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    Clinical Trial Results:
    A phase III, randomised, double blind and open label phase, active and placebo controlled study comparing the short term efficacy of two formulations of clostridium botulinum type A toxin (Dysport and Dysport NG) to placebo, and assessing the short and long term efficacy and safety of Dysport NG following repeated treatments of subjects with cervical dystonia (CD).

    Summary
    EudraCT number
    2010-019907-43
    Trial protocol
    PT   CZ   DE   BE   AT   HU  
    Global end of trial date
    04 Jun 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jun 2016
    First version publication date
    02 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Y-52-52120-134
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01261611
    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, Neurology., Ipsen Innovation, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Neurology., 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
    20 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 May 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary study objectives will be assessed in terms of improvement of the subject’s CD at a pre-defined time point after treatment. The primary study objectives are to demonstrate the superiority of Dysport NG to placebo in terms of efficacy and to test the non-inferior efficacy of Dysport NG, when compared to Dysport, in CD subjects. In addition to testing for the primary study objectives, the superiority in terms of efficacy of Dysport versus placebo, will be assessed.
    Protection of trial subjects
    This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    A large body of evidence demonstrates the safety and efficacy of Dysport across several clinical indications.This study was the first use of Dysport NG in humans with CD. The active substance (BTX-A-HAC) in Dysport NG was the same as in the currently marketed Dysport product and had the same mechanism of action. Dysport NG was, therefore, expected to have the same efficacy and safety profile in humans as Dysport, with the advantage of eliminating the potential risk of transmission of infective agents, by the substitution of plant and synthetic products for human and animal-derived products. However, due to the change of excipient, thorough assessment of the safety and efficacy of Dysport NG is necessary. Previous clinical studies indicate that the maximum effect of Dysport and maximum improvements in CD are observed approximately 4 weeks post treatment, after which there is a gradual return to baseline disease status. The Week 4 follow up visit after the first treatment cycle was therefore, chosen as the primary time point of interest. Retreatment is necessary in order to maintain the beneficial effect and the long term treatment of CD. Previously conducted long term studies demonstrate the maintenance of the therapeutic effect of Dysport following repeated treatments, with a favourable short and long term safety and immunogenicity profile.
    Actual start date of recruitment
    27 Apr 2011
    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
    Australia: 2
    Country: Number of subjects enrolled
    Russian Federation: 36
    Country: Number of subjects enrolled
    Ukraine: 62
    Country: Number of subjects enrolled
    Poland: 68
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Czech Republic: 58
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Hungary: 44
    Worldwide total number of subjects
    369
    EEA total number of subjects
    269
    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)
    328
    From 65 to 84 years
    40
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Patients recruited at 61 centres in Australia, Austria, Belgium, Czech Republic, France, Germany, Hungary, Poland, Portugal, Russia and Ukraine.

    Pre-assignment
    Screening details
    382 subjects screened, 369 randomised due to 13 screen failures.

    Period 1
    Period 1 title
    Treatment Cycle 1
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dysport NG
    Arm description
    Up to 5 treatment cycles of Dysport NG
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport NG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500U (1ml) administered as intramuscular injection on day 1 of treatment cycle 1.

    Arm title
    Dysport
    Arm description
    1 treatment cycle of Dysport
    Arm type
    Active comparator

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Dysport 500U (1ml) injected as intramuscular injection on day 1 of treatment cycle 1.

    Arm title
    Placebo
    Arm description
    1 treatment cycle of placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1ml administered as, intramuscular injection on day 1 of treatment cycle 1.

    Number of subjects in period 1
    Dysport NG Dysport Placebo
    Started
    156
    159
    54
    Completed
    152
    156
    52
    Not completed
    4
    3
    2
         Withdrawal by Subject
    3
    2
    -
         Protocol violation
    -
    -
    2
         Adverse event
    -
    1
    -
         Lost to follow-up
    1
    -
    -
    Period 2
    Period 2 title
    Treatment Cycle 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Dysport NG
    Arm description
    Up to 5 treatment cycles of Dysport NG
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport NG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500U (1ml) administered as intramuscular injection on day 1 of treatment cycle 2.

