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    Clinical Trial Results:
    Randomised trial of detrusor botulinum toxin injection (BOTOX®) compared to placebo in women with idiopathic detrusor overactivity

    Summary
    EudraCT number
    		 2004-002981-39
    Trial protocol
    		 GB  
    Global end of trial date
    18 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2019
    First version publication date
    29 Mar 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    v1.1aug05
    Additional study identifiers
    ISRCTN number
    		 ISRCTN26091555
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospitals of Leicester NHS Trust
    Sponsor organisation address
    Gwendolen Road, Leicester, United Kingdom, LE5 4PW
    Public contact
    Mrs Carolyn Maloney, University Hospitals of Leicester NHS Trust Research and Innovation, +44 01162584109, carolyn.maloney@uhl-tr.nhs.uk
    Scientific contact
    Mrs Carolyn Maloney, University Hospitals of Leicester NHS Trust Research and Innovation, +44 01162584109, carolyn.maloney@uhl-tr.nhs.uk
    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
    06 Sep 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Aug 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of detrusor muscle injection of purified botulinum toxin A (BOTOX®) in relieving symptoms of detrusor overactivity.
    Protection of trial subjects
    Trial data were reviewed periodically by an independent data monitoring committee to ensure no excess adverse events were occurring.
    Background therapy
    		 -
    Evidence for comparator
    		 the comparator was placebo in this study because there was no active alternative treatment for women who had failed treatment with oral medication at the time of the study
    Actual start date of recruitment
    22 Jun 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 240
    Worldwide total number of subjects
    240
    EEA total number of subjects
    240
    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)
    154
    From 65 to 84 years
    86
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with a urodynamic diagnosis of detrusor overactivity who had failed to improve after 8 weeks of any antimuscarinic drugs were eligible. Patients had to have at least 8 voids in 24 hours and at least 2 episodes of moderate or severe urgency in 24 hours.

    Pre-assignment
    Screening details
    		 Patients were screened at their first review appointment after commencing oral medication. Study information was given and patients were seen again two weeks later to complete the screening form to ensure eligibility (number of voids, number of urgency episodes

    Period 1
    Period 1 title
    Randomisation and treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Drug and placebo were packaged identically in opaque sealed boxes with the randomisation number on the box; boxes were used in randomisation number order. Drug and placebo were not identical so the drug was made up by the scrub nurse out of sight of the administering surgeon who was given an unlabelled syringe to administer to the patient. The drug box number was recorded in the CRF. Surgeons administering the product were not involved in data collection.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients receiving placebo injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    Placebo powder for injection, reconstituted in 20mls normal saline

    Arm title
    		 Active treatment
    Arm description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)
    Arm type
    		 Experimental

    Investigational medicinal product name
    onabotulinum toxin
    Investigational medicinal product code
    PL 0426/0074
    Other name
    BOTOX
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    200 units of powder, reconstituted in 20mls of normal saline

    Number of subjects in period 1
    		Placebo Active treatment
    Started
    118
    122
    Completed
    118
    122
    Period 2
    Period 2 title
    Six week follow up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients receiving placebo injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    Placebo powder for injection, reconstituted in 20mls normal saline

    Arm title
    		 Active treatment
    Arm description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)
    Arm type
    		 Experimental

    Investigational medicinal product name
    onabotulinum toxin
    Investigational medicinal product code
    PL 0426/0074
    Other name
    BOTOX
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    200 units of powder, reconstituted in 20mls of normal saline

    Number of subjects in period 2
    		Placebo Active treatment
    Started
    118
    122
    Completed
    114
    118
    Not completed
    4
    4
         missing visit
    2
    2
         patient withdrawal (self)
    2
    1
         Lost to follow-up
    -
    1
    Period 3
    Period 3 title
    Three month follow up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients receiving placebo injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    Placebo powder for injection, reconstituted in 20mls normal saline

    Arm title
    		 Active treatment
    Arm description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)
    Arm type
    		 Experimental

    Investigational medicinal product name
    onabotulinum toxin
    Investigational medicinal product code
    PL 0426/0074
    Other name
    BOTOX
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    200 units of powder, reconstituted in 20mls of normal saline

    Number of subjects in period 3
    		Placebo Active treatment
    Started
    114
    118
    Completed
    103
    102
    Not completed
    11
    16
         Missed visit
    9
    13
         Patient withdrawn (self)
    1
    2
         Lost to follow-up
    1
    1
    Period 4
    Period 4 title
    Six month follow up (Primary outcome)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients receiving placebo injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    Placebo powder for injection, reconstituted in 20mls normal saline

