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    Clinical Trial Results:
    A phase III, multicentre, prospective, open label extension study to assess the long term safety and efficacy of repeated treatment of Dysport intramuscular injections used for the treatment of upper limb spasticity in adult subjects with spastic hemiparesis due to stroke or traumatic brain injury

    Summary
    EudraCT number
    		 2010-019162-83
    Trial protocol
    		 BE   CZ   SK   PL   IT   HU  
    Global end of trial date
    09 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 May 2016
    First version publication date
    15 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Y-52-52120-148
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    24 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary study objective is to assess the long term safety of Dysport in hemiparetic subjects with upper limb spasticity due to stroke or traumatic brain injury over repeated treatment cycles.
    Protection of trial subjects
    This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonisation (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 Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Nov 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
    Russian Federation: 19
    Country: Number of subjects enrolled
    United States: 101
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Slovakia: 8
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Czech Republic: 24
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Italy: 7
    Worldwide total number of subjects
    258
    EEA total number of subjects
    138
    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)
    204
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was designed as a multicentre study and included 34 investigational sites in Belgium, the Czech Republic, France, Hungary, Italy, Poland, Russia, Slovakia and the United States of America (US) that included at least one subject.

    Pre-assignment
    Screening details
    		 Of 227 subjects who completed Study 145, 4 subjects entered observational phase and never received open label treatment with Dysport in Study 148. Remaining 223 subjects were eligible for retreatment and were rolled over to study 148. In addition, of 34 de novo subjects screened, 31 subjects were eligible and included in this study.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Total Dysport
    Arm description
    		 Of 227 subjects who completed study 145, 223 Subjects rolled over to this study (4 subjects entered an observational phase at the end of Study 145). Of 34 subjects screened for De-Novo study, only 31 were treated with open label Botulinum type A toxin (Dysport) dose of 1000 Units (U) in Cycle 1 and from Cycle 2 onwards Dysport 500 / 1000 / 1500 U
    Arm type
    		 Experimental

    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
    A vials containing 500 U of botulinum toxin type A reconstituted with sodium chloride 5.0 ml for 500 U and 1000 U Dysport, and 7.5ml for 1500U Dysport Intramuscular injection.

    Number of subjects in period 1 [1]
    		Total Dysport
    Started
    254
    Cycle 1
    254
    Cycle 2
    229
    Cycle 3
    175 [2]
    Cycle 4
    81 [3]
    Cycle 5
    11 [4]
    Completed
    222
    Not completed
    32
         Observational phase
    1
         Adverse Event
    5
         Other
    5
         Consent withdrawn
    18
         Lack of efficacy
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Worldwide data is reported for safety population of 258 subjects and baseline data is reported for 254 subjects for ITT population (this excludes 4 subjects who entered observational phase in study 148 and never received open label treatment with Dysport in Study 148).
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Of 254 subjects who started in cycle 1, only 175 subjects entered cycle 3. (24 subjects withdrew at cycles 1 & 2, 54 subjects ended study after 12 months follow-up and 1 subject entered observational phase)
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Of 254 subjects who started in cycle 1, only 81 subjects entered cycle 4. (30 subjects withdrew at cycles 1, 2 & 3, 142 subjects ended study after 12 months follow-up and 1 subject entered observational phase)
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Of 254 subjects who started in cycle 1, only 11 subjects entered cycle 5. (31 subjects withdrew at cycles 1 ,2, 3 & 4, 211 subjects ended study after 12 months follow-up and 1 subject entered observational phase)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Total Dysport
    Reporting group description
    		 Of 227 subjects who completed study 145, 223 Subjects rolled over to this study (4 subjects entered an observational phase at the end of Study 145). Of 34 subjects screened for De-Novo study, only 31 were treated with open label Botulinum type A toxin (Dysport) dose of 1000 Units (U) in Cycle 1 and from Cycle 2 onwards Dysport 500 / 1000 / 1500 U

    Reporting group values
    		 Total Dysport Total
    Number of subjects
    		 254 254
    Age categorical
    Units: Subjects
        <65 years
    		 201 201
        >=65 years
    		 53 53
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.4 ( 14 ) -
    Gender categorical
    Units: Subjects
        Female
    		 91 91
        Male
    		 163 163
    Race
    Units: Subjects
        Asian
    		 7 7
        Black / African American
    		 27 27
        Caucasian / White
    		 218 218
        Multiple
    		 2 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 16 16
        Not Hispanic or Latino
    		 238 238

