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    Clinical Trial Results:
    A Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Adding Mirabegron to Solifenacin in Incontinent OAB Patients who have Received Solifenacin for 4 Weeks and Warrant Additional Relief for their OAB Symptoms

    Summary
    EudraCT number
    		 2012-005401-41
    Trial protocol
    		 SK   CZ   GB   SE   IE   BE   PT   NO   AT   FI   GR   HU   ES   SI   NL   DK   PL  
    Global end of trial date
    25 Nov 2014

    Results information
    Results version number
    		 v1
    This version publication date
    21 Jul 2016
    First version publication date
    21 Jul 2016
    Other versions
    		 v2 , v3

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    905-EC-012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01908829
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Acronym: BESIDE
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe Ltd
    Sponsor organisation address
    2000 Hillswood Drive, Chertsey, United Kingdom, KT16 0RS
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe Ltd, Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe Ltd, 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
    25 Nov 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of solifenacin 5 mg in combination with mirabegron 50 mg (referred to as combination therapy from here on) vs solifenacin 5 mg monotherapy.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (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, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Algeria: 15
    Country: Number of subjects enrolled
    Armenia: 52
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Austria: 24
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Canada: 57
    Country: Number of subjects enrolled
    Czech Republic: 129
    Country: Number of subjects enrolled
    Denmark: 39
    Country: Number of subjects enrolled
    Egypt: 11
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Georgia: 23
    Country: Number of subjects enrolled
    Germany: 106
    Country: Number of subjects enrolled
    Greece: 53
    Country: Number of subjects enrolled
    Hungary: 53
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Israel: 43
    Country: Number of subjects enrolled
    Italy: 49
    Country: Number of subjects enrolled
    Kazakhstan: 23
    Country: Number of subjects enrolled
    Norway: 9
    Country: Number of subjects enrolled
    Poland: 234
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Romania: 84
    Country: Number of subjects enrolled
    Russian Federation: 241
    Country: Number of subjects enrolled
    Slovakia: 93
    Country: Number of subjects enrolled
    Slovenia: 26
    Country: Number of subjects enrolled
    Spain: 76
    Country: Number of subjects enrolled
    Sweden: 54
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Turkey: 164
    Country: Number of subjects enrolled
    Ukraine: 28
    Country: Number of subjects enrolled
    United Kingdom: 78
    Country: Number of subjects enrolled
    United States: 320
    Country: Number of subjects enrolled
    Netherlands: 15
    Worldwide total number of subjects
    2174
    EEA total number of subjects
    1183
    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)
    1492
    From 65 to 84 years
    671
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multicenter study was conducted at 281 centers globally.

    Pre-assignment
    Screening details
    		 Participants who met the screening inclusion/exclusion criteria went through a two week wash-out period and maintained a micturition diary during that the wash-out period. A total of 3815 participants were screened of which 2401 participants received solifenacin 5 mg run-in medication.

    Pre-assignment period milestones
    Number of subjects started
    		 3815 [1]
    Intermediate milestone: Number of subjects
    Received 1 dose, single-blind run-in: 2401
    Number of subjects completed
    		 2174

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Discontinued before run-in solifenacin 5 mg: 1414
    Reason: Number of subjects
    		 Exclusion/inclusion criteria not met: 169
    Reason: Number of subjects
    		 Patient withdrawn: 32
    Reason: Number of subjects
    		 Adverse event: 16
    Reason: Number of subjects
    		 Other reasons: 7
    Reason: Number of subjects
    		 Lost to follow-up: 3
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of participants included in the pre-assignment period were the total number screened. The number of participants included in the worldwide number enrolled were the total number of participants randomized.
    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The study is comprised of a 12 week double-blind treatment period (participants were randomized into the double-blind period if they experienced 1 or more incontinence episodes over the 3-day diary period prior to randomization to double-blind period and warranted additional relief for their OAB symptoms). There was 2 week safety follow up period (placebo administered). The active and placebo tablets were made indistinguishable by using a double-dummy packaging system.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Combination (solifenacin + mirabegron)
    Arm description
    		 Participants received solifenacin 5 mg, mirabegron 25 mg and solifenacin 10 mg matching placebo once daily for the first 4 weeks of double-blind period. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron tablet was replaced by a 50 mg mirabegron tablet. Placebo was given for the 2 week single-blind safety follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    solifenacin 5 mg
    Investigational medicinal product code
    YM905
    Other name
    Vesicare, Vesitrim, Vesikur, solifenacin succinate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Solifenacin was provided as the marketed formulation in the 5 mg strength. Medication was taken orally with a glass of water, with or without food.