    Arm title
    		 Active treatment
    Arm description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)
    Arm type
    		 Experimental

    Investigational medicinal product name
    onabotulinum toxin
    Investigational medicinal product code
    PL 0426/0074
    Other name
    BOTOX
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    200 units of powder, reconstituted in 20mls of normal saline

    Number of subjects in period 4
    		Placebo Active treatment
    Started
    103
    102
    Completed
    111
    116
    Not completed
    3
    1
         Patient withdrawn (self)
    1
    1
         Lost to follow-up
    2
    -
    Joined
    11
    15
         Attended despite earlier missed visit
    11
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo injection

    Reporting group title
    Active treatment
    Reporting group description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)

    Reporting group values
    		 Placebo Active treatment Total
    Number of subjects
    		 118 122 240
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 58.2 (51.5 to 69.2) 60.7 (50.8 to 67.8) -
    Gender categorical
    All patients were female
    Units: Subjects
        Female
    		 118 122 240
        Male
    		 0 0 0
    Body Mass index >30
    Units: Subjects
        BMI >30
    		 50 49 99
        BMI<=30
    		 68 73 141
    Ethnicity
    Units: Subjects
        White British
    		 109 118 227
        Other
    		 7 4 11
        not recorded
    		 2 0 2
    Smoking
    Units: Subjects
        Yes
    		 24 30 54
        No
    		 94 92 186
    Previous continence surgery
    Units: Subjects
        Any previous surgery
    		 46 44 90
        No previous surgery
    		 72 78 150
    Continence status
    Units: Subjects
        Continent, no leaks
    		 8 6 14
        Has leakage
    		 110 116 226
    Baseline voiding frequency
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    		 10.7 (9.3 to 13.3) 10.3 (9.3 to 12.7) -
    Incontinence episodes per 24 hours
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    		 6.2 (3.0 to 8.7) 6.2 (3.7 to 8.3) -
    Urgency episodes
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    		 7.7 (6.0 to 9.7) 8.0 (5.7 to 10.3) -
    Urgency severity Score
    Indevus urgency severity score; a value from 0-3 with greater score indicating greater urgency
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 2.1 (1.7 to 2.3) 2.1 (1.7 to 2.4) -
    Maximum voided urine volume
    Maximum recorded void from 3 day bladder diary
    Units: mls
        median (inter-quartile range (Q1-Q3))
    		 300 (250 to 420) 350 (275 to 450) -
    mean voided volume
    mean voided volume from three day bladder diary
    Units: mls
        median (inter-quartile range (Q1-Q3))
    		 164.4 (121.8 to 198.0) 165.8 (122. to 203.7) -
    ICIQ UI score
    International Consultation on Incontinence Short Form score; a numerical value from 0-21 with higher values indicating greater incontinence
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 16.0 (13.8 to 18.0) 17.0 (14.0 to 19.0) -
    Incontinence-Quality of LIfe score (I-QoL)
    quality of life score, with greater scores indicating better quality of life (range 0-100)
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 23.3 (12.5 to 34.1) 24.4 (11.4 to 38.6) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo injection

    Reporting group title
    Active treatment
    Reporting group description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)
    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo injection

    Reporting group title
    Active treatment
    Reporting group description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)
    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo injection

    Reporting group title
    Active treatment
    Reporting group description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)
    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo injection

    Reporting group title
    Active treatment
    Reporting group description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)

    Primary: Urinary voiding frequency at 6 months after treatment

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    End point title
    		 Urinary voiding frequency at 6 months after treatment
    End point description
    Voiding frequency at six months after treatment
    End point type
    Primary
    End point timeframe
    Six months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    99 [1]
    100 [2]
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    9.67 (8.37 to 11.67)
    8.33 (6.83 to 10.0)
    Notes
    [1] - 99 women returned valid diary data at this time point
    [2] - 100 women returned valid diary data at this time point
    Statistical analysis title
    		 Comparison of primary outcome at 6 months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Incontinence episodes per 24 hours

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    End point title
    		 Incontinence episodes per 24 hours
    End point description
    End point type
    Secondary
    End point timeframe
    Six months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    99
    100
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    6.0 (1.33 to 8.33)
    1.67 (0 to 5.33)
    Statistical analysis title
    		 Comparison of incontinence episodes
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Urgency episodes per 24 hours at six months

