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    Clinical Trial Results:
    A Phase III, Multicentre, Double Blind, Prospective, Randomised, Controlled, Multiple Treatment Study Assessing Efficacy and Safety of Dysport Used in the Treatment of Upper Limb Spasticity in Children

    Summary
    EudraCT number
    2010-021817-22
    Trial protocol
    CZ   ES   PL   BE   Outside EU/EEA  
    Global end of trial date
    04 Sep 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    13 Jun 2020
    First version publication date
    25 May 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Paediatric regulatory detail data correction

    Trial information

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    Trial identification
    Sponsor protocol code
    Y-52-52120-153
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02106351
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ipsen Innovation
    Sponsor organisation address
    Z.I. de Courtaboeuf, 5 Avenue du Canada, Cedex, France, 91940 Les Ulis
    Public contact
    Medical Director, Ipsen, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main study objective was to assess the efficacy and safety of 2 doses of Dysport (8 Units per kilogram [U/kg] and 16 U/kg) administered by intramuscular (IM) injection compared to Dysport 2 U/kg (low dose control group) used in the treatment of upper limb spasticity in children.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki in accordance with the International Conference on Harmonisation Guideline on Good Clinical Practice and in compliance with independent ethics committees/institutional review boards and informed consent regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Apr 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Turkey: 44
    Country: Number of subjects enrolled
    United States: 63
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Mexico: 24
    Country: Number of subjects enrolled
    Poland: 37
    Worldwide total number of subjects
    210
    EEA total number of subjects
    56
    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)
    143
    Adolescents (12-17 years)
    67
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Male and female subjects aged between 2 and 17 years with upper limb spasticity due to cerebral palsy (CP) were recruited from April 2014 and the study completed in September 2018. Subjects could receive a maximum of 4 treatment cycles (TC) over a minimum of 1 year and maximum of 1 year and 9 months, with at least 16 weeks between each TC.

    Pre-assignment
    Screening details
    Subjects had a body weight ≥10 kg, increased muscle tone/spasticity in at least 1 upper limb, a modified Ashworth scale (MAS) score ≥2 in the upper limb primary targeted muscle group (PTMG) of the study limb at baseline. Subjects were stratified according to age (2-9 and 10-17 years) and Botulinum Toxin (BTX) naïve or non-naïve status.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dysport 2 U/kg
    Arm description
    Subjects were randomised to receive 2 U/kg Dysport by IM injection in the study upper limb in TC 1 and Dysport 8 U/kg or 16 U/kg in subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Arm type
    Control arm

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Clostridium BTX-A-HAC, AbobotulinumtoxinA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 2 U/kg Dysport by IM injection divided between the PTMG elbow and wrist flexors and other non-PTMG muscles in the study limb.

    Arm title
    Dysport 8 U/kg
    Arm description
    Subjects were randomised to receive Dysport 8 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Clostridium BTX-A-HAC, AbobotulinumtoxinA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 8 U/kg Dysport by IM injection divided between the PTMG elbow and wrist flexors and other non-PTMG muscles in the study limb, up to maximum dose of 320 U.

    Arm title
    Dysport 16 U/kg
    Arm description
    Subjects were randomised to receive Dysport 16 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Clostridium BTX-A-HAC, AbobotulinumtoxinA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 16 U/kg Dysport by IM injection divided between the PTMG elbow and wrist flexors and other non-PTMG muscles in the study limb, up to maximum dose of 640 U.

    Number of subjects in period 1
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Started
    70
    70
    70
    Completed
    66
    67
    67
    Not completed
    4
    3
    3
         Not specified
    -
    3
    1
         Adverse event, non-fatal
    2
    -
    -
         Consent withdrawn by subject
    1
    -
    2
         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
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Dysport 8 U/kg
    Arm description
    Subjects were randomised to receive Dysport 8 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Clostridium BTX-A-HAC, AbobotulinumtoxinA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 8 U/kg Dysport by IM injection divided between the PTMG elbow and wrist flexors and other non-PTMG muscles in the study limb, up to maximum dose of 320 U.

