description
    The total urgency score (TUS) per 24 hours is the sum of the PPIUS urgency gradings from all valid diary days recorded by the subject in the 3 days prior to each visit in the micturition diary divided by the number of valid days. Each episode was graded using the following 5 point scale based on Patient Perception of Intensity of Urgency Scale (PPIUS): 0 = No urgency; 1 = Mild urgency, could postpone voiding as long as necessary; 2 = Moderate urgency, could postpone voiding for a short while; 3 = Severe urgency, could not postpone voiding, but had to rush to the toilet in order not to wet myself; 4 = Urge incontinence, leaked before arriving to the toilet. This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    49
    54
    90
    Units: units on a sclae
    least squares mean (standard error)
        Week 4 (n=65, 41, 47, 78)
    -5.63 ( 1.391 )
    1.69 ( 1.762 )
    -1.76 ( 1.644 )
    -4.88 ( 1.272 )
        Week 8 (n=64, 41, 48, 81)
    -6.85 ( 1.709 )
    -0.86 ( 2.146 )
    -2.22 ( 1.983 )
    -4.61 ( 1.527 )
        Week 12 (n=62, 41, 43, 78)
    -8.18 ( 1.612 )
    -0.7 ( 1.99 )
    -5.61 ( 1.954 )
    -7.53 ( 1.45 )
        End of Treatment (n=71, 44, 49, 87)
    -7.74 ( 1.493 )
    -0.68 ( 1.9 )
    -5.96 ( 1.806 )
    -7.57 ( 1.356 )
        Follow-Up (n=61, 39, 41, 74)
    -11.51 ( 1.617 )
    1.59 ( 2.038 )
    -4.3 ( 2 )
    -7.31 ( 1.483 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in European Quality of Life Visual Analogue Scale (EQ VAS)

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    End point title
    		 Change from Baseline to End of Treatment in European Quality of Life Visual Analogue Scale (EQ VAS)
    End point description
    On the EQ visual analogue scale (EQ-VAS) the subject is asked to rate their health as a number between 0 (The worst health you can imagine) and 100 (the best health you can imagine). This endpoint was analysed using the full analysis set; LOCF imputation was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    68
    44
    45
    81
    Units: units on a scale
        least squares mean (standard error)
    8.5 ( 2.16 )
    11.2 ( 2.69 )
    7.3 ( 2.68 )
    9 ( 2 )
    No statistical analyses for this end point

    Secondary: ASP3652 Plasma Concentration

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    End point title
    		 ASP3652 Plasma Concentration [20]
    End point description
    The lower limit of quantification (LLOQ) of ASP3652 is 0.5 ng/ml in plasma. Values that are below the LLOQ were set to 0. This endpoint was analysed using the Pharmacokinetics Analysis Set which comprised all subjects who received active treatment, for whom at least 1 blood sample was collected for measurement of the ASP3652 plasma concentrations, and for whom the time of sampling and the time of dosing on the day of sampling was known.
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 8, 1-4 hours post morning dose, Week 12 (or end of treatment), 12-16 hours post previous evening dose
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Plasma concentration of ASP3652 not calculated for subjects in the placebo treatment group.
    End point values
    		 ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    49
    49
    88
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 4 (n=41, 45, 74)
    438.945 ( 733.0389 )
    1973.302 ( 2305.887 )
    5544.765 ( 5724.552 )
        Week 8 (n=43, 47, 77)
    450.359 ( 511.6218 )
    2088.381 ( 2485.641 )
    5082.27 ( 6004.383 )
        Week 12 (n=47, 46, 84)
    59.243 ( 195.945 )
    352.891 ( 1443.167 )
    411.458 ( 1366.536 )
    No statistical analyses for this end point