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    End point title
    		 Urgency episodes per 24 hours at six months
    End point description
    End point type
    Secondary
    End point timeframe
    Six months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    99
    100
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    6.33 (4.0 to 8.67)
    3.83 (1.17 to 6.67)
    Statistical analysis title
    		 Comparison of urgency episodes at six months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Urgency severity score (IUSS) at six months

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    End point title
    		 Urgency severity score (IUSS) at six months
    End point description
    End point type
    Secondary
    End point timeframe
    Six months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    99
    100
    Units: Score
        median (inter-quartile range (Q1-Q3))
    1.9 (1.5 to 2.3)
    1.5 (1.0 to 2.0)
    Statistical analysis title
    		 Comparison of IUSS score at six months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Continence rate at six months

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    End point title
    		 Continence rate at six months
    End point description
    End point type
    Secondary
    End point timeframe
    Six months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    99
    100
    Units: Number of continent patients
    number (not applicable)
        Continent-yes
    12
    31
        Continent-no
    87
    69
    Statistical analysis title
    		 Comparison of continent rate
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 OR and 95% CI
    Confidence interval

    Secondary: ICIQ score at six months

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    End point title
    		 ICIQ score at six months
    End point description
    End point type
    Secondary
    End point timeframe
    Six months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    99
    100
    Units: Score
        median (inter-quartile range (Q1-Q3))
    15.0 (11.0 to 18.0)
    10.0 (4.0 to 15.0)
    Statistical analysis title
    		 Comparison of ICIQ score at six months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: IQoL score at six months

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    End point title
    		 IQoL score at six months
    End point description
    End point type
    Secondary
    End point timeframe
    Six months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    99
    100
    Units: Score
        median (inter-quartile range (Q1-Q3))
    27.27 (18.18 to 46.59)
    55.11 (23.3 to 78.41)
    Statistical analysis title
    		 Comparison of IQOL score at six months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Voiding frequency per 24 hours at six weeks

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    End point title
    		 Voiding frequency per 24 hours at six weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Six weeks after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    98
    97 [3]
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    9.67 (8.37 to 11.67)
    8.0 (6.33 to 10.0)
    Notes
    [3] - 97patients returned valid urinary diaries for this data point
    Statistical analysis title
    		 Comparison of voiding frequency at 6 weeks
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Incontinence episodes per 24 hours at six weeks

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    End point title
    		 Incontinence episodes per 24 hours at six weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Six weeks after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    98
    97
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    5.33 (1.67 to 7.0)
    0.33 (0 to 4.0)
    Statistical analysis title
    		 Comparison of incontinence episodes at six weeks
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Urgency episodes per 24 hours at six weeks

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    End point title
    		 Urgency episodes per 24 hours at six weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Six weeks after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    98
    97
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    6.17 (4.0 to 9.0)
    2.67 (0 to 6.33)
    Statistical analysis title
    		 Comparison of urgency episodes at six weeks
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Urgency severity score (IUSS) at six weeks

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    End point title
    		 Urgency severity score (IUSS) at six weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Six weeks after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    98
    97
    Units: Score
        median (inter-quartile range (Q1-Q3))
    1.90 (1.40 to 2.20)
    1.30 (0.7 to 1.90)
    Statistical analysis title
    		 Comparison of IUSS score at six weeks
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Continence rate at six weeks

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    End point title
    		 Continence rate at six weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Six weeks after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    98
    97
    Units: Number
    number (not applicable)
        Continent-yes
    13
    43
        Continent-no
    85
    54
    Statistical analysis title
    		 Comparison of continence rate at six weeks
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 OR and 95% CI
    Confidence interval

    Secondary: ICIQ score at six weeks

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    End point title
    		 ICIQ score at six weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Six weeks after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    98
    97
    Units: Score
        median (inter-quartile range (Q1-Q3))
    14.0 (1.0 to 18.0)
    7.0 (1.0 to 18.0)
    Statistical analysis title
    		 Comparison of ICIQ score at six weeks
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: IQoL score at six weeks

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    End point title
    		 IQoL score at six weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Six weeks after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    98
    97
    Units: Score
        median (inter-quartile range (Q1-Q3))
    30.68 (17.05 to 51.14)
    55.68 (22.72 to 85.23)
    Statistical analysis title
    		 Comparison of IQOL score at six weeks
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Voiding frequency per 24 hours at three months