    Arm title
    Dysport 16 U/kg
    Arm description
    Subjects were randomised to receive Dysport 16 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Clostridium BTX-A-HAC, AbobotulinumtoxinA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 16 U/kg Dysport by IM injection divided between the PTMG elbow and wrist flexors and other non-PTMG muscles in the study limb, up to maximum dose of 640 U.

    Number of subjects in period 2
    Dysport 8 U/kg Dysport 16 U/kg
    Started
    88
    90
    Completed
    83
    87
    Not completed
    5
    3
         Not specified
    2
    2
         Adverse event, non-fatal
    2
    -
         Consent withdrawn by subject
    1
    1
    Period 3
    Period 3 title
    Treatment Cycle 3
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dysport 8 U/kg
    Arm description
    Subjects were randomised to receive Dysport 8 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Clostridium BTX-A-HAC, AbobotulinumtoxinA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 8 U/kg Dysport by IM injection divided between the PTMG elbow and wrist flexors and other non-PTMG muscles in the study limb, up to maximum dose of 320 U.

    Arm title
    Dysport 16 U/kg
    Arm description
    Subjects were randomised to receive Dysport 16 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Clostridium BTX-A-HAC, AbobotulinumtoxinA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 16 U/kg Dysport by IM injection divided between the PTMG elbow and wrist flexors and other non-PTMG muscles in the study limb, up to maximum dose of 640 U.

    Number of subjects in period 3
    Dysport 8 U/kg Dysport 16 U/kg
    Started
    49
    58
    Completed
    45
    53
    Not completed
    4
    5
         Not specified
    2
    3
         Adverse event, non-fatal
    1
    -
         Consent withdrawn by subject
    -
    2
         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
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dysport 8 U/kg
    Arm description
    Subjects were randomised to receive Dysport 8 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Clostridium BTX-A-HAC, AbobotulinumtoxinA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 8 U/kg Dysport by IM injection divided between the PTMG elbow and wrist flexors and other non-PTMG muscles in the study limb, up to maximum dose of 320 U.

    Arm title
    Dysport 16 U/kg
    Arm description
    Subjects were randomised to receive Dysport 16 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Arm type
    Experimental

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Clostridium BTX-A-HAC, AbobotulinumtoxinA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 16 U/kg Dysport by IM injection divided between the PTMG elbow and wrist flexors and other non-PTMG muscles in the study limb, up to maximum dose of 640 U.

    Number of subjects in period 4 [1]
    Dysport 8 U/kg Dysport 16 U/kg
    Started
    22
    33
    Completed
    21
    31
    Not completed
    1
    2
         Not specified
    1
    -
         Consent withdrawn by subject
    -
    2
    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: Not all subjects who received treatment in TC 3 required retreatment in TC 4.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dysport 2 U/kg
    Reporting group description
    Subjects were randomised to receive 2 U/kg Dysport by IM injection in the study upper limb in TC 1 and Dysport 8 U/kg or 16 U/kg in subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.

    Reporting group title
    Dysport 8 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 8 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.

    Reporting group title
    Dysport 16 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 16 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.

    Reporting group values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg Total
    Number of subjects
    70 70 70 210
    Age categorical
    Units: Subjects
        2 - 9 Years
    40 40 40 120
        10 - 17 Years
    30 30 30 90
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.91 ± 4.55 8.97 ± 4.27 9.17 ± 4.30 -
    Gender categorical
    Units: Subjects
        Female
    32 24 28 84
        Male
    38 46 42 126
    Race, Customised
    Units: Subjects
        Asian
    2 1 0 3
        Black or African American
    7 6 3 16
        White
    49 54 54 157
        American Indian or Alaska Native
    0 1 0 1
        Multiple
    12 8 13 33
    Ethnicity, Customised
    Units: Subjects
        Hispanic or Latino
    16 13 15 44
        Not Hispanic or Latino
    54 57 55 166
    BTX Status
    Units: Subjects
        BTX naïve
    25 23 24 72
        BTX non-naïve
    45 47 46 138
    Baseline MAS Score in the PTMG
    The MAS has 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch + release or by minimal resistance at the end of the range of motion [ROM]) when the affected part is moved in flexion/extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion/extension). '1+' was given a derived score of '2'; following scores were incremented by 1.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    3.1 ± 0.3 3.1 ± 0.3 3.1 ± 0.5 -

    End points

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    End points reporting groups
    Reporting group title
    Dysport 2 U/kg
    Reporting group description
    Subjects were randomised to receive 2 U/kg Dysport by IM injection in the study upper limb in TC 1 and Dysport 8 U/kg or 16 U/kg in subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.