    Investigational medicinal product name
    solifenacin 10 mg matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo of solifenacin succinate 10 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.

    Investigational medicinal product name
    mirabegron 25 mg
    Investigational medicinal product code
    YM178
    Other name
    Betanis, Betmiga, Myrbetriq
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Mirabegron was supplied as the marketed formulation in the 25 mg OCAS (Oral Controlled Absorption System) modified release tablets. Medication was taken orally with a glass of water, with or without food.

    Investigational medicinal product name
    mirabegron 50 mg
    Investigational medicinal product code
    YM178
    Other name
    Betanis, Betmiga, Myrbetriq
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Mirabegron was supplied as the marketed formulation in the 50 mg OCAS (Oral Controlled Absorption System) modified release tablets. Medication was taken orally with a glass of water, with or without food.

    Arm title
    		 Solifenacin 5 mg
    Arm description
    		 Participants received solifenacin 5 mg, mirabegron 25 mg matching placebo and solifenacin 10 mg matching placebo once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    solifenacin 5 mg
    Investigational medicinal product code
    YM905
    Other name
    Vesicare, Vesitrim, Vesikur, solifenacin succinate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Solifenacin was provided as the marketed formulation in the 5 mg strength. Medication was taken orally with a glass of water, with or without food.

    Investigational medicinal product name
    solifenacin 10 mg matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo of solifenacin succinate 10 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.

    Investigational medicinal product name
    mirabegron 25 mg matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo of mirabegron OCAS 25 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.

    Investigational medicinal product name
    mirabegron 50 mg matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo of mirabegron OCAS 50 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.

    Arm title
    		 Solifenacin 10 mg
    Arm description
    		 Participants received solifenacin 5 mg matching placebo, mirabegron 25 mg matching placebo and solifenacin 10 mg once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    solifenacin 5 mg matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo of solifenacin succinate 5 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.

    Investigational medicinal product name
    solifenacin 10 mg
    Investigational medicinal product code
    YM905
    Other name
    Vesicare, Vesitrim, Vesikur, solifenacin succinate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Solifenacin was provided as the marketed formulation in the 10 mg strength. Medication was taken orally with a glass of water, with or without food.

    Investigational medicinal product name
    mirabegron 25 mg matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo of mirabegron OCAS 25 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.

    Investigational medicinal product name
    mirabegron 50 mg matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo of mirabegron OCAS 50 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.

    Number of subjects in period 1
    		Combination (solifenacin + mirabegron) Solifenacin 5 mg Solifenacin 10 mg
    Started
    727
    728
    719
    Treated with double-blind drug
    725
    728
    719
    Completed
    678
    679
    680
    Not completed
    49
    49
    39
         Randomized no double-blind drug received
    1
    -
    1
         Discontinued (no EoT page)
    2
    -
    -
         Other
    -
    2
    -
         Adverse event
    13
    11
    13
         Protocol Violation
    2
    2
    -
         Lost to follow-up
    4
    2
    1
         Lack of efficacy
    1
    3
    2
         Withdrawal by subject
    26
    29
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Combination (solifenacin + mirabegron)
    Reporting group description
    		 Participants received solifenacin 5 mg, mirabegron 25 mg and solifenacin 10 mg matching placebo once daily for the first 4 weeks of double-blind period. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron tablet was replaced by a 50 mg mirabegron tablet. Placebo was given for the 2 week single-blind safety follow-up period.

    Reporting group title
    Solifenacin 5 mg
    Reporting group description
    		 Participants received solifenacin 5 mg, mirabegron 25 mg matching placebo and solifenacin 10 mg matching placebo once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.

    Reporting group title
    Solifenacin 10 mg
    Reporting group description
    		 Participants received solifenacin 5 mg matching placebo, mirabegron 25 mg matching placebo and solifenacin 10 mg once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.

    Reporting group values
    		 Combination (solifenacin + mirabegron) Solifenacin 5 mg Solifenacin 10 mg Total
    Number of subjects
    		 727 728 719
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.2 ± 13.1 56.9 ± 13.5 57.4 ± 13.2 -
    Gender categorical
    Units:
        Male
    		 123 124 119 366
        Female
    		 604 604 600 1808

    End points

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    End points reporting groups
    Reporting group title
    Combination (solifenacin + mirabegron)
    Reporting group description
    		 Participants received solifenacin 5 mg, mirabegron 25 mg and solifenacin 10 mg matching placebo once daily for the first 4 weeks of double-blind period. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron tablet was replaced by a 50 mg mirabegron tablet. Placebo was given for the 2 week single-blind safety follow-up period.