    Number of subjects in period 2 [1]
    Dysport NG
    Started
    359
    Completed
    346
    Not completed
    13
         Withdrawal by Subject
    4
         Completed study
    4
         Protocol Violations
    2
         Not otherwise specified
    2
         Adverse Events
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of 360 subjects who completed double blind period (Dysport NG / Dysport / Placebo arms) 359 subjects entered open label period (only one arm: Dysport NG). One subject was never retreated and then stayed at cycle 1 during all the study.
    Period 3
    Period 3 title
    Treatment Cycle 3
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Dysport NG
    Arm description
    Up to 5 treatment cycles of Dysport NG
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport NG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    250U (0.5ml), 500U (1ml) or 750U (1.5ml) administered as intramuscular injection on day 1 of treatment cycle 3.

    Number of subjects in period 3
    Dysport NG
    Started
    346
    Completed
    316
    Not completed
    30
         Withdrawal by Subject
    4
         Completed study
    24
         Adverse Events
    1
         Lost to Follow-up
    1
    Period 4
    Period 4 title
    Treatment Cycle 4
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Dysport NG
    Arm description
    Up to 5 treatment cycles of Dysport NG
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport NG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    250U (0.5ml), 500U (1ml), 750U (1.5ml) or 1000U (2ml) administered as intramuscular injection on day 1 of treatment cycle 4.

    Number of subjects in period 4
    Dysport NG
    Started
    316
    Completed
    220
    Not completed
    96
         Withdrawal by Subject
    3
         Completed study
    87
         Not otherwise specified
    3
         Adverse Events
    1
         Lost to Follow-up
    2
    Period 5
    Period 5 title
    Treatment Cycle 5
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Dysport NG
    Arm description
    Up to 5 treatment cycles of Dysport NG
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport NG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    250U (0.5ml), 500U (1ml), 750U (1.5ml) or 1000U (2ml) administered as intramuscular injection on day 1 of treatment cycle 5.

    Number of subjects in period 5
    Dysport NG
    Started
    220
    Completed
    217
    Not completed
    3
         Withdrawal by Subject
    1
         Adverse Events
    1
         Lost to Follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dysport NG
    Reporting group description
    Up to 5 treatment cycles of Dysport NG

    Reporting group title
    Dysport
    Reporting group description
    1 treatment cycle of Dysport

    Reporting group title
    Placebo
    Reporting group description
    1 treatment cycle of placebo.

    Reporting group values
    Dysport NG Dysport Placebo Total
    Number of subjects
    156 159 54 369
    Age categorical
    Units: Subjects
    Age continuous
    ITT population was all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered.
    Units: years
        arithmetic mean (standard deviation)
    51.6 ± 12.4 49.1 ± 12 49.7 ± 10.8 -
    Gender categorical
    ITT population
    Units: Subjects
        Female
    100 101 34 235
        Male
    56 58 20 134
    Race (NIH/OMB)
    ITT population
    Units: Subjects
        Asian
    0 0 1 1
        Black or African American
    0 1 1 2
        White
    154 154 49 357
        Unknown or Not Reported
    2 4 3 9
    Time since diagnosis of CD, years
    Units: years
        arithmetic mean (standard deviation)
    7.13 ± 7.95 6.88 ± 7.49 6.25 ± 7.31 -
    Baseline TWSTRS score
    Units: unit on scale
        arithmetic mean (standard deviation)
    44.56 ± 9.2 46.23 ± 8.82 47.02 ± 9.19 -

    End points

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    End points reporting groups
    Reporting group title
    Dysport NG
    Reporting group description
    Up to 5 treatment cycles of Dysport NG

    Reporting group title
    Dysport
    Reporting group description
    1 treatment cycle of Dysport

    Reporting group title
    Placebo
    Reporting group description
    1 treatment cycle of placebo.
    Reporting group title
    Dysport NG
    Reporting group description
    Up to 5 treatment cycles of Dysport NG
    Reporting group title
    Dysport NG
    Reporting group description
    Up to 5 treatment cycles of Dysport NG
    Reporting group title
    Dysport NG
    Reporting group description
    Up to 5 treatment cycles of Dysport NG
    Reporting group title
    Dysport NG
    Reporting group description
    Up to 5 treatment cycles of Dysport NG