    End points

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    End points reporting groups
    Reporting group title
    Total Dysport
    Reporting group description
    		 Of 227 subjects who completed study 145, 223 Subjects rolled over to this study (4 subjects entered an observational phase at the end of Study 145). Of 34 subjects screened for De-Novo study, only 31 were treated with open label Botulinum type A toxin (Dysport) dose of 1000 Units (U) in Cycle 1 and from Cycle 2 onwards Dysport 500 / 1000 / 1500 U

    Primary: Assessment of the long term safety of Treatment Emergent Adverse Events

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    End point title
    		 Assessment of the long term safety of Treatment Emergent Adverse Events [1]
    End point description
    TEAEs (treatment emergent adverse event) AESIs (adverse event of special interest) SAEs (serious adverse event) Safety population are all enrolled subjects who provided informed consent to participate in this open label study.
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Number of subjects
        TEAEs: Cycle 1 (n=254)
    102
        TEAEs: Cycle 2 (n=229)
    62
        TEAEs: Cycle 3 (n=175)
    47
        TEAEs: Cycle 4 (n=81)
    11
        TEAEs: Cycle 5 (n=11)
    2
        Treatment related TEAE: Cycle 1 (n=254)
    18
        Treatment related TEAE: Cycle 2 (n=229)
    8
        Treatment related TEAE: Cycle 3 (n=175)
    5
        Treatment related TEAE: Cycle 4 (n=81)
    2
        Treatment related TEAE: Cycle 5 (n=11)
    0
        Severe TEAEs: Cycle 1 (n=254)
    14
        Severe TEAEs: Cycle 2 (n=229)
    8
        Severe TEAEs: Cycle 3 (n=175)
    4
        Severe TEAEs: Cycle 4 (n=81)
    1
        Severe TEAEs: Cycle 5 (n=11)
    0
        TEAEs Leading to Withdrawal: Cycle 1 (n=254)
    2
        TEAEs Leading to Withdrawal: Cycle 2 (n=229)
    1
        TEAEs Leading to Withdrawal: Cycle 3 (n=175)
    2
        TEAEs Leading to Withdrawal: Cycle 4 (n=81)
    0
        TEAEs Leading to Withdrawal: Cycle 5 (n=11)
    0
        AESIs: Cycle 1 (n=254)
    2
        AESIs: Cycle 2 (n=229)
    0
        AESIs: Cycle 3 (n=175)
    0
        AESIs: Cycle 4 (n=81)
    0
        AESIs: Cycle 5 (n=11)
    0
        SAEs: Cycle 1 (n=254)
    10
        SAEs: Cycle 2 (n=229)
    6
        SAEs: Cycle 3 (n=175)
    6
        SAEs: Cycle 4 (n=81)
    1
        SAEs: Cycle 5 (n=11)
    0
        Fatal SAEs: Cycle 1 (n=254)
    1
        Fatal SAEs: Cycle 2 (n=229)
    1
        Fatal SAEs: Cycle 3 (n=175)
    1
        Fatal SAEs: Cycle 4 (n=81)
    0
        Fatal SAEs: Cycle 5 (n=11)
    0
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in Diastolic and Systolic BP

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in Diastolic and Systolic BP [2]
    End point description
    Safety population
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: mm Hg
    arithmetic mean (full range (min-max))
        Diastolic BP (n=238)
    0 (-29 to 34)
        Systolic BP (n=238)
    -2.8 (-63 to 41)
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in Heart Rate

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in Heart Rate [3]
    End point description
    Safety population
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: bpm
    arithmetic mean (full range (min-max))
        Heart rate (n=239)
    2.5 (-28 to 30)
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in RBC count

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in RBC count [4]
    End point description
    Safety population
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Tera/L
    arithmetic mean (full range (min-max))
        RBC Count (n=219)
    0.03 (-1.15 to 1.06)
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in Haemoglobin and MCHC

