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    Clinical Trial Results:
    BOTOX® Treatment in Pediatric Upper Limb Spasticity: Double-blind Study

    Summary
    EudraCT number
    2012-000062-38
    Trial protocol
    DE   PL   HU   IT  
    Global end of trial date
    06 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Jun 2018
    First version publication date
    11 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    191622-101
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01603602
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Allergan Limited
    Sponsor organisation address
    1st Floor Marlow International The Parkway, Marlow, Buckinghamshire, United Kingdom, SL7 1YL
    Public contact
    EU Regulatory Department, Allergan Limited, +44 1628 494444, ml-eu_reg_affairs@allergan.com
    Scientific contact
    EU Regulatory Department, Allergan Limited, +44 1628 494444, ml-eu_reg_affairs@allergan.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will evaluate the safety and efficacy of BOTOX® (botulinum toxin Type A) in pediatric participants with upper limb spasticity.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Jul 2012
    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
    United States: 63
    Country: Number of subjects enrolled
    Poland: 79
    Country: Number of subjects enrolled
    Korea, Republic of: 48
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Philippines: 4
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Turkey: 2
    Worldwide total number of subjects
    235
    EEA total number of subjects
    88
    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)
    182
    Adolescents (12-17 years)
    53
    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
    -

    Pre-assignment
    Screening details
    Pediatric participants with upper limb spasticity were randomized 1:1:1 to one of three treatment groups: BOTOX® 3 or 6 U/kg (unit per kilogram) or placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BOTOX® 6 U/kg
    Arm description
    Intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).
    Arm type
    Experimental

    Investigational medicinal product name
    BOTOX®
    Investigational medicinal product code
    Other name
    botulinum toxin Type A, onabotulinumtoxinA
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) into specified muscles of the upper limb.

    Arm title
    BOTOX® 3 U/kg
    Arm description
    Intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly OT.
    Arm type
    Experimental

    Investigational medicinal product name
    BOTOX®
    Investigational medicinal product code
    Other name
    botulinum toxin Type A, onabotulinumtoxinA
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) into specified muscles of the upper limb.

    Arm title
    Placebo
    Arm description
    Intramuscular injections of normal saline (placebo) into specified muscles of the upper limb on Day 1. Participants received weekly OT.
    Arm type
    Placebo

    Investigational medicinal product name
    Normal Saline
    Investigational medicinal product code
    Other name
    0.9% Saline Solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received intramuscular injections into specified muscles of the upper limb.

    Number of subjects in period 1
    BOTOX® 6 U/kg BOTOX® 3 U/kg Placebo
    Started
    77
    78
    80
    Completed
    75
    78
    79
    Not completed
    2
    0
    1
         Adverse event, non-fatal
    1
    -
    -
         Personal Reasons
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BOTOX® 6 U/kg
    Reporting group description
    Intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).

    Reporting group title
    BOTOX® 3 U/kg
    Reporting group description
    Intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly OT.

    Reporting group title
    Placebo
    Reporting group description
    Intramuscular injections of normal saline (placebo) into specified muscles of the upper limb on Day 1. Participants received weekly OT.

    Reporting group values
    BOTOX® 6 U/kg BOTOX® 3 U/kg Placebo Total
    Number of subjects
    77 78 80 235
    Age categorical
    Units: Subjects
        Children (2-11 years)
    61 56 65 182
        Adolescents (12-17 years)
    16 22 15 53
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    7.6 ± 3.66 8.3 ± 4.48 7.8 ± 4.06 -
    Sex: Female, Male
    Units: Subjects
        Female
    27 36 32 95
        Male
    50 42 48 140
    Modified Ashworth Scale-Bohannon (MAS-B) Score of the Principal Muscle Group Change
    The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the principal muscle group (elbow and wrist) by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). 1 Participant in the Placebo arm was not included in the analysis.
    Units: score on a scale
        arithmetic mean (standard deviation)
    3.3 ± 0.45 3.3 ± 0.45 3.3 ± 0.44 -

    End points

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    End points reporting groups
    Reporting group title
    BOTOX® 6 U/kg
    Reporting group description
    Intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).