    Subject analysis set title
    Dysport NG
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All doses

    Primary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score Following First Treatment Cycle

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    End point title
    Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score Following First Treatment Cycle
    End point description
    TWSTRS is comprised of three different components namely severity, disability and pain. There is an ordinal scale score and range for each component. Severity scores range from 0 (absence of severity) to 35 (maximum severity), Disability scores range from 0 (no disability) to 30 (maximum disability) and pain scores range from 0 (no pain) to 20 (maximum pain). TWSTRS total score is the sum of the 3 component scores ranging from 0 to a maximum of 85. Analysis based on number of subjects in the Intent to Treat (ITT) population.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    Dysport NG Dysport Placebo
    Number of subjects analysed
    156
    159
    54
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -12.46 (-14.3 to -10.62)
    -13.99 (-15.78 to -12.21)
    -3.93 (-6.74 to -1.12)
    Statistical analysis title
    LS mean difference - Dysport NG vs Placebo
    Comparison groups
    Dysport NG v Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    ANCOVA
    Confidence interval
    Notes
    [1] - An ANCOVA on the change from baseline with treatment, baseline TWSTRS total score, BTX status at baseline and pooled centre as explanatory variables had been performed.
    Statistical analysis title
    LS mean difference - Dysport vs Placebo
    Comparison groups
    Dysport v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.0001
    Method
    ANCOVA
    Confidence interval
    Notes
    [2] - An ANCOVA on the change from baseline with treatment, baseline TWSTRS total score, BTX status at baseline and pooled centre as explanatory variables had been performed.
    Statistical analysis title
    LS mean difference - Dysport NG vs Dysport
    Comparison groups
    Dysport NG v Dysport
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    Parameter type
    LS mean difference
    Point estimate
    1.532
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.819
         upper limit
    3.883
    Notes
    [3] - An ANCOVA on the change from baseline with treatment, baseline TWSTRS total score, BTX status at baseline and pooled centre as explanatory variables had been performed. The non-inferiority margin was 3 points.

    Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Following First Treatment Cycle

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    End point title
    Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Following First Treatment Cycle
    End point description
    TWSTRS Severity scores range from 0 (absence of severity) to 35 (maximum severity). Analysis based on number of subjects in the Intent to Treat (ITT) population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Dysport NG Dysport Placebo
    Number of subjects analysed
    156
    159
    54
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -6.2 (-7 to -5.4)
    -6.6 (-7.3 to -5.8)
    -1.9 (-3.1 to -0.6)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Subscale Score Following First Treatment Cycle

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    End point title
    Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Subscale Score Following First Treatment Cycle
    End point description
    TWSTRS Disability scores range from 0 (no disability) to 30 (maximum disability). Analysis based on number of subjects in the Intent to Treat (ITT) population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Dysport NG Dysport Placebo
    Number of subjects analysed
    156
    159
    54
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -3.3 (-4.1 to -2.6)
    -3.9 (-4.7 to -3.2)
    -0.8 (-1.9 to 0.4)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score Following First Treatment Cycle

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    End point title
    Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score Following First Treatment Cycle
    End point description
    TWSTRS Pain scores range from 0 (no pain) to 20 (maximum pain).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Dysport NG Dysport Placebo
    Number of subjects analysed
    156
    159
    54
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -3.1 (-3.7 to -2.51)
    -3.44 (-4.03 to -2.86)
    -1.21 (-2.12 to -0.29)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia Following First Treatment Cycle

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    End point title
    Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia Following First Treatment Cycle
    End point description
    The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no pain) to 100 mm (worst possible pain). Analysis based on number of subjects in the Intent to Treat (ITT) population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Dysport NG Dysport Placebo
    Number of subjects analysed
    156
    159
    54
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -14.8 (-19 to -10.7)
    -19.2 (-23.3 to -15.2)
    -3.4 (-9.8 to 3)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia Following First Treatment Cycle