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    End point title
    		 Voiding frequency per 24 hours at three months
    End point description
    End point type
    Secondary
    End point timeframe
    Thre months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    86 [4]
    86 [5]
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    9.67 (8.0 to 11.0)
    8.0 (6.3 to 10.0)
    Notes
    [4] - 86 women returned valid urinary diaries for this period
    [5] - 86 women returned valid urinary diaries for this period
    Statistical analysis title
    		 Comparison of voiding frequency at 3 months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Incontinence episodes per 24 hours at 3 months

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    End point title
    		 Incontinence episodes per 24 hours at 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    Three months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    86
    86
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    5.33 (2.0 to 8.33)
    1.0 (0 to 6.0)
    Statistical analysis title
    		 Comparison of incontinence episodes @ three months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Urgency episodes per 24 hours at three months

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    End point title
    		 Urgency episodes per 24 hours at three months
    End point description
    End point type
    Secondary
    End point timeframe
    Three months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    86
    86
    Units: Episodes
        median (inter-quartile range (Q1-Q3))
    7.0 (3.67 to 8.67)
    3.0 (0.67 to 6.33)
    Statistical analysis title
    		 Comparison of urgency episodes at three months
    Comparison groups
    Active treatment v Placebo
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Urgency severity score (IUSS) at 3 months

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    End point title
    		 Urgency severity score (IUSS) at 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    Three months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    86
    86
    Units: Score
        median (inter-quartile range (Q1-Q3))
    1.90 (1.40 to 2.30)
    1.30 (0.80 to 2.0)
    Statistical analysis title
    		 Comparison of IUSS score at three months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Continence rate at 3 months

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    End point title
    		 Continence rate at 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    Three months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    86
    86
    Units: Number
    number (not applicable)
        Continent-yes
    12
    36
        Continent-no
    74
    50
    Statistical analysis title
    		 Comparison of continent rate at 3 months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 OR and 95% CI
    Confidence interval

    Secondary: ICIQ score at 3 months

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    End point title
    		 ICIQ score at 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    Three months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    86
    86
    Units: Score
        median (inter-quartile range (Q1-Q3))
    15.0 (9.0 to 17.0)
    8.0 (3.0 to 14.0)
    Statistical analysis title
    		 Comparison of ICIQ score at three months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: IQOL score at 3 months

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    End point title
    		 IQOL score at 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    Three months after treatment
    End point values
    		 Placebo Active treatment
    Number of subjects analysed
    86
    86
    Units: Score
        median (inter-quartile range (Q1-Q3))
    25.0 (14.77 to 44.32)
    64.77 (27.27 to 90.91)
    Statistical analysis title
    		 Comparison of IQOL score at three months
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reported was open throughout treatment and follow up phases of the study, according to ICH-GCP guidelines in force during the trial.
    Adverse event reporting additional description
    Standard European Directive definitions of adverse events and adverse reactions were followed (Directive 2001/20/EC). Fatal or life threatening events were reported as soon as possible but within seven days of the event. Non-fatal or life threatening were reported as soon as possible within fifteen days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICH-GCP
    Dictionary version
    2001
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo injection

    Reporting group title
    Active treatment
    Reporting group description
    		 Patients receiving 200 units onabotulinum toxin (BOTOX)