    Reporting group title
    Dysport 8 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 8 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.

    Reporting group title
    Dysport 16 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 16 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Reporting group title
    Dysport 8 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 8 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.

    Reporting group title
    Dysport 16 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 16 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Reporting group title
    Dysport 8 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 8 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.

    Reporting group title
    Dysport 16 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 16 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.
    Reporting group title
    Dysport 8 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 8 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.

    Reporting group title
    Dysport 16 U/kg
    Reporting group description
    Subjects were randomised to receive Dysport 16 U/kg by IM injection into the study upper limb in TC 1 and all subsequent TCs (2, 3 and 4). Retreatment was based on clinical need with a minimum retreatment interval of 16 weeks. From TC 2 onwards dose adaptation was permitted as well as treatment of the non-study upper limb and lower limbs.

    Primary: Mean Change from Baseline to TC 1, Week 6 in MAS Score in the TC 1 PTMG

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    End point title
    Mean Change from Baseline to TC 1, Week 6 in MAS Score in the TC 1 PTMG
    End point description
    The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone.
    End point type
    Primary
    End point timeframe
    Baseline (TC 1, Day 1) and TC 1, Week 6.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    69
    69
    70
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.5 ± 1.1
    -1.9 ± 1.0
    -2.2 ± 0.9
    Statistical analysis title
    Dysport 8 U/kg vs Dysport 2 U/kg
    Statistical analysis description
    The treatment difference between Dysport 8 U/kg and Dysport 2 U/kg was analysed using an analysis of covariance (ANCOVA) on the ranked changes from baseline. The model included treatment group, the baseline value, the 2 stratification factors (age range and BTX status at baseline) and the pooled centre as fixed effects. The derived least squares (LS) means were back transformed to the original scale and the treatment difference determined.
    Comparison groups
    Dysport 2 U/kg v Dysport 8 U/kg
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0118 [1]
    Method
    ANCOVA
    Confidence interval
    Notes
    [1] - ANCOVA is performed on the ranked values. The 2-tailed significance level was 0.05. LS mean difference, back transformed = -0.4
    Statistical analysis title
    Dysport 16 U/kg vs Dysport 2 U/kg
    Statistical analysis description
    The treatment difference between Dysport 16 U/kg and Dysport 2 U/kg was analysed using an ANCOVA on the ranked changes from baseline. The model included treatment group, the baseline value, the 2 stratification factors (age range and BTX status at baseline) and the pooled centre as fixed effects. The derived LS means were back transformed to the original scale and the treatment difference determined.
    Comparison groups
    Dysport 2 U/kg v Dysport 16 U/kg
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Confidence interval
    Notes
    [2] - ANCOVA is performed on the ranked values. The 2-tailed significance level was 0.05. LS mean difference, back-transformed = -0.7

