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    Clinical Trial Results:
    A PHASE III, MULTICENTRE, RANDOMISED, DOUBLE BLIND, PARALLEL GROUP, PLACEBO CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF ONE OR MORE INTRADETRUSOR TREATMENTS OF 600 OR 800 UNITS OF DYSPORT® FOR THE TREATMENT OF URINARY INCONTINENCE IN SUBJECTS WITH NEUROGENIC DETRUSOR OVERACTIVITY DUE TO SPINAL CORD INJURY OR MULTIPLE SCLEROSIS

    Summary
    EudraCT number
    		 2015-003471-30
    Trial protocol
    		 RO   PT   CZ   IT   NL   PL  
    Global end of trial date
    14 Feb 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 May 2021
    First version publication date
    01 Mar 2020
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    New data added

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D-FR-52120-222
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02660138
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ipsen Innovation
    Sponsor organisation address
    5 Avenue du Canada, Les Ulis, France, 91940
    Public contact
    Medical Director, Ipsen Innovation, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen Innovation, clinical.trials@ipsen.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
    14 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of two doses of Dysport® (600 Units [U] and 800 U) in adult subjects with urinary incontinence (UI) caused by neurogenic detrusor overactivity (NDO) due to spinal cord injury (SCI) or multiple sclerosis (MS) and who had not been adequately managed with oral medication and routinely required clean intermittent catheterisation to manage their bladder function.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Mar 2016
    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
    Turkey: 31
    Country: Number of subjects enrolled
    United States: 76
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Romania: 30
    Worldwide total number of subjects
    226
    EEA total number of subjects
    99
    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)
    205
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 227 subjects with UI, caused by NDO due to SCI or MS, were enrolled at 64 study sites worldwide. One of the 226 randomised subjects did not receive any treatment. The study was terminated early by the sponsor due to lack of recruitment.

    Pre-assignment
    Screening details
    		 Subjects were randomised to 1 of 4 sequences: A) placebo in a double blind placebo controlled (DBPC) cycle then Dysport® 600 Units (U) in subsequent double blind cycles: B) placebo in DBPC cycle then Dysport® 800 U in subsequent cycles: C) Dysport® 600 U in all cycles: D) Dysport® 800 U in all cycles. The minimum re-treatment interval was 12 weeks.

    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, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 millilitres (mL) divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Placebo was injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each.

    Arm title
    		 Dysport® 600 U
    Arm description
    		 Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dysport®
    Investigational medicinal product code
    AbobotulinumtoxinA
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Dysport® 600 U was injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each.

    Arm title
    		 Dysport® 800 U
    Arm description
    		 Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dysport®
    Investigational medicinal product code
    AbobotulinumtoxinA
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Dysport® 800 U was injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each.

    Number of subjects in period 1
    		Placebo Dysport® 600 U Dysport® 800 U
    Started
    76
    75
    75
    Completed
    6
    2
    3
    Not completed
    70
    73
    72
         Consent withdrawn by subject
    7
    6
    6
         Adverse event, non-fatal
    -
    3
    2
         Sponsor Decision to Terminate Study
    57
    57
    62
         Unspecified
    1
    1
    -
         Lost to follow-up
    4
    4
    1
         Lack of efficacy
    1
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 millilitres (mL) divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.

    Reporting group title
    Dysport® 600 U
    Reporting group description
    		 Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.

    Reporting group title
    Dysport® 800 U
    Reporting group description
    		 Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.

    Reporting group values
    		 Placebo Dysport® 600 U Dysport® 800 U Total
    Number of subjects
    		 76 75 75 226
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 68 71 66 205
        From 65-84 years
    		 8 4 9 21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.9 ( 13.15 ) 43.0 ( 12.38 ) 46.8 ( 13.58 ) -
    Gender categorical
    Units: Subjects
        Female
    		 38 27 30 95
        Male
    		 38 48 45 131
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 4 2 4 10
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 4 3 4 11
        White
    		 65 70 64 199
        More than one race
    		 1 0 0 1
        Unknown or Not Reported
    		 2 0 3 5
    Aetiology of NDO
    Units: Subjects
        SCI
    		 51 49 48 148
        MS
    		 25 26 27 78

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 millilitres (mL) divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.

    Reporting group title
    Dysport® 600 U
    Reporting group description
    		 Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.

    Reporting group title
    Dysport® 800 U
    Reporting group description
    		 Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.