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in Haemoglobin and MCHC [5]
    End point description
    MCHC (mean corpuscular haemoglobin concentration) Haematology Variables Safety population
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: g/L
    arithmetic mean (full range (min-max))
        Haemoglobin (n=219)
    -0.7 (-33 to 37)
        MCHC (n=219)
    -0.8 (-26 to 34)
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in Haematocrit

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in Haematocrit [6]
    End point description
    Haematology Variables Safety population
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: N/A
    arithmetic mean (full range (min-max))
        Haematocrit (n=219)
    -0.0011 (-0.104 to 0.087)
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in MCH

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in MCH [7]
    End point description
    MCH (mean corpuscular haemoglobin) Haematology Variables Safety population
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: pg
    arithmetic mean (full range (min-max))
        MCH (n=219)
    -0.33 (-5 to 4.9)
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in MCV

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in MCV [8]
    End point description
    MCV (mean corpuscular volume) Haematology Variables Safety population
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: fL
    arithmetic mean (full range (min-max))
        MCV (n=219)
    -0.77 (-9.9 to 8.2)
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in WBC count, Neutrophils, Lymphocytes and Platelets

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in WBC count, Neutrophils, Lymphocytes and Platelets [9]
    End point description
    WBC (white blood cell) Haematology Variables Safety population
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Giga/L
    arithmetic mean (full range (min-max))
        WBC count (n=219)
    0.04 (-6.5 to 5.2)
        Neutrophils (n=219)
    0 (-6.8 to 5.6)
        Lymphocytes (n=219)
    0.01 (-1.9 to 1.2)
        Platelets (n=214)
    3.2 (-142 to 249)
    No statistical analyses for this end point

    Primary: Mean change from baseline to end of study (EOS)/early withdrawal in 12 lead Electrocardiogram (ECG)

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    End point title
    		 Mean change from baseline to end of study (EOS)/early withdrawal in 12 lead Electrocardiogram (ECG) [10]
    End point description
    Safety population
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    243
    Units: milliseconds (ms)
    arithmetic mean (standard deviation)
        QT Duration - Baseline (n=233)
    403.6 ( 31.9 )
        QT Duration - Change from Baseline to EOS (n=210)
    -6.3 ( 22.1 )
        QTcF - Baseline (n=233)
    417.8 ( 22.9 )
        QTcF - Change from Baseline to EOS (n=210)
    -1 ( 15.5 )
        QTcB - Baseline (n=233)
    425.6 ( 25.5 )
        QTcB - Change from Baseline to EOS (n=210)
    1.9 ( 20.2 )
        QRS Duration - Baseline (n=235)
    94.9 ( 15.3 )
        QRS Duration - Change from Baseline to EOS (n=210)
    -0.4 ( 6.4 )
        PR Duration - Baseline (n=233)
    165.6 ( 25.4 )
        PR Duration - Change from Baseline to EOS (n=210)
    -0.3 ( 13.2 )
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in ALP, SGOT, SGPT and GGT

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in ALP, SGOT, SGPT and GGT [11]
    End point description
    ALP=alkaline phosphatase; GGT=gamma glutamyl transferase; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase.
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: IU/L
    arithmetic mean (full range (min-max))
        ALP (n=226)
    -0.6 (-39 to 83)
        SGOT (n=226)
    1.4 (-32 to 45)
        SGPT (n=226)
    1.2 (-81 to 57)
        GGT (n=226)
    1.5 (-105 to 195)
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in Total Bilirubin and Creatinine

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in Total Bilirubin and Creatinine [12]
    End point description
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: μmol/L
    arithmetic mean (full range (min-max))
        Total Bilirubin (n=226)
    -0.27 (-18.7 to 12.2)
        Creatinine (n=226)
    -3.7 (-115 to 35)
    No statistical analyses for this end point

    Primary: Mean Change from Baseline to End of Study/Early Withdrawal in BUN and Fasting Blood Glucose

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    End point title
    		 Mean Change from Baseline to End of Study/Early Withdrawal in BUN and Fasting Blood Glucose [13]
    End point description
    BUN=blood urea nitrogen
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: mmol/L
    arithmetic mean (full range (min-max))
        BUN (n=226)
    -0.033 (-12.85 to 8.93)
        Fasting Blood Glucose (n=101)
    0.132 (-3.66 to 7.94)
    No statistical analyses for this end point