    Secondary: Mean Physician's Global Assessment (PGA) Score at TC 1, Week 6

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    End point title
    Mean Physician's Global Assessment (PGA) Score at TC 1, Week 6
    End point description
    The PGA of treatment response was assessed by asking the investigator the following question: 'How would you rate the response to treatment in the subject's upper limb since the start of the study?'. Answers were on a 9-point rating scale (-4: markedly worse, -3: much worse, -2: worse, -1: slightly worse, 0: no change, +1: slightly improved, +2: improved, +3: much improved and +4: markedly improved). The mean scores for each treatment group at TC 1, Week 6 are presented. Data is presented for the mITT population.
    End point type
    Secondary
    End point timeframe
    TC 1, Week 6.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    68
    69
    70
    Units: score on a scale
        arithmetic mean (standard deviation)
    1.7 ± 0.9
    2.0 ± 0.9
    2.0 ± 0.9
    Statistical analysis title
    Dysport 2 U/kg vs Dysport 8 U/kg
    Statistical analysis description
    The treatment difference between Dysport 8 U/kg and Dysport 2 U/kg was analysed using an analysis of variance (ANOVA) on the rank of the PGA score at TC 1, Week 6. The model included treatment group, the 2 stratification factors (age range and BTX status at baseline) and the centre as fixed effects. The derived LS means were back transformed to the original scale and the treatment difference determined.
    Comparison groups
    Dysport 2 U/kg v Dysport 8 U/kg
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2043 [3]
    Method
    ANOVA
    Confidence interval
    Notes
    [3] - ANOVA was performed on the ranked values. The 2-tailed significance level was 0.05. LS mean difference, back transformed = 0.2.
    Statistical analysis title
    Dysport 2 U/kg vs Dysport 16 U/kg
    Statistical analysis description
    The treatment difference between Dysport 16 U/kg and Dysport 2 U/kg was analysed using an ANOVA on the rank of the PGA score at TC 1, Week 6. The model included treatment group, the 2 stratification factors (age range and BTX status at baseline) and the centre as fixed effects. The derived LS means were back transformed to the original scale and the treatment difference determined.
    Comparison groups
    Dysport 16 U/kg v Dysport 2 U/kg
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.188 [4]
    Method
    ANOVA
    Confidence interval
    Notes
    [4] - ANOVA was performed on ranked values. The 2-tailed significance level was 0.05. LS mean difference, back transformed = 0.2.

    Secondary: Mean Goal Attainment Scale (GAS) Total Score at TC 1, Week 6

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    End point title
    Mean Goal Attainment Scale (GAS) Total Score at TC 1, Week 6
    End point description
    The GAS is a functional 5-point scale used to measure progress towards individual therapy goals. At the start of each TC, 1 to 3 individual goals were defined for each subject by the investigator and the child's parents/guardians/caregivers prior to treatment. The outcome to reach each goal was rated on a 5-point scale (-2: much less than expected outcome, -1: somewhat less than expected outcome, 0: expected outcome, 1+: somewhat more than expected outcome, 2+: much more than expected outcome). A total GAS score was calculated taking into account the post-baseline outcome of each goal as well as the importance and difficulty of the goals and transformed into a standardised measure (T score). Therefore a score of 50 indicates that all individual goals had the expected outcome.
    End point type
    Secondary
    End point timeframe
    TC 1, Week 6.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    68
    66
    70
    Units: score on a scale
        arithmetic mean (standard deviation)
    51.3 ± 9.9
    52.6 ± 10.1
    52.0 ± 9.6
    Statistical analysis title
    Dysport 2 U/kg vs Dysport 8 U/kg
    Statistical analysis description
    The treatment difference between Dysport 8 U/kg and Dysport 2 U/kg was analysed using ANOVA on the GAS Total score at TC 1, Week 6. The model included treatment group, the 2 stratification factors (age range and BTX status at baseline) and the centre as fixed effects.
    Comparison groups
    Dysport 2 U/kg v Dysport 8 U/kg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7648 [5]
    Method
    ANOVA
    Parameter type
    LS mean difference
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.7
         upper limit
    3.7
    Notes
    [5] - The 2-tailed significance level was 0.05.
    Statistical analysis title
    Dysport 2 U/kg vs Dysport 16 U/kg
    Statistical analysis description
    The treatment difference between Dysport 16 U/kg and Dysport 2 U/kg was analysed using ANOVA on the GAS Total score at TC 1, Week 6. The model included treatment group, the 2 stratification factors (age range and BTX status at baseline) and the centre as fixed effects.
    Comparison groups
    Dysport 2 U/kg v Dysport 16 U/kg
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7429
    Method
    ANOVA
    Parameter type
    LS mean difference
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.6
         upper limit
    3.7