    Reporting group title
    BOTOX® 3 U/kg
    Reporting group description
    Intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly OT.

    Reporting group title
    Placebo
    Reporting group description
    Intramuscular injections of normal saline (placebo) into specified muscles of the upper limb on Day 1. Participants received weekly OT.

    Primary: Average Change from Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of the Principal Muscle Group at Weeks 4 and 6

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    End point title
    Average Change from Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of the Principal Muscle Group at Weeks 4 and 6
    End point description
    The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the principal muscle group (elbow and wrist) by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). The scores at Weeks 4 and 6 were averaged. A Mixed Model Repeated Measures (MMRM) model was used for analysis. A negative change from Baseline indicates improvement. Participants from the Modified Intent-to treat (mITT) population, all randomized participants with a valid MAS-B baseline score and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B of the principal muscle group and the CGI by physician, with data available for analysis.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) to Weeks 4 and 6
    End point values
    BOTOX® 6 U/kg BOTOX® 3 U/kg Placebo
    Number of subjects analysed
    74
    76
    75
    Units: score on a scale
        least squares mean (standard error)
    -1.87 ± 0.102
    -1.92 ± 0.101
    -1.21 ± 0.102
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Mixed Model Repeated Measures (MMRM)
    Parameter type
    Least Squares (LS) Mean Difference
    Point estimate
    -0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.938
         upper limit
    -0.379
    Notes
    [1] - MMRM model with baseline MAS-B score as covariate; factors of age, principal muscle group, treatment, visit, treatment-by-visit interaction, study center and previous botulinum toxin exposure, stratified by age and principal muscle group categories.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [2]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.992
         upper limit
    -0.426
    Notes
    [2] - MMRM model with baseline MAS-B score as covariate; factors of age, principal muscle group, treatment, visit, treatment-by-visit interaction, study center and previous botulinum toxin exposure, stratified by age and principal muscle group categories.

    Secondary: Average Clinical Global Impression (CGI) of Overall Change by Physician at Weeks 4 and 6

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    End point title
    Average Clinical Global Impression (CGI) of Overall Change by Physician at Weeks 4 and 6
    End point description
    The CGI of overall change (improvement or worsening) was assessed by the physician considering the participant’s clinical condition and severity of side effects using a 9-point scale where: -4=very marked worsening to +4=very marked improvement. The scores at Weeks 4 and 6 were averaged. A MMRM model was used for analysis. Participants from the mITT population were used for analysis and included all randomized participants with a valid MAS-B baseline score and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B of the principal muscle group and the CGI by physician, with data available for analysis at the given time-point.
    End point type
    Secondary
    End point timeframe
    Weeks 4 and 6
    End point values
    BOTOX® 6 U/kg BOTOX® 3 U/kg Placebo
    Number of subjects analysed
    74
    76
    75
    Units: score on a scale
        least squares mean (standard error)
    1.87 ± 0.108
    1.88 ± 0.108
    1.66 ± 0.108
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.155 [3]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.082
         upper limit
    0.511
    Notes
    [3] - MMRM model with baseline MAS-B score as covariate; factors of age, principal muscle group, treatment, visit, treatment-by-visit interaction, study center and previous botulinum toxin exposure, stratified by age and principal muscle group categories.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.147 [4]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.079
         upper limit
    0.523
    Notes
    [4] - MMRM model with baseline MAS-B score as covariate; factors of age, principal muscle group, treatment, visit, treatment-by-visit interaction, study center and previous botulinum toxin exposure, stratified by age and principal muscle group categories.