    Serious adverse events
    		 Placebo Active treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 118 (1.69%)
    2 / 122 (1.64%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary clot retention
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Generalised muscle weakness
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Active treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 118 (33.05%)
    85 / 122 (69.67%)
    Renal and urinary disorders
    Urinary tract infection
    Additional description: Defined in the protocol as a non-serious adverse event because it was an expected outcome; adverse event was based on patient reported symptoms and receipt of an antibiotic prescription from the GP. Numbers included are all patients 1 or more UTI
         subjects affected / exposed
    12 / 118 (10.17%)
    36 / 122 (29.51%)
         occurrences all number
    12
    36
    Voiding difficulty
    Additional description: Voiding difficulty was not classed as a serious adverse event in the trial protocol because it was expected. Patient reported outcome, not based on scan measured residual volume
         subjects affected / exposed
    1 / 118 (0.85%)
    10 / 122 (8.20%)
         occurrences all number
    1
    10
    Need for intermittent self-catheterisation
    Additional description: Classified as a non-serious amendment in the study protocol because it was expected. Defined as the need to perform ISC to assist with voiding
         subjects affected / exposed
    4 / 118 (3.39%)
    18 / 122 (14.75%)
         occurrences all number
    4
    18
    Need for analgesia before discharge
         subjects affected / exposed
    22 / 118 (18.64%)
    21 / 122 (17.21%)
         occurrences all number
    22
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2005
    • New protocol version 1.1 • Reduce dosage from 300 units to 200 units. • Revised urinary retention rate of 17% • Appeal against decision not to allow CI to treat. • Request to contact not active patients directly. MREC approval granted 08/09/05 MHRA approval granted 12/12/05 R&D approval granted: 22/06/2006
    18 Nov 2005
    • New protocol version 1.2 • Primary outcome changed to change in frequency episodes from baseline to follow-up. • Sample size therefore reduced to 180. • Follow-up shortened, so primary outcome is 6 months. MREC approval granted 05/12/05 MHRA approval granted 05/01/06 R&D approval granted: 22/06/2006
    19 Dec 2005
    (Submitted electronically to MHRA after phone conversation with Mike Nicholls – effectively merged with amendment 2) • New protocol version 1.3 • Primary outcome changed to urinary frequency between groups at 6 months. • Sample size therefore increased to 240. MREC approval granted 03/02/06 MHRA approval granted 05/01/06 R&D approval granted: 22/06/2006
    04 Sep 2006
    • Addition of reminder letters to be sent to patients regarding six week and six month follow up visits. • DMEC charter MREC approval granted 24/10/06 following modification MHRA approval granted 07/09/07 R&D approval granted: 21/03/2007
    13 Oct 2006
    • Revised versions of information leaflet and consent form to allow administrator access to casenotes. MREC approval granted 31/10/06 MHRA approval granted 25/09/07 R&D approval granted: 21/03/2007
    07 Feb 2007
    • New protocol version 6.1 • Includes detailed plans for open label extension, and approval of Extension documents (Consent Form, PI Leaflet, new PI leaflet for main study, GP letter) MREC approval granted 19/03/07 following modification MHRA approval granted 07/09/07 R&D approval granted: 21/03/2007
    23 Mar 2007
    • Notification of intention to add additional centres to the trial MREC approval granted by date of each SSA approval: Wolverhampton 18/07/07 Ashford 14/08/07 Yeovil 30/08/07 MHRA approval granted 03/09/07
    20 Jun 2007
    • New protocol version 6.2 • Notification of change of personnel in trial office, and approval of advertising posters for centres and GP practices in catchment areas of recruiting hospitals. MREC approval for protocol (considered a NSA) granted 28/06/2007 MREC approval for amendment 9 granted 04/07/2007 MHRA approval granted 25/09/07 R&D approval granted: 05/10/2007
    02 Aug 2007
    • 3 month forms letter to be sent to a patient for their 3 month follow-up with a Form 5, Diary and Questionnaires MREC approval granted 05/09/07 MHRA approval granted 25/09/07 R&D approval granted: 11/10/2007
    14 Sep 2007
    • Notification of new safety data from the manufacturers, and updated SPC. • Copies of recent publications • New versions of PIL and consent (v1.9 12th September) • New investigator brochure v1.3 MREC approval granted: 11th December 2007 MHRA approval granted: 12th October 2007 R&D approval: 24th January 2008
    30 Jul 2008
    • Amendment of Form 7 (Form 7a) • Help sheet for Forms 5 and 7 • For MHRA only – send copies of SSI approvals for latest three collaborating centres MREC approval granted: 21st August 2008 MHRA approval granted: 20th August 2008 R&D approval: 14/11/2008
    29 Aug 2008
    • Updated protocol, version 6.3, dated 28th August 2008 MREC approval granted: 19th September 2008 MHRA approval granted: 15th September 2008 R&D approval: 14/11/2008
    29 Jul 2011
    RELAX Plus, qualitative sub-study; qualitative interviews with recruited patients to explore their lived experience of severe overactive bladder symptoms. Including: • Study protocol v 1.0 18th may 2011-06-20 • Interview consent form v 1.0 20th June 2011 • Patient information leaflet v 1.0 20th June 2011 • Research personnel CV & GCP • Invitation letter v 1.0 20th June 2011 • Reply slip v 1.0 20th June 2011 MREC approval granted: 26/08/2011 MHRA approval granted: 30/08/2011 R&D approval: 27/10/2011

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/22236796
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