    Other pre-specified: Mean Change from Baseline to TC 1 Week 16 in MAS score in the TC 1 PTMG

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    End point title
    Mean Change from Baseline to TC 1 Week 16 in MAS score in the TC 1 PTMG
    End point description
    The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone. Data is presented for the mITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (TC 1, Day 1) and TC 1, Week 16.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    68
    68
    68
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.0 ± 1.0
    -1.4 ± 1.1
    -1.6 ± 1.2
    No statistical analyses for this end point

    Other pre-specified: Mean Change from Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Elbow Flexors of the Study Limb

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    End point title
    Mean Change from Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Elbow Flexors of the Study Limb
    End point description
    The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone. Data is presented for subjects injected in the elbow flexors. n= number of subjects analysed at each timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (TC 1, Day 1) and TC 1, Weeks 6 and 16.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    69
    69
    70
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 6 n=63, 63, 62
    -1.0 ± 1.1
    -1.7 ± 1.1
    -1.9 ± 1.2
        Week 16 n= 62, 62, 60
    -0.6 ± 1.0
    -1.2 ± 1.2
    -1.3 ± 1.4
    No statistical analyses for this end point

    Other pre-specified: Mean Change from Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Wrist Flexors of the Study Limb

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    End point title
    Mean Change from Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Wrist Flexors of the Study Limb
    End point description
    The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone. Data is presented for subjects injected in the wrist flexors. n= number of subjects analysed at each timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (TC 1, Day 1) and TC 1, Weeks 6 and 16.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    69
    69
    70
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 6 n=50, 53, 61
    -1.3 ± 1.1
    -1.5 ± 1.2
    -1.7 ± 1.3
        Week 16 n=50, 53, 59
    -0.9 ± 1.2
    -1.0 ± 1.2
    -1.3 ± 1.2
    No statistical analyses for this end point

    Other pre-specified: Mean Change from Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Finger Flexors of the Study Limb

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    End point title
    Mean Change from Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Finger Flexors of the Study Limb
    End point description
    The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone. Data is presented for subjects injected in the finger flexors. n= number of subjects analysed at each timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (TC 1, Day 1) and TC 1, Weeks 6 and 16.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    69
    69
    70
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 6 n=23, 23, 19
    -0.8 ± 0.9
    -1.8 ± 1.1
    -1.9 ± 1.0
        Week 16 n=22, 23, 19
    -0.8 ± 1.3
    -1.3 ± 0.8
    -1.8 ± 1.0
    No statistical analyses for this end point

    Other pre-specified: Mean PGA Score at TC 1 Week 16

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    End point title
    Mean PGA Score at TC 1 Week 16
    End point description
    The PGA of treatment response was assessed by asking the investigator the following question: 'How would you rate the response to treatment in the subject's upper limb since the start of the study?'. Answers were on a 9-point rating scale (-4: markedly worse, -3: much worse, -2: worse, -1: slightly worse, 0: no change, +1: slightly improved, +2: improved, +3: much improved and +4: markedly improved). The mean scores for each treatment group at TC 1 Week 16 are presented. n= number of subjects analysed at each timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (TC 1, Day 1) and TC 1, Week 16.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    69
    69
    70
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 16 n=68, 67, 68
    1.7 ± 1.0
    1.6 ± 1.1
    1.9 ± 1.2
    No statistical analyses for this end point

    Other pre-specified: Mean GAS Total Score at TC 1 Week 16

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    End point title
    Mean GAS Total Score at TC 1 Week 16
    End point description
    The GAS is a functional scale used to measure progress towards individual therapy goals. At the start of each TC, 1 to 3 individual goals were defined for each subject prior to treatment. The outcome to reach each goal was rated on a 5-point scale (-2: much less than expected outcome, -1: somewhat less than expected outcome, 0: expected outcome, 1: somewhat more than expected outcome, 2: much more than expected outcome). A total GAS score was calculated taking into account the post-baseline outcome of each goal as well as the importance and difficulty of the goals and transformed into a standardised measure (T score). Therefore a score of 50 indicates that all individual goals had the expected outcome. The mean GAS scores at TC 1 Week 16 are presented. n= number of subjects analysed at each timepoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (TC 1, Day 1) and TC 1, Week 16.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    69
    69
    70
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 16 n=66, 67, 69
    54.7 ± 9.8
    54.2 ± 9.7
    55.1 ± 10.1
    No statistical analyses for this end point