    Secondary: Average Change from Baseline in MAS-B Score of the Finger Flexor Muscle Group at Weeks 4 and 6

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    End point title
    Average Change from Baseline in MAS-B Score of the Finger Flexor Muscle Group at Weeks 4 and 6
    End point description
    The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the finger flexor muscle group by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). The scores at Weeks 4 and 6 were averaged. An Analysis of Covariance (ANCOVA) model was used for analysis. A negative change from Baseline indicates improvement. Participants from the mITT population were used for analysis and included all randomized participants with a valid MAS-B baseline score and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B of the principal muscle group and the CGI by physician, with data available for analysis at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Weeks 4 and 6
    End point values
    BOTOX® 6 U/kg BOTOX® 3 U/kg Placebo
    Number of subjects analysed
    28
    30
    29
    Units: score on a scale
        least squares mean (standard error)
    -1.41 ± 0.184
    -1.46 ± 0.169
    -1.02 ± 0.170
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.111 [5]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.861
         upper limit
    0.091
    Notes
    [5] - ANCOVA model including baseline MAS-B score of finger flexor muscle group as a covariate and factors of age group, treatment group, study center, and previous botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.078 [6]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.933
         upper limit
    0.051
    Notes
    [6] - ANCOVA model including baseline MAS-B score of finger flexor muscle group as a covariate and factors of age group, treatment group, study center, and previous botulinum toxin exposure where age group is represented by stratification categories.

    Secondary: Goal Attainment Score (GAS) as Assessed by Physician Using a 6-Point Scale

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    End point title
    Goal Attainment Score (GAS) as Assessed by Physician Using a 6-Point Scale
    End point description
    Two functional goals, one active and one passive, were selected by the participant and family in consultation with the physician investigator and/or treating physical therapist relative to the lower limb impairment due to spasticity. The physician assessed the achievement of the goals using a 6-point scale: where -3=worse than start to +2=much more than expected: improvements clearly exceed the defined therapeutic goal. An ANCOVA model was used for analysis. Participants from the mITT population were used for analysis and included all randomized participants with a valid MAS-B baseline score and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B of the principal muscle group and the CGI by physician, with data available for analysis. The number of subjects analysed in each arm at each time point is indicated by n.
    End point type
    Secondary
    End point timeframe
    Week 8 and 12
    End point values
    BOTOX® 6 U/kg BOTOX® 3 U/kg Placebo
    Number of subjects analysed
    77
    78
    79
    Units: score on a scale
    least squares mean (standard error)
        Week 8, Active Goal (n=75, 76, 77)
    0.11 ± 0.148
    0.12 ± 0.148
    0.21 ± 0.148
        Week 8, Passive Goal (n=75, 76, 77)
    0.30 ± 0.146
    0.23 ± 0.146
    0.06 ± 0.146
        Week 12, Active Goal (n=73, 78, 79)
    0.49 ± 0.143
    0.26 ± 0.139
    0.52 ± 0.139
        Week 12, Passive Goal (n=72, 78, 79)
    0.71 ± 0.143
    0.31 ± 0.139
    0.11 ± 0.139
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 8, Active Goal
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.636 [7]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.498
         upper limit
    0.305
    Notes
    [7] - ANCOVA model including baseline MAS-B score as a covariate; factors of age, principal muscle group, treatment, study center and previous botulinum toxin exposure where age and principal muscle group were represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Week 8, Active Goal
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.658 [8]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.502
         upper limit
    0.318
    Notes
    [8] - ANCOVA model including baseline MAS-B score as a covariate; factors of age, principal muscle group, treatment, study center and previous botulinum toxin exposure where age and principal muscle group were represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Week 8, Passive Goal
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.243 [9]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.162
         upper limit
    0.635
    Notes
    [9] - ANCOVA model including baseline MAS-B score as a covariate; factors of age, principal muscle group, treatment, study center and previous botulinum toxin exposure where age and principal muscle group were represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Week 8, Passive Goal
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.412 [10]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.237
         upper limit
    0.576
    Notes
    [10] - ANCOVA model including baseline MAS-B score as a covariate; factors of age, principal muscle group, treatment, study center and previous botulinum toxin exposure where age and principal muscle group were represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Week 12, Active Goal
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.904 [11]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.408
         upper limit
    0.361
    Notes
    [11] - ANCOVA model including baseline MAS-B score as a covariate; factors of age, principal muscle group, treatment, study center and previous botulinum toxin exposure where age and principal muscle group were represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Week 12, Active Goal
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2 [12]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.641
         upper limit
    0.135
    Notes
    [12] - ANCOVA model including baseline MAS-B score as a covariate; factors of age, principal muscle group, treatment, study center and previous botulinum toxin exposure where age and principal muscle group were represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Week 12, Passive Goal
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [13]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.21
         upper limit
    0.978
    Notes
    [13] - ANCOVA model including baseline MAS-B score as a covariate; factors of age, principal muscle group, treatment, study center and previous botulinum toxin exposure where age and principal muscle group were represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Week 12, Passive Goal
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.327 [14]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.194
         upper limit
    0.58
    Notes
    [14] - ANCOVA model including baseline MAS-B score as a covariate; factors of age, principal muscle group, treatment, study center and previous botulinum toxin exposure where age and principal muscle group were represented by stratification categories.