    Secondary: N-arachidonoyl-ethanolamide (Anandamide) Plasma Concentration

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    End point title
    		 N-arachidonoyl-ethanolamide (Anandamide) Plasma Concentration
    End point description
    The LLOQ of N-arachidonoyl-ethanolamide is 0.05 ng/mL in plasma. This endpoint was analysed using the Pharmacodynamic Analysis Set (PDAS) which comprised subjects who received at least 1 dose of study drug and for whom at least 1 blood sample was collected for measurement of the anandamide concentrations.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose), Weeks 4 and 8, 1-4 hours post morning dose and Week 12 (or end of treatment), 12-16 hours post previous evening dose.
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    81
    50
    52
    93
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n=79, 48, 52, 90)
    0.506 ( 0.2359 )
    0.549 ( 0.3 )
    0.557 ( 0.284 )
    0.515 ( 0.2268 )
        Week 4 (n=60, 41, 45, 74)
    0.436 ( 0.2193 )
    1.52 ( 0.6961 )
    2.099 ( 0.8471 )
    2.217 ( 0.8053 )
        Week 8 (n=63, 43, 48, 78)
    0.378 ( 0.1723 )
    1.532 ( 0.7422 )
    2.013 ( 0.8204 )
    2.085 ( 0.8143 )
        Week 12 (n=70, 46, 43, 82)
    0.482 ( 0.2397 )
    1.01 ( 0.4713 )
    1.405 ( 0.7689 )
    1.76 ( 0.7981 )
    No statistical analyses for this end point

    Secondary: Oleoylethanolamide Plasma Concentration

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    End point title
    		 Oleoylethanolamide Plasma Concentration
    End point description
    The LLOQ for oleoylethanolamide is 0.5 ng/mL in plasma. This endpoint was analysed using the pharmacodynamics analysis set.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose), Weeks 4 and 8, 1-4 hours post morning dose and Week 12 (or end of treatment), 12-16 hours post previous evening dose.
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    81
    50
    52
    93
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n=79, 48, 52, 90)
    2.578 ( 0.9946 )
    2.726 ( 1.2024 )
    2.812 ( 1.3616 )
    2.633 ( 0.9027 )
        Week 4 (n=60, 41, 45, 74)
    2.157 ( 0.9664 )
    7.125 ( 2.7562 )
    8.86 ( 2.7888 )
    9.277 ( 2.9515 )
        Week 8 (n=63, 43, 48, 78)
    1.903 ( 0.7191 )
    7.119 ( 2.6435 )
    8.607 ( 2.5604 )
    8.923 ( 3.0675 )
        Week 12 (n=70, 46, 43, 82)
    2.313 ( 0.9464 )
    5.21 ( 1.9694 )
    6.967 ( 3.2457 )
    8.184 ( 3.1632 )
    No statistical analyses for this end point

    Secondary: Palmitoylethanolamide Plasma Concentration

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    End point title
    		 Palmitoylethanolamide Plasma Concentration
    End point description
    The LLOQ for palmitoylethanolamide in plasma is 0.5 ng/mL. This endpoint was analysed using the pharmacodynamics analysis set.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose), Weeks 4 and 8, 1-4 hours post morning dose and Week 12 (or end of treatment), 12-16 hours post previous evening dose.
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    81
    50
    52
    93
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n=79, 48, 52, 90)
    2.544 ( 0.9556 )
    2.627 ( 1.0885 )
    2.846 ( 1.4928 )
    2.597 ( 0.9674 )
        Week 4 (n=60, 41, 45, 74)
    2.243 ( 0.9792 )
    4.93 ( 1.6596 )
    5.736 ( 1.9207 )
    5.833 ( 1.696 )
        Week 8 (n=63, 43, 48, 78)
    2.016 ( 0.7513 )
    4.852 ( 1.4955 )
    5.578 ( 1.6733 )
    5.502 ( 1.6368 )
        Week 12 (n=70, 46, 43, 82)
    2.405 ( 0.8336 )
    3.941 ( 1.0663 )
    4.813 ( 1.8189 )
    4.154 ( 1.7693 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in Post-Void Residual (PVR) Volume