    Reporting group title
    Solifenacin 5 mg
    Reporting group description
    		 Participants received solifenacin 5 mg, mirabegron 25 mg matching placebo and solifenacin 10 mg matching placebo once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.

    Reporting group title
    Solifenacin 10 mg
    Reporting group description
    		 Participants received solifenacin 5 mg matching placebo, mirabegron 25 mg matching placebo and solifenacin 10 mg once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.

    Primary: Change from Baseline to End of Treatment (EoT) in Mean Number of Incontinence Episodes Per 24 Hours During the 3-Day Diary Period

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    End point title
    		 Change from Baseline to End of Treatment (EoT) in Mean Number of Incontinence Episodes Per 24 Hours During the 3-Day Diary Period
    End point description
    The mean number of incontinence episodes (complaint of any involuntary leakage of urine) per day was derived from number of incontinence episodes recorded on valid diary days during the 3-day micturition diary period divided by the number of valid diary days during the 3-day micturition diary period. The analysis population consisted of the Full Analysis Set (FAS) which is comprised of all the Randomized Analysis Set's (RAS) participants who met the following criteria: took at least 1 dose of double-blind study drug after randomization, reported at least 1 micturition in the baseline diary & at least 1 micturition postbaseline & reported at least 1 incontinence episode in the baseline diary. For participants who withdrew before EoT (week 12) and have no measurement available for that diary period, the Last Observation Carried Forward (LOCF) value during the double-blind study period was used as EoT value to derive the primary variable. N=number of participants with available data.
    End point type
    Primary
    End point timeframe
    Baseline and end of treatment (up to 12 weeks)
    End point values
    		 Combination (solifenacin + mirabegron) Solifenacin 5 mg Solifenacin 10 mg
    Number of subjects analysed
    706
    704
    697
    Units: incontinence episodes
    least squares mean (standard error)
        Adjusted Change from Baseline (FAS)
    -1.8 ± 0.08
    -1.53 ± 0.08
    -1.67 ± 0.08
    Statistical analysis title
    		 Adjusted Difference Combination vs Solifenacin 5mg
    Statistical analysis description
    Differences of adjusted means were calculated by subtracting adjusted mean of solifenacin monotherapy groups from adjusted mean of combination group based on ANCOVA model. Means (LS means) and 95% CIs are from an ANCOVA model with sex, age group (< 65, ≥ 65 years), geographic region, and 4-week incontinence episode reduction group as fixed factors and mean number of incontinence episodes per 24 hours at baseline as a covariate.
    Comparison groups
    Combination (solifenacin + mirabegron) v Solifenacin 5 mg
    Number of subjects included in analysis
    1410
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.001 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares (LS) Means
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 -0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [1] - Primary analysis of the FAS.
    [2] - P values for pairwise comparisons are from the stratified rank ANCOVA model. P < 0.05 indicates superiority in favor of treatment group with the largest improvement.

    Secondary: Change from Baseline to EoT in Mean Number of Micturitions Per 24 Hours

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    End point title
    		 Change from Baseline to EoT in Mean Number of Micturitions Per 24 Hours
    End point description
    The average number of micturitions (urinations) per 24 hours was derived from number of micturitions recorded on valid diary days during the 3-day micturition diary period divided by the number of valid diary days during the 3-day micturition diary period (excluding incontinence only episodes). LOCF was used. The analysis population included the FAS. N=number of participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment (up to 12 weeks)
    End point values
    		 Combination (solifenacin + mirabegron) Solifenacin 5 mg Solifenacin 10 mg
    Number of subjects analysed
    706
    704
    697
    Units: micturitions
    least squares mean (standard error)
        Adjusted Change from Baseline (FAS)
    -1.59 ± 0.08
    -1.14 ± 0.08
    -1.12 ± 0.08
    Statistical analysis title
    		 Adjusted Difference Combination vs Solifenacin 5mg
    Statistical analysis description
    Differences of adjusted means were calculated by subtracting adjusted mean of solifenacin monotherapy from adjusted mean of combination group. Adjusted change from baseline values as well as 95% CIs for pairwise comparisons and P values are from the ANCOVA model with sex, age group (< 65, ≥ 65 years), geographic region, and 4-week incontinence episode reduction group as fixed factors and mean number of micturitions per 24 hours at baseline as a covariate.
    Comparison groups
    Combination (solifenacin + mirabegron) v Solifenacin 5 mg
    Number of subjects included in analysis
    1410
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.67
         upper limit
    		 -0.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [3] - Primary analysis of the FAS.
    [4] - P<0.05 indicates superiority in favor of treatment group with largest improvement.