    Secondary: Change from Baseline in Severity of Spasticity of the Principal Muscle Group (R2-R1) Calculated Using the Modified Tardieu Scale (MTS)

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    End point title
    Change from Baseline in Severity of Spasticity of the Principal Muscle Group (R2-R1) Calculated Using the Modified Tardieu Scale (MTS)
    End point description
    The MTS measured the difference between slow and fast range of motion (R2-R1) and respective change from baseline to each posttreatment visit. The MTS of the ankle was used to determine the passive range of movement at different movement velocities, V1 (as slow as possible) and V3 (as fast as possible) with the relative difference between a slow and a fast velocity passive stretch determining the dynamic component of the muscle contracture for the joint. At each visit, the investigator measured 2 joint angles by goniometer: the R1 angle which is the angle of catch after a fast velocity (V3) stretch and the R2 angle defined as the passive joint range of movement following a slow velocity (V1) stretch. The R2–R1 value indicated the level of the dynamic component of spasticity in the joint. The difference between slow (R2) and fast (R1) range of motion and respective change from baseline to each posttreatment visit on the MTS was derived. The mITT population was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 6
    End point values
    BOTOX® 6 U/kg BOTOX® 3 U/kg Placebo
    Number of subjects analysed
    77
    78
    79
    Units: angle
    least squares mean (standard error)
        Change to Week 2, Elbow(n=48, 48, 44)
    33.27 ± 5.246
    29.58 ± 5.268
    21.17 ± 5.602
        Change to Week 4, Elbow (n=48, 47, 47)
    31.49 ± 4.116
    28.63 ± 4.160
    16.78 ± 4.272
        Change to Week 6, Elbow (n=46, 48, 47)
    37.62 ± 4.372
    28.00 ± 4.268
    16.65 ± 4.408
        Change to Week 8, Elbow (n=47, 48, 48)
    31.17 ± 4.238
    23.14 ± 4.188
    15.92 ± 4.276
        Change to Week 12, Elbow (n=46, 48, 48)
    14.69 ± 3.828
    14.06 ± 3.775
    10.19 ± 3.854
        Change to Week 2, Wrist (n=29, 30, 30)
    -15.72 ± 4.096
    -24.20 ± 3.831
    -9.60 ± 3.877
        Change to Week 4, Wrist (n=28, 30, 31)
    -22.97 ± 4.965
    -25.43 ± 4.557
    -12.33 ± 4.447
        Change to Week 6, Wrist (n=28, 30, 30)
    -24.33 ± 5.036
    -18.47 ± 4.641
    -7.22 ± 4.570
        Change to Week 8, Wrist (n=29, 30, 30)
    -20.87 ± 4.621
    -18.90 ± 4.307
    -3.16 ± 4.303
        Change to Week 12, Wrist (n=29, 30, 31)
    -16.87 ± 4.927
    -15.14 ± 4.607
    -1.62 ± 4.509
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change from Baseline to Week 2, Elbow
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.117 [15]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    12.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.089
         upper limit
    27.293
    Notes
    [15] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Change from Baseline to Week 2, Elbow
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.273 [16]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    8.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.717
         upper limit
    23.527
    Notes
    [16] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Change from Baseline to Week 4, Elbow
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.015 [17]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    14.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.958
         upper limit
    26.458
    Notes
    [17] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Change from Baseline to Week 4, Elbow
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.046 [18]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    11.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.203
         upper limit
    23.504
    Notes
    [18] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Change from Baseline to Week 6, Elbow
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [19]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    20.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.801
         upper limit
    33.137
    Notes
    [19] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Change from Baseline to Week 6, Elbow
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.064 [20]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    11.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.662
         upper limit
    23.362
    Notes
    [20] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Change from Baseline to Week 8, Elbow
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.013 [21]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    15.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.317
         upper limit
    27.178
    Notes
    [21] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Change from Baseline to Week 8, Elbow
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.225 [22]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    7.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.488
         upper limit