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    End point title
    		 Change from Baseline to End of Treatment in Post-Void Residual (PVR) Volume
    End point description
    PVR volume was assessed by a transabdominal ultrasound bladder scan. This endpoint was analysed using the safety analysis set; LOCF imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    76
    51
    53
    93
    Units: mL
        arithmetic mean (standard deviation)
    0.8 ( 17.23 )
    3.5 ( 23.17 )
    3.6 ( 14.25 )
    -1.9 ( 33.15 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in Profile of Mood States (POMS) Total Mood Disturbance Score

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    End point title
    		 Change from Baseline to End of Treatment in Profile of Mood States (POMS) Total Mood Disturbance Score
    End point description
    Psychotropic effects emerging during the study were measured using the POMS questionnaire, which asks subjects to rate how they feel in relation to each of 65 adjectives commonly used to describe mood states. Responses are given on a 5-point scale (0=Not at all, 1=A little, 2=Moderate, 3=Quite a bit, and 4=Extremely). The responses to groups of questions can be summed to calculate six factors: Tension-Anxiety (range 0 to 36), Depression-Rejection (range 0 to 60), Anger-Hostility (range 0 to 48), Vigor-Activity (range 0 to 32), Fatigue-Inertia (range 0 to 28) and Confusion-Bewilderment (range 0 to 28). The Total Mood Disturbance (TMD) score is calculated by summing the six factors while weighting the Vigor-Activity score negatively. The range of this total score is from -32 to 200. A score below -30 or above 68 is considered abnormal. This endpoint was analysed using the safety analysis set; LOCF imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    75
    51
    50
    91
    Units: units on a scale
        arithmetic mean (standard deviation)
    -10.1 ( 24.11 )
    -6.5 ( 23.29 )
    -14.6 ( 24.43 )
    -3.2 ( 24.73 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Treatment in Center for Epidemiologic Studies Depression Scale (CES-D) score

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    End point title
    		 Change from Baseline to End of Treatment in Center for Epidemiologic Studies Depression Scale (CES-D) score
    End point description
    The 20-item CES-D scale questionnaire is a validated, short, self-report scale designed to measure depressive symptomatology. Responses to each item are from 0 (“rarely or not at all”) to 3 (“most or all of the time”). The total score is calculated as the sum of the scores for the 20 questions and has a range from 0 to 60. Negative changes from Baseline indicate improvements in depressive symptoms during the study. This endpoint was analysed in the safety analysis set; LOCF imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    69
    47
    46
    83
    Units: units on a scale
        arithmetic mean (standard deviation)
    1 ( 8.81 )
    3.2 ( 8.19 )
    0.8 ( 10.02 )
    2 ( 10.12 )
    No statistical analyses for this end point

    Secondary: Change from End of Treatment to Follow-up in the Physician Withdrawal Checklist (PWC) Score

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    End point title
    		 Change from End of Treatment to Follow-up in the Physician Withdrawal Checklist (PWC) Score
    End point description
    Withdrawal effects from study drug were measured by the PWC. The PWC has twenty items, each rated on a 4-point scale (0=not present; 1=mild; 2=moderate; 3=severe). It is evaluated after permanent discontinuation of treatment, i.e., at the Follow-up visit. The total score was calculated as the sum of the scores provided in response to the 20 items. It has a range from 0 to 60. Missing value were not imputed. This endpoint was analysed using the safety analysis set.
    End point type
    Secondary
    End point timeframe
    Week 12 (or end of treatment if earlier) and 2 weeks after the end of treatment
    End point values
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Number of subjects analysed
    53
    42
    40
    67
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.2 ( 2.19 )
    0 ( 1.55 )
    -0.1 ( 1.48 )
    -0.3 ( 1.58 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study medication until 2 days after the last dose. Overall mean duration of drug exposure was 78 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects took matching placebo tablets twice a day for 12 weeks, followed by a 2-week follow-up period.