    Primary: Mean Change From Baseline in Weekly Number of UI Episodes at Week 6 of DBPC Cycle

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    End point title
    		 Mean Change From Baseline in Weekly Number of UI Episodes at Week 6 of DBPC Cycle
    End point description
    The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The least square (LS) mean of the change in weekly number of UI episodes at 6 weeks after the first study treatment was calculated using a mixed model repeated measures (MMRM) analysis. Results are presented for the modified intention to treat (mITT) population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.
    End point type
    Primary
    End point timeframe
    Baseline and Week 6 of DBPC Cycle
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    64
    62
    67
    Units: Weekly UI episodes
        least squares mean (standard error)
    -12.7 ( 2.01 )
    -23.5 ( 2.04 )
    -24.9 ( 1.97 )
    Statistical analysis title
    		 Comparison of Dysport® 600 U to Placebo
    Statistical analysis description
    Treatment group, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [Botulinum toxin [BTX]-naïve or BTX-non-naïve]) and study baseline value (weekly number of UI episodes) as fixed effect variables, and subject as a random effect.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -10.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.36
         upper limit
    		 -5.31
    Notes
    [1] - If both p-values for the 2 primary tests (the test of Dysport® 800 U vs. placebo and the test of Dysport® 600 U vs. placebo) were lower than 0.05, both were declared statistically significant. If 1 of the primary tests had a p-value greater than or equal to 0.05, then the other test was declared statistically significant if its p-value was lower than 0.025.
    Statistical analysis title
    		 Comparison of Dysport® 800 U to Placebo
    Statistical analysis description
    Treatment group, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [Botulinum toxin [BTX]-naïve or BTX-non-naïve]) and study baseline value (weekly number of UI episodes) as fixed effect variables, and subject as a random effect.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -12.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.65
         upper limit
    		 -6.73
    Notes
    [2] - If both p-values for the 2 primary tests (the test of Dysport® 800 U vs. placebo and the test of Dysport® 600 U vs. placebo) were lower than 0.05, both were declared statistically significant. If 1 of the primary tests had a p-value greater than or equal to 0.05, then the other test was declared statistically significant if its p-value was lower than 0.025.

    Secondary: Mean Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 6 of DBPC Cycle

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    End point title
    		 Mean Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 6 of DBPC Cycle
    End point description
    All subjects had a standardised urodynamic (filling cystometry) assessment at baseline (screening) and again at Week 6 to determine the MCC. The LS mean of the change in MCC at 6 weeks after the first study treatment was calculated using an analysis of covariance (ANCOVA). Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6 of DBPC Cycle
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    66
    60
    70
    Units: mL
        least squares mean (standard error)
    -8.5 ( 18.06 )
    152.4 ( 19.10 )
    180.7 ( 17.70 )
    Statistical analysis title
    		 Comparison of Dysport® 600 U with Placebo
    Statistical analysis description
    Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and baseline value of MCC as covariates.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    160.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 109.9
         upper limit
    		 211.9
    Notes
    [3] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.
    Statistical analysis title
    		 Comparison of Dysport® 800 U with Placebo
    Statistical analysis description
    Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and baseline value of MCC as covariates.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    189.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 140.1
         upper limit
    		 238.2
    Notes
    [4] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.

    Secondary: Mean Change From Baseline in Maximum Detrusor Pressure (MDP) at Week 6 of DBPC Cycle

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    End point title
    		 Mean Change From Baseline in Maximum Detrusor Pressure (MDP) at Week 6 of DBPC Cycle
    End point description
    All subjects had a standardised urodynamic filling cystometry assessment at baseline (screening) and again at Week 6 to determine the MDP. The LS mean of the change in MDP at 6 weeks after the first study treatment was calculated using an ANCOVA. Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6 of DBPC Cycle
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    58
    54
    65
    Units: centimetres of water
        least squares mean (standard error)
    -5.4 ( 2.83 )
    -29.8 ( 2.96 )
    -34.1 ( 2.71 )
    Statistical analysis title
    		 Comparison of Dysport® 600 U with Placebo
    Statistical analysis description
    Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and baseline value of MDP as covariates.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -24.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.3
         upper limit
    		 -16.4
    Notes
    [5] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.
    Statistical analysis title
    		 Comparison of Dysport® 800 U with Placebo
    Statistical analysis description
    Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and baseline value of MDP as covariates.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -28.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.2
         upper limit
    		 -21.1
    Notes
    [6] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.