    18.934
    Notes
    [22] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 9
    Statistical analysis description
    Change from Baseline to Week 12, Elbow
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.409 [23]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.239
         upper limit
    15.236
    Notes
    [23] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 10
    Statistical analysis description
    Change from Baseline to Week 12, Elbow
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.47 [24]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    3.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.69
         upper limit
    14.419
    Notes
    [24] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 11
    Statistical analysis description
    Change from Baseline to Week 2, Wrist
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.263 [25]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -6.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.962
         upper limit
    4.706
    Notes
    [25] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 12
    Statistical analysis description
    Change from Baseline to Week 2, Wrist
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.012 [26]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -14.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.846
         upper limit
    -3.36
    Notes
    [26] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 13
    Statistical analysis description
    Change from Baseline to Week 4, Wrist
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.098 [27]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -10.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.277
         upper limit
    1.996
    Notes
    [27] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 14
    Statistical analysis description
    Change from Baseline to Week 4, Wrist
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.051 [28]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -13.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.26
         upper limit
    0.068
    Notes
    [28] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 15
    Statistical analysis description
    Change from Baseline to Week 6, Wrist
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01 [29]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -17.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -30.031
         upper limit
    -4.189
    Notes
    [29] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 16
    Statistical analysis description
    Change from Baseline to Week 6, Wrist
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.098 [30]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -11.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.622
         upper limit
    2.131
    Notes
    [30] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 17
    Statistical analysis description
    Change from Baseline to Week 8, Wrist
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [31]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -17.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.888
         upper limit
    -5.537
    Notes
    [31] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 18
    Statistical analysis description
    Change from Baseline to Week 8, Wrist
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.015 [32]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -15.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -28.293
         upper limit
    -3.194
    Notes
    [32] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 19
    Statistical analysis description
    Change from Baseline to Week 12, Wrist
    Comparison groups
    BOTOX® 6 U/kg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02 [33]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -15.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -28.01
         upper limit
    -2.492
    Notes
    [33] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 20
    Statistical analysis description
    Change from Baseline to Week 12, Wrist
    Comparison groups
    BOTOX® 3 U/kg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.046 [34]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -13.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.797
         upper limit
    -0.243
    Notes
    [34] - ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) to end of the study (Week 12)
    Adverse event reporting additional description
    The Safety Population, all treated participants based on the treatment received, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    BOTOX® 6 U/kg
    Reporting group description
    Intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).

    Reporting group title
    BOTOX® 3 U/kg
    Reporting group description
    Intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).

    Reporting group title
    Placebo
    Reporting group description
    Intramuscular injections of normal saline (placebo) into specified muscles of the upper limb on Day 1. Participants received weekly OT.