    Other pre-specified: Mean Change from Baseline to TC 1, Week 16 in the Paediatric Quality of Life (PedsQL) Scores

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    End point title
    Mean Change from Baseline to TC 1, Week 16 in the Paediatric Quality of Life (PedsQL) Scores
    End point description
    Parents/guardians completed questionnaires on their child's quality of life. The PedsQL parent inventory measured heathcare concepts for children/adolescents aged 2-18 years. The Generic Core Scales include physical, emotional, social and school aspects. The CP module was also completed. Scores were transformed on a scale from 0 to 100 with higher scores indicating a better quality of life. Mean changes from baseline to TC 1, Week 16 are presented for the General Core Scale and for the CP module. A positive change from baseline indicates an improvement in quality of life. n= number of subjects analysed.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (TC 1, Day 1) and TC 1, Week 16.
    End point values
    Dysport 2 U/kg Dysport 8 U/kg Dysport 16 U/kg
    Number of subjects analysed
    69
    69
    70
    Units: score on a scale
    arithmetic mean (standard deviation)
        Generic Core Scale n=67, 67, 67
    3.4 ± 9.7
    3.4 ± 17.1
    2.0 ± 12.0
        CP Module n=64, 64, 65
    4.8 ± 16.8
    2.1 ± 14.9
    2.8 ± 16.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events (TEAEs) were collected from the first injection of study treatment up to the end of TC 4 (up to 21 months).
    Adverse event reporting additional description
    TEAEs are reported for the dose received prior to onset of the AE. Due to dose adaptation due to safety lower doses were permitted for TCs 2 - 4.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    TC1: Dysport 2 U/kg
    Reporting group description
    Subjects randomised to Dysport 2 U/kg in TC 1.

    Reporting group title
    TC 1: Dysport 8 U/kg
    Reporting group description
    Subjects randomised to Dysport 8 U/kg in TC 1.

    Reporting group title
    TC 1: Dysport 16 U/kg
    Reporting group description
    Subjects randomised to Dysport 16 U/kg in TC 1.

    Reporting group title
    TC 2: Dysport 8 U/kg
    Reporting group description
    Subjects who received Dysport 8 U/kg in TC 2.

    Reporting group title
    TC 2: Dysport 16 U/kg
    Reporting group description
    Subjects who received Dysport 16 U/kg in TC 2.

    Reporting group title
    TC 3: Dysport 8 U/kg
    Reporting group description
    Subjects who received Dysport 8 U/kg in TC 3.

    Reporting group title
    TC 3: Dysport 16 U/kg
    Reporting group description
    Subjects who received Dysport 16 U/kg in TC 3.

    Reporting group title
    TC 4: Dysport 8 U/kg
    Reporting group description
    Subjects who received Dysport 8 U/kg in TC 4.

    Reporting group title
    TC 4: Dysport 16 U/kg
    Reporting group description
    Subjects who received Dysport 16 U/kg in TC 4.