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    End point title
    Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia Following First Treatment Cycle
    End point description
    The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no symptoms) to 100mm (worst possible symptoms). Analysis based on number of subjects in the Intent to Treat (ITT) population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Dysport NG Dysport Placebo
    Number of subjects analysed
    156
    159
    54
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -18.7 (-22.7 to -14.7)
    -23.6 (-27.5 to -19.7)
    -3.3 (-9.4 to 2.8)
    No statistical analyses for this end point

    Secondary: Percentage of Treatment Responders Following First Treatment Cycle

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    End point title
    Percentage of Treatment Responders Following First Treatment Cycle
    End point description
    Analysis based on number of subjects in the Intent to Treat (ITT) population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Dysport NG Dysport Placebo
    Number of subjects analysed
    156
    156
    54
    Units: percentage of participants
        number (not applicable)
    45.8
    55.8
    20.8
    No statistical analyses for this end point

    Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score for Treatment Cycles 2 to 5

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    End point title
    Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score for Treatment Cycles 2 to 5
    End point description
    The change in TWSTRS total score is the score at week 4 minus the score at baseline. Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.
    End point type
    Secondary
    End point timeframe
    Treatment cycle Baseline and Week 4
    End point values
    Dysport NG
    Number of subjects analysed
    359
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Cycle 2 (n=359)
    -15.35 (-16.36 to -14.34)
        Cycle 3 (n=346)
    -14.85 (-15.86 to -13.84)
        Cycle 4 (n=316)
    -15.58 (-16.61 to -14.55)
        Cycle 5 (n=220)
    -15.28 (-16.42 to -14.14)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Score for Treatment Cycles 2 to 5

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    End point title
    Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Score for Treatment Cycles 2 to 5
    End point description
    TWSTRS Severity scores range from 0 (absence of severity) to 35 (maximum severity). Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.
    End point type
    Secondary
    End point timeframe
    Treatment cycle Baseline and Week 4
    End point values
    Dysport NG
    Number of subjects analysed
    349
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Cycle 2 (n=359)
    -7.2 (-7.6 to -6.7)
        Cycle 3 (n=346)
    -7.1 (-7.5 to -6.6)
        Cycle 4 (n=316)
    -7.3 (-7.7 to -6.8)
        Cycle 5 (n=220)
    -7 (-7.5 to -6.4)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Score for Treatment Cycles 2 to 5

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    End point title
    Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Score for Treatment Cycles 2 to 5
    End point description
    TWSTRS Disability scores range from 0 (no disability) to 30 (maximum disability). Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.
    End point type
    Secondary
    End point timeframe
    Treatment cycle Baseline and Week 4
    End point values
    Dysport NG
    Number of subjects analysed
    359
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Cycle 2 (n=359)
    -4.7 (-5.2 to -4.3)
        Cycle 3 (n=346)
    -4.6 (-5 to -4.1)
        Cycle 4 (n=316)
    -5 (-5.5 to -4.5)
        Cycle 5 (n=220)
    -4.9 (-5.5 to -4.3)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score for Treatment Cycles 2 to 5

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    End point title
    Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score for Treatment Cycles 2 to 5
    End point description
    TWSTRS Pain scores range from 0 (no pain) to 20 (maximum pain). Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.
    End point type
    Secondary
    End point timeframe
    Treatment cycle Baseline and Week 4
    End point values
    Dysport NG
    Number of subjects analysed
    359
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Cycle 2 (n=359)
    -3.45 (-3.8 to -3.1)
        Cycle 3 (n=346)
    -3.21 (-3.57 to -2.85)
        Cycle 4 (n=316)
    -3.34 (-3.69 to -2.98)
        Cycle 5 (n=220)
    -3.41 (-3.79 to -3.04)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia for Treatment Cycles 2 to 5

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    End point title
    Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia for Treatment Cycles 2 to 5
    End point description
    The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no pain) to 100 mm (worst possible pain).
    End point type
    Secondary
    End point timeframe
    Treatment cycle Baseline and Week 4
    End point values
    Dysport NG
    Number of subjects analysed
    359
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Cycle 2 (n=359)
    -20.1 (-22.5 to -17.6)
        Cycle 3 (n=346)
    -17.8 (-20.4 to -15.2)
        Cycle 4 (n=316)
    -18 (-20.5 to -15.4)
        Cycle 5 (n=220)
    -16.1 (-19.3 to -12.8)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia for Treatment Cycles 2 to 5