    Reporting group title
    ASP3652 50 mg BID
    Reporting group description
    		 Subjects took two 25 mg ASP3652 tablets and one placebo tablet twice a day (BID) for 12 weeks, followed by a 2-week follow-up period.

    Reporting group title
    ASP3652 150 mg BID
    Reporting group description
    		 Subjects took two 25 mg and one 100 mg ASP3652 tablet twice a day for 12 weeks, followed by a 2-week follow-up period.

    Reporting group title
    ASP3652 300 mg BID
    Reporting group description
    		 Subjects took three 100 mg ASP3652 tablets twice a day for 12 weeks, followed by a 2-week follow-up period.

    Serious adverse events
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    2 / 96 (2.08%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Meniscus lesion
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo ASP3652 50 mg BID ASP3652 150 mg BID ASP3652 300 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 82 (15.85%)
    9 / 53 (16.98%)
    7 / 55 (12.73%)
    16 / 96 (16.67%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 82 (3.66%)
    1 / 53 (1.89%)
    3 / 55 (5.45%)
    4 / 96 (4.17%)
         occurrences all number
    3
    1
    3
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 82 (1.22%)
    3 / 53 (5.66%)
    1 / 55 (1.82%)
    3 / 96 (3.13%)
         occurrences all number
    1
    3
    1
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 53 (0.00%)
    2 / 55 (3.64%)
    0 / 96 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Constipation
         subjects affected / exposed
    3 / 82 (3.66%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    3 / 96 (3.13%)
         occurrences all number
    3
    1
    0
    4
    Diarrhoea
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 96 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    2 / 96 (2.08%)
         occurrences all number
    0
    1
    1
    2
    Dyspepsia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    2 / 96 (2.08%)
         occurrences all number
    0
    1
    0
    2
    Nausea
         subjects affected / exposed
    3 / 82 (3.66%)
    0 / 53 (0.00%)
    3 / 55 (5.45%)
    1 / 96 (1.04%)
         occurrences all number
    3
    0
    3
    1
    Vomiting
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    2 / 96 (2.08%)
         occurrences all number
    1
    1
    1
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    2 / 96 (2.08%)
         occurrences all number
    1
    1
    0
    2
    Renal and urinary disorders
    Bladder pain
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 53 (0.00%)
    2 / 55 (3.64%)
    2 / 96 (2.08%)
         occurrences all number
    1
    0
    2
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    2 / 96 (2.08%)
         occurrences all number
    0
    0
    1
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 82 (1.22%)
    2 / 53 (3.77%)
    0 / 55 (0.00%)
    0 / 96 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Cystitis
         subjects affected / exposed
    2 / 82 (2.44%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 96 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 96 (0.00%)
         occurrences all number
    2
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2013
    1. Initially, patients were required to undergo a cystoscopy at Screening to ascertain BPS/IC disease characteristics (i.e., the presence/absence of Hunner’s lesions and glomerulations). The cystoscopy at Screening could be omitted provided results of a previous cystoscopy with hydrodistension were available which could enable the classification of patients into subgroups with and without Hunner’s lesions (glomerulations have been implied in previous diagnostic criteria, but are currently not regarded as specific for BPS/IC). However, the omission of the procedure had no consequences for selection criteria, as the cystoscopy was not meant for diagnosing confounding or confusable bladder conditions. 2. The original protocol stated that the use of antibiotics was not permitted between visit 1/screening and visit 7/FU. In the protocol amendment, these restrictions were reduced to allow antibiotic treatments of up to 2 weeks in duration for indications/infections not including the genitourinary tract. Short regimens of systemic antibiotics for treatment of infections other than UTI were not expected to influence BPS/IC efficacy and safety endpoints. A clinical study with long term antibiotics in BPS/IC did not show convincing efficacy (Warren et al, 2000) and AUA (Hanno et al, 2011) and EAU (2010) guidelines do not regard the use of antibiotics as an effective treatment of BPS/IC.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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