    Primary: Mean change from baseline to end of study/early withdrawal in 12 lead ECG - Heart Rate

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    End point title
    		 Mean change from baseline to end of study/early withdrawal in 12 lead ECG - Heart Rate [14]
    End point description
    Safety population EOS= End of Study bpm = beats per minute
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    243
    Units: bpm
    arithmetic mean (standard deviation)
        Baseline (n=243)
    68.2 ( 11.3 )
        Change from Baseline to EOS (n=226)
    2.7 ( 10.5 )
    No statistical analyses for this end point

    Primary: Number of subjects with Botulinum Toxin A Binding and Neutralising Putative Antibodies

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    End point title
    		 Number of subjects with Botulinum Toxin A Binding and Neutralising Putative Antibodies [15]
    End point description
    Number of subjects who were positive / Negative at baseline and positive post baseline for binding and neutralizing Safety population +ve = positive -ve = negative
    End point type
    Primary
    End point timeframe
    Up to visit V20 (week 52)
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this endpoint
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Number of subjects
        +ve at baseline – binding
    5
        -ve at baseline & +ve post baseline-binding
    20
        +ve at baseline – neutralizing
    4
        -ve at baseline & +ve post baseline-Neutralizing
    11
    No statistical analyses for this end point

    Secondary: Mean change from baseline MAS in the overall PTMG for upper limb

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    End point title
    		 Mean change from baseline MAS in the overall PTMG for upper limb
    End point description
    The MAS consists of 6 grades: 0, 1, 1+, 2, 3, or 4 that can be applied to muscles of both the upper and lower limbs. The MAS was applied by the rater by stretching the joint through its full available range over 1 second. The intention to treat (ITT) population was defined as all enrolled subjects who received at least one injection of study medication in this open label extension study. PTMG (Primary Targeted Muscle Group) MAS (Modified Ashworth Scale Score)
    End point type
    Secondary
    End point timeframe
    At week 4 (visit 2)
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Unit in scale
    arithmetic mean (standard deviation)
        Study 145 (n=152)
    -1.2 ( 1 )
        Cycle 1 (n=252)
    -1.4 ( 1.1 )
        Cycle 2 (n=226)
    -1.6 ( 1.2 )
        Cycle 3 (n=163)
    -1.5 ( 1.1 )
        Cycle 4 (n=80)
    -1.4 ( 1.1 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects with at least one grade reduction in MAS for overall PTMG

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    End point title
    		 Percentage of subjects with at least one grade reduction in MAS for overall PTMG
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Percentage of subjects
    number (not applicable)
        One Grade Reduction from Baseline:Study 145(n=152)
    75
        One Grade Reduction from Baseline: Cycle 1(n=254)
    77.6
        One Grade Reduction from Baseline: Cycle 2(n=229)
    79.5
        One Grade Reduction from Baseline: Cycle 3(n=175)
    77.1
        One Grade Reduction from Baseline: Cycle 4(n=81)
    75.3
    No statistical analyses for this end point

    Secondary: Physicians Global Assessment of Treatment Response

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    End point title
    		 Physicians Global Assessment of Treatment Response
    End point description
    Physician’s Global Assessment is 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, +4=markedly improved. ITT population
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units in scale
    arithmetic mean (standard deviation)
        Study 145 (n=151)
    1.5 ( 1.1 )
        Cycle 1 (n=253)
    1.7 ( 1 )
        Cycle 2 (n=227)
    1.9 ( 1 )
        Cycle 3 (n=167)
    1.9 ( 1 )
        Cycle 4 (n=80)
    2 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline in Disability Assessment Scale Score for the Principal Target of Treatment