    Secondary: Mean Change From Baseline in Volume at First Involuntary Detrusor Contraction (Vol@1stIDC) at Week 6 of DBPC Cycle

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    End point title
    		 Mean Change From Baseline in Volume at First Involuntary Detrusor Contraction (Vol@1stIDC) at Week 6 of DBPC Cycle
    End point description
    All subjects had a standardised urodynamic (filling cystometry) assessment at baseline (screening) and again at Week 6 to determine the Vol@1stIDC which is the instilled volume when first IDC commences. Subjects who did not exhibit a post-treatment IDC at Week 6 had Vol@1stIDC imputed using the recorded corrected MCC volume at Week 6. The LS mean of the change in Vol@1stIDC at 6 weeks after the first study treatment was calculated using an ANCOVA. Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6 of DBPC Cycle
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    63
    56
    66
    Units: mL
        least squares mean (standard error)
    14.0 ( 19.45 )
    169.4 ( 20.72 )
    195.7 ( 19.12 )
    Statistical analysis title
    		 Comparison of Dysport® 600 U with Placebo
    Statistical analysis description
    Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and baseline value of Vol@1stIDC as covariates.
    Comparison groups
    Dysport® 600 U v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    155.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 100.5
         upper limit
    		 210.4
    Notes
    [7] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.
    Statistical analysis title
    		 Comparison of Dysport® 800 U with Placebo
    Statistical analysis description
    Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and baseline value of Vol@1stIDC as covariates.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    181.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 129.2
         upper limit
    		 234.3
    Notes
    [8] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.

    Secondary: Number of Subjects With No Episodes of UI at Week 6 of DBPC Cycle

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    End point title
    		 Number of Subjects With No Episodes of UI at Week 6 of DBPC Cycle
    End point description
    The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The number of subjects with no UI episodes at 6 weeks after the first study treatment was recorded. Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6 of DBPC Cycle
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    64
    62
    67
    Units: subjects
    3
    21
    21
    Statistical analysis title
    		 Comparison of Dysport® 600 U with Placebo
    Statistical analysis description
    Treatment group, recorded stratification factors, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0006
    Method
    		 Generalised linear mixed model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    9.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.72
         upper limit
    		 35.6
    Notes
    [9] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.
    Statistical analysis title
    		 Comparison of Dysport® 800 U with Placebo
    Statistical analysis description
    Treatment group, recorded stratification factors, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.0003
    Method
    		 Generalised linear mixed model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    10.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.05
         upper limit
    		 39.61
    Notes
    [10] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.

    Secondary: Number of Subjects With No IDCs During Storage at Week 6 of DBPC Cycle

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    End point title
    		 Number of Subjects With No IDCs During Storage at Week 6 of DBPC Cycle
    End point description
    All subjects had a standardised urodynamic filling cystometry assessment at baseline (screening) and again at Week 6 to determine the occurrence of IDCs. The number of subjects without IDCs at 6 weeks after the first study treatment was recorded. Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6 of DBPC Cycle
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    63
    60
    71
    Units: subjects
    6
    20
    42
    Statistical analysis title
    		 Comparison of Dysport® 600 U with Placebo
    Statistical analysis description
    Treatment group, and recorded stratification factors (aetiology of NDO, previous BTX-A usage) and study baseline (prior intradetrusor BTX-A usage for UI) as explanatory variables.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.02
         upper limit
    		 16.24
    Variability estimate
    Standard deviation
    Notes
    [11] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.
    Statistical analysis title
    		 Comparison of Dysport® 800 U with Placebo
    Statistical analysis description
    Treatment group, and recorded stratification factors (aetiology of NDO, previous BTX-A usage) and study baseline (prior intradetrusor BTX-A usage for UI) as explanatory variables.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    16.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.82
         upper limit
    		 44.43
    Variability estimate
    Standard deviation
    Notes
    [12] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.

    Secondary: Mean Change From Baseline in Volume Per Void at Week 6 of DBPC Cycle

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    End point title
    		 Mean Change From Baseline in Volume Per Void at Week 6 of DBPC Cycle
    End point description
    The volume per void was measured during one 24-hour period of the 7-day bladder diary. The LS mean of the change in volume per void at 6 weeks after the first study treatment was calculated using a MMRM analysis. Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6 of DBPC Cycle
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    62
    60
    65
    Units: mL
        least squares mean (standard error)
    2.3 ( 14.92 )
    87.1 ( 15.10 )
    112.8 ( 14.50 )
    Statistical analysis title
    		 Comparison of Dysport® 600 U with Placebo
    Statistical analysis description
    Treatment group, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and study baseline value (total volume per void) as fixed effect variables, and subject as a random effect.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    84.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 43.73
         upper limit
    		 125.89
    Notes
    [13] - This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
    Statistical analysis title
    		 Comparison of Dysport® 800 U with Placebo
    Statistical analysis description
    Treatment group, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and study baseline value (total volume per void) as fixed effect variables, and subject as a random effect.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    110.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 70.17
         upper limit
    		 150.98
    Notes
    [14] - This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate..