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    End point title
    Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia for Treatment Cycles 2 to 5
    End point description
    The assessment was made on a continuous 100-mm horizontal line with a scale of 0 mm (no symptoms) to 100 mm (worst possible symptoms). Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.
    End point type
    Secondary
    End point timeframe
    Treatment cycle Baseline and Week 4
    End point values
    Dysport NG
    Number of subjects analysed
    359
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Cycle 2 (n=359)
    -24 (-26.4 to -21.7)
        Cycle 3 (n=346)
    -18.9 (-21.4 to -16.4)
        Cycle 4 (n=316)
    -21 (-23.5 to -18.5)
        Cycle 5 (n=220)
    -18.2 (-21.2 to -15.2)
    No statistical analyses for this end point

    Secondary: Percentage of Treatment Responders for Treatment Cycles 2 to 5

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    End point title
    Percentage of Treatment Responders for Treatment Cycles 2 to 5
    End point description
    Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.
    End point type
    Secondary
    End point timeframe
    Treatment cycle Baseline and Week 4
    End point values
    Dysport NG
    Number of subjects analysed
    359
    Units: percentage of participants
    number (not applicable)
        Cycle 2 (n=359)
    58.5
        Cycle 3 (n=346)
    56.8
        Cycle 4 (n=316)
    63.5
        Cycle 5 (n=220)
    57.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    2 years
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Dysport NG, 250 U
    Reporting group description
    -

    Reporting group title
    Dysport NG, 500 U
    Reporting group description
    -

    Reporting group title
    Dysport NG, 750 U
    Reporting group description
    -

    Reporting group title
    Dysport NG, 1000 U
    Reporting group description
    -

    Reporting group title
    Dysport, 500 U
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Dysport NG, 250 U Dysport NG, 500 U Dysport NG, 750 U Dysport NG, 1000 U Dysport, 500 U Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    16 / 363 (4.41%)
    3 / 210 (1.43%)
    1 / 57 (1.75%)
    3 / 156 (1.92%)
    0 / 55 (0.00%)
         number of deaths (all causes)
    0
    2
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    2
    0
    0
    0
    0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    1 / 210 (0.48%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paget-Schroetter syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    1 / 156 (0.64%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    1 / 156 (0.64%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion malignant
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    1 / 156 (0.64%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    1 / 210 (0.48%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    0 / 210 (0.00%)
    1 / 57 (1.75%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    0 / 210 (0.00%)
    1 / 57 (1.75%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    1 / 210 (0.48%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    1 / 156 (0.64%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroid cyst
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Proctitis infectious
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal abscess
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 363 (0.28%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 363 (0.00%)
    0 / 210 (0.00%)
    0 / 57 (0.00%)
    1 / 156 (0.64%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Dysport NG, 250 U Dysport NG, 500 U Dysport NG, 750 U Dysport NG, 1000 U Dysport, 500 U Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    59 / 363 (16.25%)
    29 / 210 (13.81%)
    7 / 57 (12.28%)
    15 / 156 (9.62%)
    1 / 55 (1.82%)
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    38 / 363 (10.47%)
    20 / 210 (9.52%)
    5 / 57 (8.77%)
    11 / 156 (7.05%)
    0 / 55 (0.00%)
         occurrences all number
    0
    54
    25
    5
    11
    0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 4 (25.00%)
    11 / 363 (3.03%)
    13 / 210 (6.19%)
    6 / 57 (10.53%)
    0 / 156 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    1
    15
    14
    6
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    21 / 363 (5.79%)
    9 / 210 (4.29%)
    2 / 57 (3.51%)
    4 / 156 (2.56%)
    1 / 55 (1.82%)
         occurrences all number
    0
    26
    9
    2
    4
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2012
    Protocol Amendment 5 (Substantial): The protocol was amended to update the contact information for the Sponsor’s Medical and Clinical contacts, remove the pharmacovigilance/emergency contact details from the US, to replace Ipsen Pharma with Kymos Pharma as a CRO for processing binding antibody samples and ensure consistency across all studies with regard to the IB used for assessment of expectedness.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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