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    End point title
    		 Mean change from baseline in Disability Assessment Scale Score for the Principal Target of Treatment
    End point description
    Disability Assessment Scale is a 4-point scale, the extent of functional impairment in four functional domains (dressing, hygiene, limb position and pain) was rated as follows: 0=no disability, 1=mild disability (noticeable but does not interfere significantly with normal activities), 2=moderate disability (normal activities require increased effort and/or assistance) and 3=severe disability (normal activities limited). ITT population
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Scale in units
    arithmetic mean (standard deviation)
        Study 145 (n=151)
    -0.7 ( 0.8 )
        Cycle 1 (n=252)
    -0.9 ( 0.8 )
        Cycle 2 (n=226)
    -1.1 ( 0.8 )
        Cycle 3 (n=166)
    -1.1 ( 0.8 )
        Cycle 4 (n=80)
    -1.1 ( 0.8 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects with at least one grade reduction in DAS for PTT

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    End point title
    		 Percentage of subjects with at least one grade reduction in DAS for PTT
    End point description
    ITT population DAS (Disability Assessment Scale) PTT (Principal Target of Treatment)
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units in scale
    number (not applicable)
        PTT: Study 145 (n=152)
    55.3
        PTT: Cycle 1 (n=254)
    68.5
        PTT: Cycle 2 (n=229)
    75.1
        PTT: Cycle 3 (n=175)
    73.7
        PTT: Cycle 4 (n=81)
    74.1
    No statistical analyses for this end point

    Secondary: Mean change from baseline for X (angle of spasticity) of the TS in extrinsic finger flexors as PTMG

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    End point title
    		 Mean change from baseline for X (angle of spasticity) of the TS in extrinsic finger flexors as PTMG
    End point description
    The TS was used to measure spasticity in the shoulder extensors, elbow flexors, wrist flexors and extrinsic finger flexors. Assessments were made at slow (V1) and fast (V3) speeds of stretch. The angle of arrest at slow speed (XV1), the angle of catch at fast speed (XV3) and the spasticity grade (Y) at fast speed were recorded in the eCRF. The spasticity angle was automatically calculated in the eCRF as the difference between the angle of arrest at slow speed (XV1) and the angle of catch at fast speed (XV3). The spasticity grade (Y) is an ordinal variable that grades the intensity of the muscle reaction to fast stretch. TS (Tardieu Scale) PTMG (Primary Targeted Muscle group) ITT population
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units in scale
    arithmetic mean (standard deviation)
        Angle of Spasticity (X): Study 145 (n=88)
    -23.5 ( 48.3 )
        Angle of Spasticity (X): Cycle 1 (n=144)
    -33.5 ( 54 )
        Angle of Spasticity (X): Cycle 2 (n=133)
    -33.9 ( 55.9 )
        Angle of Spasticity (X): Cycle 3 (n=98)
    -43.3 ( 57.8 )
        Angle of Spasticity (X): Cycle 4 (n=56)
    -35.9 ( 48 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline for X (angle of spasticity) of the TS in elbow flexors as PTMG

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    End point title
    		 Mean change from baseline for X (angle of spasticity) of the TS in elbow flexors as PTMG
    End point description
    ITT population
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units in scale
    arithmetic mean (standard deviation)
        Angle of Spasticity (X): Study 145 (n=43)
    -25.7 ( 24.5 )
        Angle of Spasticity (X): Cycle 1 (n=69)
    -26.4 ( 24.9 )
        Angle of Spasticity (X): Cycle 2 (n=59)
    -31 ( 27.7 )
        Angle of Spasticity (X): Cycle 3 (n=42)
    -33.3 ( 26 )
        Angle of Spasticity (X): Cycle 4 (n=14)
    -46.4 ( 17.3 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline for X (angle of spasticity) of the TS in wrist flexors as PTMG

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    End point title
    		 Mean change from baseline for X (angle of spasticity) of the TS in wrist flexors as PTMG
    End point description
    ITT population
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units in scale
    arithmetic mean (standard deviation)
        Angle of Spasticity (X): Study 145 (n=21)
    -19.8 ( 30 )
        Angle of Spasticity (X): Cycle 1 (n=39)
    -23.3 ( 32.5 )
        Angle of Spasticity (X): Cycle 2 (n=34)
    -28.8 ( 37.1 )
        Angle of Spasticity (X): Cycle 3 (n=23)
    -21.7 ( 35.2 )
        Angle of Spasticity (X): Cycle 4 (n=10)
    -13.5 ( 29.3 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline in active range of motion (AROM) in the 3 possible PTMGs