    Secondary: Number of Subjects with a UI Response at Improvement Levels ≥30%, ≥50%, and ≥75% at Week 6 of the DBPC Cycle

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    End point title
    		 Number of Subjects with a UI Response at Improvement Levels ≥30%, ≥50%, and ≥75% at Week 6 of the DBPC Cycle
    End point description
    The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The number of subjects showing an improvement of ≥30%, ≥50% and ≥75% were recorded. Results are presented for the mITT population: all randomised subjects who received at least 1 administration of study treatment. Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6 of DBPC Cycle
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    64
    62
    67
    Units: Subjects
        ≥30% Improvement
    32
    50
    52
        ≥50% Improvement
    19
    47
    50
        ≥75% Improvement
    9
    39
    44
    Statistical analysis title
    		 Treatment comparison at ≥30% Improvement
    Statistical analysis description
    Dysport® 600 U versus Placebo. Treatment group, recorded stratification factors, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0007
    Method
    		 GLMM
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 8.86
    Notes
    [15] - This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
    Statistical analysis title
    		 Treatment comparison at ≥30% Improvement
    Statistical analysis description
    Dysport® 800 U versus Placebo. Treatment group, recorded stratification factors, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.0012
    Method
    		 GLMM
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.68
         upper limit
    		 7.86
    Notes
    [16] - This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
    Statistical analysis title
    		 Treatment comparison at ≥50% Improvement
    Statistical analysis description
    Dysport® 600 U versus Placebo. Treatment group, recorded stratification factors, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.0001
    Method
    		 GLMM
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    8.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.56
         upper limit
    		 18.09
    Notes
    [17] - This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
    Statistical analysis title
    		 Treatment comparison at ≥50% Improvement
    Statistical analysis description
    Dysport® 800 U versus Placebo. Treatment group, recorded stratification factors, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 < 0.0001
    Method
    		 GLMM
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    8.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.66
         upper limit
    		 18.47
    Notes
    [18] - This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
    Statistical analysis title
    		 Treatment comparison at ≥75% Improvement
    Statistical analysis description
    Dysport® 600 U versus Placebo. Treatment group, recorded stratification factors, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.0001
    Method
    		 GLMM
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    10.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.59
         upper limit
    		 24.95
    Notes
    [19] - This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
    Statistical analysis title
    		 Treatment comparison at ≥75% Improvement
    Statistical analysis description
    Dysport® 800 U versus Placebo. Treatment group, recorded stratification factors, visit (Week 2, Week 6 and Week 12), treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 < 0.0001
    Method
    		 GLMM
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    12.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.4
         upper limit
    		 29.56
    Notes
    [20] - This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.

    Secondary: Median Time Between Treatments

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    End point title
    		 Median Time Between Treatments
    End point description
    Duration of effect for time between treatments was calculated by: (the date of the first retreatment visit - date of first treatment administration in the DBPC cycle). The median number of days between treatments was determined based on the Kaplan-Meier method. Subjects with no retreatment were censored at the last visit. Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment).
    End point type
    Secondary
    End point timeframe
    Day of first treatment (baseline) and day of retreatment
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    76
    75
    75
    Units: Days
        median (full range (min-max))
    120.5 (44 to 616)
    215.0 (37 to 590)
    224.0 (82 to 647)
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Incontinence Quality of Life (I-QoL) Questionnaire Total Summary Score at Week 6 of DBPC Cycle