    Serious adverse events
    BOTOX® 6 U/kg BOTOX® 3 U/kg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 78 (1.28%)
    1 / 79 (1.27%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondrosis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 78 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infectious mononucleosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BOTOX® 6 U/kg BOTOX® 3 U/kg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 77 (19.48%)
    12 / 78 (15.38%)
    17 / 79 (21.52%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 78 (2.56%)
    4 / 79 (5.06%)
         occurrences all number
    1
    3
    8
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 77 (2.60%)
    3 / 78 (3.85%)
    5 / 79 (6.33%)
         occurrences all number
    2
    4
    10
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 78 (1.28%)
    4 / 79 (5.06%)
         occurrences all number
    2
    1
    12
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 77 (9.09%)
    4 / 78 (5.13%)
    2 / 79 (2.53%)
         occurrences all number
    8
    4
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 77 (7.79%)
    4 / 78 (5.13%)
    5 / 79 (6.33%)
         occurrences all number
    7
    5
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Apr 2012
    Amendment 1: -Corrected typographical error regarding the maximum dose allowed in the 3 U/kg group to read “not to exceed 100 U” -Clarified that in the primary efficacy analyses, if a pairwise comparison in MAS-B was not statistically significant, the corresponding pairwise comparison in CGI by Physician would not be considered statistically significant regardless of the actual p value -Added clarification of when dose effectiveness would be concluded to address comments by US FDA (United States Food and Drug Administration) during the Special Protocol Assessment review -Clarified the ideal order in the timing of the CGI by Physician and spasticity assessments -Revised the question for the Patient-reported Onset of Spasticity Symptom Relief assessment from “have you noticed any treatment effect” to “have you noticed any effect” to minimize potential bias
    28 Jan 2014
    Amendment 2: -Added distinction between US FDA and non-US FDA clinical hypotheses, measures, and analyses -Specified that the C-SSRS (Columbia Suicide Severity Rating Scale) was to be performed as a safety measure for participants ≥ 6 years of age at Day 1, and provided description of scale, data handling, and reference information -Added participant-reported benefit of injection question -Modified Exclusion regarding seizure frequency for exclusion -Modified Exclusion regarding vulnerable respiratory state -Added Exclusion to exclude participants with significant risk of suicide from treatment -Added a statement that participants may have stayed in the study even if a prohibited medication was administered -Clarified that school-based therapy, if relevant per local legislation, was permitted during the study -Added “or EMG” to the devices for muscle localization techniques -The original multiple testing procedure (Fisher’s Protected Testing procedure) was changed to a gatekeeping procedure to control type I error rate -Pairwise comparison for high dose (BOTOX 6 U/kg) versus low dose (BOTOX 3 U/kg) was removed to incorporate US FDA recommendation -Overall test for among-group comparison was removed since the gatekeeping procedure for the 2 pairwise comparisons was sufficient -Clarified that CGI by Physician was removed for non-US FDA primary analyses and was added for non-US FDA analyses as a secondary measure -Removed subgroup efficacy analyses by type of anesthesia -Revised sample size calculation to base the calculation on a 2-sample t-test -Removed passive range of motion bullet to indicate that assessment of passive range of motion could be performed as part of the MTS using the angle of slow stretch (R2) -Clarified that MAS-B and MTS for finger flexors were to be analyzed for the subgroup of participants with wrist identified as the principal muscle group
    22 Jul 2016
    Amendment 3: -Number of participants and sample size calculations were revised such that the estimated number of participants needed to complete study decreased from 351 to 213 based on adjusted treatment differences from upper limb studies -The intent-to-treat (ITT) population was replaced with the mITT population based on US FDA recommendation -Text describing sensitivity analyses was edited to spell out the covariate and factors in the MMRM model -Edited text and figure to specify that the principal muscle group should have been the wrist in participants with the same MAS-B scores in the elbow and the wrist at baseline -Added a responder status based on +1 score of CGI by Physician -The sensitivity analyses of MAS-B and CGI were changed to use the MI method for missing values instead of observed cases; sensitivity analyses using last observation carried forward (LOCF) were removed -The primary MAS-B analysis and US FDA coprimary MAS-B and CGI analyses were changed to use MMRM with observed data; ANCOVA with MI and observed data were used as sensitivity analyses -Subgroup analyses of AEs were deleted -Changed the multiple testing procedure (gatekeeping procedure) to the Hochberg procedure for the coprimary analysis for US FDA

    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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