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    End point title
    		 Mean change from baseline in active range of motion (AROM) in the 3 possible PTMGs
    End point description
    ITT population The active range of extension achieved by the subjects moving each joint without assistance was measured at baseline and at all subsequent study visits during each cycle. A goniometer was used for measurements in the elbow and wrist flexors but not for measurements in the extrinsic finger flexors.
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units in scale
    arithmetic mean (standard deviation)
        Extrinsic Finger Flexors: Study 145 (n=88)
    19.8 ( 28.8 )
        Extrinsic Finger Flexors: Cycle 1 (n=144)
    31.3 ( 40.9 )
        Extrinsic Finger Flexors: Cycle 2 (n=133)
    34.4 ( 45 )
        Extrinsic Finger Flexors: Cycle 3 (n=98)
    33.5 ( 47.1 )
        Extrinsic Finger Flexors: Cycle 4 (n=56)
    38 ( 53.4 )
        Elbow Flexors: Study 145 (n=43)
    14.3 ( 22.3 )
        Elbow Flexors: Cycle 1 (n=69)
    10.7 ( 25.5 )
        Elbow Flexors: Cycle 2 (n=59)
    17.6 ( 23.3 )
        Elbow Flexors: Cycle 3 (n=42)
    14.5 ( 24.1 )
        Elbow Flexors: Cycle 4 (n=14)
    13.6 ( 20.6 )
        Wrist Flexors: Study 145 (n=21)
    21.8 ( 24.6 )
        Wrist Flexors: Cycle 1 (n=39)
    17.3 ( 28.6 )
        Wrist Flexors: Cycle 2 (n=34)
    23 ( 32.7 )
        Wrist Flexors: Cycle 3 (n=23)
    22 ( 30.9 )
        Wrist Flexors: Cycle 4 (n=10)
    3 ( 25.1 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline in Ease of Applying a Splint

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    End point title
    		 Mean change from baseline in Ease of Applying a Splint
    End point description
    The ease of applying a splint was evaluated on a 6-point scale (0: no splint needed, –1: splint needed and applied with no difficulty, –2: splint needed and applied with mild difficulty, –3: splint needed and applied with moderate difficulty, –4: splint needed and applied with severe difficulty, –5: splint needed, but unable to apply). ITT population
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units in scale
    arithmetic mean (standard deviation)
        Study 145 (n=149)
    -0.3 ( 1 )
        Cycle 1 (n=218)
    -0.4 ( 1.1 )
        Cycle 2 (n=196)
    -0.4 ( 1.3 )
        Cycle 3 (n=137)
    -0.4 ( 1.4 )
        Cycle 4 (n=56)
    -0.4 ( 1 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline in Modified Frenchay Scale (MFS)

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    End point title
    		 Mean change from baseline in Modified Frenchay Scale (MFS)
    End point description
    ITT population The MFS was used to measure upper limb active function. Each subject was videotaped while performing specific tasks. The videos were sent to a central provider and were read and scored by two independent readers blinded to the timing of the video and to treatment. These central assessments were used for the analysis of efficacy endpoints
    End point type
    Secondary
    End point timeframe
    At week 4
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units in scale
    arithmetic mean (standard deviation)
        Study 145 (n=152)
    0.21 ( 0.53 )
        Cycle 1 (n=219)
    0.4 ( 0.77 )
        Cycle 2 (n=190)
    0.51 ( 0.8 )
        Cycle 3 (n=138)
    0.44 ( 0.82 )
        Cycle 4 (n=56)
    0.4 ( 0.75 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Short Form (36) Health Survey (SF-36) Quality of Life