    Secondary: Number of Incontinence Episodes Reported During the 3-Day Diary at EoT

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    End point title
    		 Number of Incontinence Episodes Reported During the 3-Day Diary at EoT
    End point description
    The number of incontinence episodes (complaint of any involuntary leakage of urine) per day was derived from total number of incontinence episodes on valid diary days recorded during the 3-day micturition diary period. The analysis population included the FAS. LOCF was used. N=number of participants with available data at EoT.
    End point type
    Secondary
    End point timeframe
    End of treatment (up to 12 weeks)
    End point values
    		 Combination (solifenacin + mirabegron) Solifenacin 5 mg Solifenacin 10 mg
    Number of subjects analysed
    706
    704
    697
    Units: incontinence episodes
    least squares mean (standard error)
        EoT (FAS) (N = 706, 704, 697)
    4.25 ± 0.29
    4.87 ± 0.28
    4.72 ± 0.31
    Statistical analysis title
    		 Rate Ratio (Combination vs 5 mg solifenacin)
    Statistical analysis description
    Rate ratio, 95% CIs, & p-value for number of incontinence episodes during EoT 3-day diary between combination & solifenacin treatment was calculated from Mixed Effects Poisson (negative binomial) regression model including treatment group, sex, age group (<65, >=65 years), geographic region & 4-week incontinence episode reduction group as factors, log of (number of incontinence episodes/number of valid diary days) at baseline as covariate & log of number of valid diary days as offset variable.
    Comparison groups
    Combination (solifenacin + mirabegron) v Solifenacin 5 mg
    Number of subjects included in analysis
    1410
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.014 [6]
    Method
    		 Mixed Effects Poisson
    Parameter type
    		 LS Means
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 0.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08
    Notes
    [5] - Primary analysis of the FAS. Statistical test of hypothesis analysis method was Mixed Effects Poisson (negative binomial) regression.
    [6] - P<0.05 indicates superiority in favor of treatment group with lowest rate of incontinence episodes.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of double blind treatment until 30 days after last dose
    Adverse event reporting additional description
    Population consisted of the SAF. An AE was defined as any untoward medical occurrence in a subject administered a study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Combination
    Reporting group description
    		 Participants received solifenacin 5 mg, mirabegron 25 mg and solifenacin 10 mg matching placebo once daily for the first 4 weeks of double-blind period. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron tablet was replaced by a 50 mg mirabegron tablet. Placebo was given for the 2 week single-blind safety follow-up period.

    Reporting group title
    Solifenacin 5 mg
    Reporting group description
    		 Participants received solifenacin 5 mg, mirabegron 25 mg matching placebo and solifenacin 10 mg matching placebo once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.

    Reporting group title
    Solifenacin 10 mg
    Reporting group description
    		 Participants received solifenacin 5 mg matching placebo, mirabegron 25 mg matching placebo and solifenacin 10 mg once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.

    Serious adverse events
    		 Combination Solifenacin 5 mg Solifenacin 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 725 (1.79%)
    10 / 728 (1.37%)
    15 / 719 (2.09%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal cancer
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Joint resurfacing surgery
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin neoplasm excision
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adhesion
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervix haemorrhage uterine
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract oedema
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriogram coronary normal
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthroscopy
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonoscopy
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Polyneuropathy
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 725 (0.00%)
    1 / 728 (0.14%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 725 (0.00%)
    0 / 728 (0.00%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 725 (0.14%)
    1 / 728 (0.14%)
    1 / 719 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis herpes
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 725 (0.14%)
    0 / 728 (0.00%)
    0 / 719 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Combination Solifenacin 5 mg Solifenacin 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 725 (5.93%)
    41 / 728 (5.63%)
    68 / 719 (9.46%)
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    43 / 725 (5.93%)
    41 / 728 (5.63%)
    68 / 719 (9.46%)
         occurrences all number
    44
    44
    70

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    One participant was randomized to the Combination arm, but actually received Solifenacin 10 mg. In terms of actual treatment received, the patient was allocated to the solifenacin 10 mg arm.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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