    Serious adverse events
    TC1: Dysport 2 U/kg TC 1: Dysport 8 U/kg TC 1: Dysport 16 U/kg TC 2: Dysport 8 U/kg TC 2: Dysport 16 U/kg TC 3: Dysport 8 U/kg TC 3: Dysport 16 U/kg TC 4: Dysport 8 U/kg TC 4: Dysport 16 U/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 70 (5.71%)
    2 / 70 (2.86%)
    2 / 70 (2.86%)
    6 / 88 (6.82%)
    1 / 90 (1.11%)
    3 / 49 (6.12%)
    2 / 58 (3.45%)
    2 / 22 (9.09%)
    1 / 33 (3.03%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical device removal
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    1 / 49 (2.04%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Muscle release
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    1 / 49 (2.04%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Ostectomy
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    1 / 49 (2.04%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Radiotherapy to bone
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    1 / 49 (2.04%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Scoliosis surgery
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram ST segment elevation
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Testicular malignant teratoma
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    1 / 90 (1.11%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    2 / 88 (2.27%)
    0 / 90 (0.00%)
    1 / 49 (2.04%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 70 (1.43%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    2 / 58 (3.45%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 70 (1.43%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cerebral ventricle dilatation
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    1 / 58 (1.72%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    1 / 49 (2.04%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    TC1: Dysport 2 U/kg TC 1: Dysport 8 U/kg TC 1: Dysport 16 U/kg TC 2: Dysport 8 U/kg TC 2: Dysport 16 U/kg TC 3: Dysport 8 U/kg TC 3: Dysport 16 U/kg TC 4: Dysport 8 U/kg TC 4: Dysport 16 U/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 70 (21.43%)
    23 / 70 (32.86%)
    19 / 70 (27.14%)
    18 / 88 (20.45%)
    17 / 90 (18.89%)
    14 / 49 (28.57%)
    10 / 58 (17.24%)
    14 / 22 (63.64%)
    5 / 33 (15.15%)
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 70 (5.71%)
    2 / 70 (2.86%)
    7 / 88 (7.95%)
    1 / 90 (1.11%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    2
    5
    2
    8
    1
    0
    0
    1
    0
    Injection site bruising
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injection site rash
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Anaemia postoperative
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Postoperative ileus
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Contusion
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 70 (0.00%)
    5 / 70 (7.14%)
    1 / 70 (1.43%)
    1 / 88 (1.14%)
    1 / 90 (1.11%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    6
    1
    1
    1
    0
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 70 (0.00%)
    4 / 70 (5.71%)
    2 / 70 (2.86%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    6
    2
    0
    0
    0
    0
    0
    0
    Epilepsy
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    3 / 49 (6.12%)
    2 / 58 (3.45%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    3
    0
    0
    Nausea
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Dental caries
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash erythematous
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 70 (4.29%)
    4 / 70 (5.71%)
    0 / 88 (0.00%)
    5 / 90 (5.56%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    3
    4
    0
    5
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    10 / 70 (14.29%)
    6 / 70 (8.57%)
    6 / 70 (8.57%)
    7 / 88 (7.95%)
    6 / 90 (6.67%)
    6 / 49 (12.24%)
    5 / 58 (8.62%)
    0 / 22 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    13
    7
    7
    8
    6
    9
    8
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 70 (7.14%)
    6 / 70 (8.57%)
    8 / 70 (11.43%)
    5 / 88 (5.68%)
    4 / 90 (4.44%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    6
    8
    10
    5
    4
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    6 / 70 (8.57%)
    3 / 70 (4.29%)
    4 / 70 (5.71%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    4 / 49 (8.16%)
    2 / 58 (3.45%)
    0 / 22 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    8
    3
    4
    0
    0
    4
    2
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    1 / 49 (2.04%)
    3 / 58 (5.17%)
    1 / 22 (4.55%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    1
    2
    Ear infection
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Impetigo
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Laryngitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 49 (0.00%)
    0 / 58 (0.00%)
    1 / 22 (4.55%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jul 2017
    - Change in the statistical analysis of the primary efficacy endpoint and the first secondary efficacy endpoint: MAS and PGA are ordinal scales. The sponsor proposed as primary efficacy analysis an ANCOVA analysis that instead were based on ranked MAS change from Baseline/PGA scores to better normalise the data. For sensitivity analysis, the sponsor proposed to use a proportional odds cumulative logit model that avoids scoring and retains the ordered nature of the data. -Clarification on efficacy endpoints list: those performed using the treatment cycle baseline were removed. They were replaced by endpoints for the subsets of subjects having kept the same PTMG throughout the study. -Clarification on subgroups analysis: notably those concerning physiotherapy and occupational therapy. -New subgroups added: analysis by gender for the primary and first secondary efficacy endpoints.

    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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