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    End point title
    		 Mean Change from Baseline in Short Form (36) Health Survey (SF-36) Quality of Life
    End point description
    ITT population Subjects were asked to complete the SF 36 questionnaires prior to the study treatment at baseline and at the end of study/early withdrawal visit. The SF 36 is a generic nonpreference based health status measure. This instrument assessed subject health across eight dimensions, which are specific health domains such as physical functioning, social functioning and vitality. Physical Component Summary (PCS); Mental Component Summary (MCS); Change = Change from Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1) and Final visit (up to year 1)
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units on scale
    arithmetic mean (standard deviation)
        PCS Baseline - Double-blind study 145 (n=145)
    37.89 ( 8.85 )
        PCS Change - Double-blind study 145 (n=137)
    0.95 ( 6.04 )
        PCS Baseline - Open label study 148 (n=244)
    37.49 ( 8.94 )
        PCS Change - Open label study 148 (n=229)
    1.07 ( 6.76 )
        MCS Baseline - Double-blind study 145 (n=145)
    47.77 ( 13.43 )
        MCS Change - Double-blind study 145 (n=137)
    0.41 ( 10.05 )
        MCS Baseline - Open label study 148 (n=244)
    46.88 ( 13.09 )
        MCS Change - Open label study 148 (n=229)
    0.96 ( 11.11 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in European Quality of Life - 5 Dimensions (EQ-5D) Quality of Life

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    End point title
    		 Mean Change from Baseline in European Quality of Life - 5 Dimensions (EQ-5D) Quality of Life
    End point description
    ITT population Subjects were asked to complete the EQ 5D Quality of Life (QoL) questionnaires prior to the study treatment at baseline and at the end of study/early withdrawal visit. The EQ 5D index is a generic preference based measure of health related QoL producing utility scores that represent subject preferences for particular health states. This instrument rated subject health state looking at five specific dimensions such as mobility, self-care, usual activity, pain/discomfort and anxiety/depression and scored their general health state. Double Blind (DB); Open Label (OL); Visual Analogue Scale (VAS); Change = Change from Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1) and Final visit (up to year 1)
    End point values
    		 Total Dysport
    Number of subjects analysed
    254
    Units: Units on scale
    arithmetic mean (standard deviation)
        Anxiety/Depression Baseline-DB study 145 (n=150)
    1.8 ( 0.9 )
        Anxiety/Depression Change - DB study 145 (n=140)
    0 ( 0.8 )
        Anxiety/Depression Baseline - OL study 148 (n=249)
    1.9 ( 0.9 )
        Anxiety/Depression Change - OL study 148 (n=231)
    -0.1 ( 0.9 )
        Mobility Baseline - DB study 145 (n=150)
    2.7 ( 0.9 )
        Mobility Change - DB study 145 (n=140)
    0 ( 0.8 )
        Mobility Baseline - OL study 148 (n=249)
    2.8 ( 0.9 )
        Mobility Change - OL study 148 (n=231)
    0 ( 0.8 )
        Pain/Discomfort Baseline - DB study 145 (n=150)
    2.1 ( 1 )
        Pain/Discomfort Change - DB study 145 (n=140)
    -0.1 ( 0.9 )
        Pain/Discomfort Baseline - OL study 148 (n=249)
    2.1 ( 1 )
        Pain/Discomfort Change - OL study 148 (n=231)
    -0.2 ( 0.9 )
        Self-Care Baseline - DB study 145 (n=150)
    2.5 ( 1 )
        Self-Care Change - DB study 145 (n=140)
    0 ( 0.9 )
        Self-Care Baseline - OL study 148 (n=249)
    2.4 ( 1 )
        Self-Care Change - OL study 148 (n=231)
    0 ( 0.8 )
        Usual Activities Baseline - DB study 145 (n=150)
    2.8 ( 1 )
        Usual Activities Change - DB study 145 (n=140)
    -0.1 ( 0.9 )
        Usual Activities Baseline - OL study 148 (n=249)
    2.8 ( 1 )
        Usual Activities Change - OL study 148 (n=231)
    -0.2 ( 1 )
        VAS Baseline - DB study 145 (n=150)
    63.4 ( 20.3 )
        VAS Change - DB study 145 (n=140)
    2.4 ( 17.3 )
        VAS - OL study 148 (n=249)
    63.6 ( 19.7 )
        VAS Change - OL study 148 (n=231)
    2.8 ( 19 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to visit 20 (week 52)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Total Dysport
    Reporting group description
    		 223 Subjects who rolled over from study 145 plus 31 subjects from observational De-Novo study entered this open label Botulinum type A toxin (Dysport) dose of 1000 Units (U) in Cycle 1 and from Cycle 2 onwards Dysport 500 / 1000 / 1500 U