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    End point title
    		 Mean Change from Baseline in Incontinence Quality of Life (I-QoL) Questionnaire Total Summary Score at Week 6 of DBPC Cycle
    End point description
    The I-QoL questionnaire is a validated, disease-specific questionnaire designed to measure the effect of UI on subjects' QoL. It consists of 22 items in 3 domains (avoidance and limiting behaviour, psychosocial impact and social embarrassment). Subjects used a 5-point response scale for each of the 22 items with values ranging from 1 (extremely) to 5 (not at all). The total summary score was transformed to a 100 point scale ranging from 0 to 100, with higher scores indicating a better QoL. The LS mean of the change in the I-QoL total summary score at 6 weeks after the first study treatment was calculated using a MMRM analysis. Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6 of DBPC Cycle
    End point values
    		 Placebo Dysport® 600 U Dysport® 800 U
    Number of subjects analysed
    71
    61
    68
    Units: score on a scale
        least squares mean (standard error)
    5.8 ( 2.52 )
    19.1 ( 2.63 )
    23.0 ( 2.51 )
    Statistical analysis title
    		 Comparison of Dysport® 600 U to Placebo
    Statistical analysis description
    Treatment group, visit (Week 6 and Week 12), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and study baseline value (I-QoL summary total score) as fixed variables, and subject as a random effect.
    Comparison groups
    Placebo v Dysport® 600 U
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.0003
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    13.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.22
         upper limit
    		 20.37
    Notes
    [21] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.
    Statistical analysis title
    		 Comparison of Dysport® 800 U to Placebo
    Statistical analysis description
    Treatment group, visit (Week 6 and Week 12), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and study baseline value (I-QoL summary total score) as fixed variables, and subject as a random effect.
    Comparison groups
    Placebo v Dysport® 800 U
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    17.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.36
         upper limit
    		 24.15
    Notes
    [22] - This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events are presented for the full DBPC cycle (i.e. approximately 35 weeks for both Dysport® groups and approximately 25 weeks for the Placebo group).
    Adverse event reporting additional description
    The safety population included all subjects who received at least 1 administration of study treatment (including only partial administration). Safety subjects were analysed according to their actual treatment received. Number of deaths (all causes) is presented for the duration of the study (up to a maximum of 113 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 millilitres (mL) divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.

    Reporting group title
    Dysport® 800 U
    Reporting group description
    		 Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.

    Reporting group title
    Dysport® 600 U
    Reporting group description
    		 Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.

    Serious adverse events
    		 Placebo Dysport® 800 U Dysport® 600 U
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 76 (10.53%)
    6 / 77 (7.79%)
    9 / 73 (12.33%)
         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)
    Metastases to abdominal cavity
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Multiple injuries
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    0 / 73 (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
    Ligament sprain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    0 / 73 (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
    Tibia fracture
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 77 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
    0 / 73 (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
    Hypertension
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         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
    Ileus
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    0 / 73 (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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    0 / 73 (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
    Arthralgia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 77 (1.30%)
    3 / 73 (4.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
    0 / 73 (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
    Clostridium difficile infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
    0 / 73 (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
    Cystitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
    0 / 73 (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
    Epididymitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
    0 / 73 (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
    Osteomyelitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    0 / 73 (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
    Fournier's gangrene
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    0 / 73 (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
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Dysport® 800 U Dysport® 600 U
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 76 (30.26%)
    23 / 77 (29.87%)
    20 / 73 (27.40%)
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    2 / 73 (2.74%)
         occurrences all number
    0
    0
    2
    Dizziness
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences all number
    2
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 77 (0.00%)
    2 / 73 (2.74%)
         occurrences all number
    2
    0
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 77 (1.30%)
    2 / 73 (2.74%)
         occurrences all number
    1
    1
    2
    Abdominal pain
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences all number
    3
    0
    1
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    2 / 73 (2.74%)
         occurrences all number
    0
    0
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 77 (2.60%)
    3 / 73 (4.11%)
         occurrences all number
    1
    2
    3
    Dysuria
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 77 (2.60%)
    2 / 73 (2.74%)
         occurrences all number
    1
    2
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    13 / 76 (17.11%)
    21 / 77 (27.27%)
    13 / 73 (17.81%)
         occurrences all number
    26
    27
    26
    Influenza
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 77 (2.60%)
    0 / 73 (0.00%)
         occurrences all number
    0
    2
    0
    Pharyngitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    2 / 73 (2.74%)
         occurrences all number
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 77 (0.00%)
    1 / 73 (1.37%)
         occurrences all number
    4
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2018
    • Decrease in sample size from 408 to 330 subjects; statistical power lowered from 90% to 80%. • Clarification added regarding the primary analysis (i.e. previously referred to as an ‘interim’ analysis). • Removal of the internal data monitoring committee. • Clarification added throughout the protocol regarding description of the Screening period (i.e. time between Screening Visit 1 and Screening Visit 2, as well as time between Screening and administration of study treatment).

    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.
    This study was terminated early by the sponsor on 01 October 2018, due to low subject recruitment.
    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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