    Serious adverse events
    		 Total Dysport
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 254 (8.27%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Device malfunction
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Affect lability
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Affective disorder
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mania
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ulna fracture
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    2 / 254 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Nephrogenic anaemia
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    2 / 254 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Total Dysport
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    142 / 254 (55.91%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    4
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    20 / 254 (7.87%)
         occurrences all number
    25
    Hand fracture
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Contusion
         subjects affected / exposed
    4 / 254 (1.57%)
         occurrences all number
    4
    Humerus fracture
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 254 (1.57%)
         occurrences all number
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 254 (2.36%)
         occurrences all number
    6
    Epilepsy
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    6
    Paraesthesia
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 254 (1.97%)
         occurrences all number
    5
    Fatigue
         subjects affected / exposed
    7 / 254 (2.76%)
         occurrences all number
    8
    Pyrexia
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    5
    Peripheral swelling
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Oedema peripheral
         subjects affected / exposed
    4 / 254 (1.57%)
         occurrences all number
    4
    Injection site bruising
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    4
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Nasal congestion
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    4
    Oropharyngeal pain
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Rhinorrhoea
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 254 (1.97%)
         occurrences all number
    5
    Depression
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    14 / 254 (5.51%)
         occurrences all number
    18
    Muscular weakness
         subjects affected / exposed
    13 / 254 (5.12%)
         occurrences all number
    14
    Musculoskeletal pain
         subjects affected / exposed
    5 / 254 (1.97%)
         occurrences all number
    5
    Arthralgia
         subjects affected / exposed
    8 / 254 (3.15%)
         occurrences all number
    9
    Joint swelling
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 254 (1.97%)
         occurrences all number
    5
    Nasopharyngitis
         subjects affected / exposed
    6 / 254 (2.36%)
         occurrences all number
    7
    Urinary tract infection
         subjects affected / exposed
    6 / 254 (2.36%)
         occurrences all number
    10
    Influenza
         subjects affected / exposed
    4 / 254 (1.57%)
         occurrences all number
    4
    Sinusitis
         subjects affected / exposed
    4 / 254 (1.57%)
         occurrences all number
    4
    Cystitis
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Gastroenteritis viral
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Herpes zoster
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3
    Upper respiratory tract
         subjects affected / exposed
    3 / 254 (1.18%)
         occurrences all number
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Feb 2012
    Protocol Amendment 2 - Made the following changes: •The sponsor’s Medically Responsible Person was changed. •Pronator muscles were excluded from the MAS and TS assessments. •The study entry criteria was simplified to exclude subjects who had undergone previous surgery to treat spasticity of the affected upper limb (instead of those who had received previous surgery on muscles, ligaments, tendons, nerve trunks or bones of the upper limb). •A new exclusion criterion was added to exclude treatment with intrathecal baclofen during the course of the study. •Subjects not requiring a new treatment cycle at the Week 24 follow up visit of Treatment Cycle 1 or 2 (instead of Cycle 1 and potentially Cycle 2) were required to have follow up visits every 4 weeks until a new treatment cycle was required or they reached 12 months follow up. •The Central Laboratory was changed. •12-lead ECG was to be recorded after 5 minutes rest instead of after 30 minutes rest. •Section 9.6 concerning dosage of concomitant medications was amended to include oral baclofen. •Item 9 of the Modified Frenchay Scale was altered to specify that the affected hand was to hold the fork for this task.
    25 Apr 2013
    Protocol Amendment 4 - Made the following changes: •The Sponsor’s Co-ordinating and Monitoring Officer was changed. •The protocol was substantially updated to include de novo patients as well as rollover subjects from Study 145. The changes specified included: -The study design was amended to include the definition of baseline for MAS de novo patients, the maximum number of treatment cycles in the extension study for the rollover and de novo subjects, the start time of the first treatment cycle for the two populations and the maximum study duration. -Separate inclusion criteria were provided for rollover and de novo subjects -The start of the observation period was specified separately for rollover and de novo subjects. -A separate definition was provided for the selection of primary targeted muscle groups in the de novo subjects. -Separate schedules of assessment were defined for de novo and rollover subjects. -Separate conditions were defined for rollover and de novo subjects who required injections within 2 weeks of the Week 12 visit of any treatment cycle. -Separate study flow diagrams were provided for rollover and de novo subjects.

    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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