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

    Summary
    EudraCT number
    2012-000042-35
    Trial protocol
    DE   PL   HU   IT  
    Global end of trial date
    28 Jun 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    191622-111
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01603628
    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
    Allergan Limited, EU Regulatory Department, +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
    28 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 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 lower 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
    11 Sep 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
    Poland: 137
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 96
    Country: Number of subjects enrolled
    United States: 84
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Philippines: 4
    Worldwide total number of subjects
    384
    EEA total number of subjects
    156
    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)
    326
    Adolescents (12-17 years)
    58
    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 lower limb spasticity were randomized 1:1:1 to one of three treatment groups: BOTOX® 4 or 8 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® 8 U/kg
    Arm description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 units (U) per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).
    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 lower limb.

    Arm title
    BOTOX® 4 U/kg
    Arm description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.
    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 lower limb.

    Arm title
    Placebo
    Arm description
    Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.
    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® 8 U/kg BOTOX® 4 U/kg Placebo
    Started
    128
    126
    130
    Completed
    125
    123
    128
    Not completed
    3
    3
    2
         Personal Reasons
    1
    1
    2
         Other Miscellaneous Reason
    1
    -
    -
         Lost to follow-up
    -
    1
    -
         Protocol deviation
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BOTOX® 8 U/kg
    Reporting group description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 units (U) per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).

    Reporting group title
    BOTOX® 4 U/kg
    Reporting group description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.

    Reporting group title
    Placebo
    Reporting group description
    Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.

    Reporting group values
    BOTOX® 8 U/kg BOTOX® 4 U/kg Placebo Total
    Number of subjects
    128 126 130 384
    Age categorical
    Units: Subjects
        Children (2-11 years)
    108 110 108 326
        Adolescents (12-17 years)
    20 16 22 58
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    6.7 ( 3.9 ) 6.4 ( 3.6 ) 6.6 ( 3.9 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    57 58 62 177
        Male
    71 68 68 207
    Modified Ashworth Scale-Bohannon (MAS-B) Ankle Score with Knee Extended
    The MAS-B evaluates spasticity, grading the resistance encountered in the principal muscle group (elbow and wrist) by passively moving a limb through its range of motion at a specified velocity. The resistance encountered to passive stretch was graded on a 6-point scale: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). 2 participants in the Placebo arm are not included in the analysis.
    Units: score on a scale
        arithmetic mean (standard deviation)
    3.5 ( 0.52 ) 3.5 ( 0.53 ) 3.5 ( 0.50 ) -

    End points

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    End points reporting groups
    Reporting group title
    BOTOX® 8 U/kg
    Reporting group description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 units (U) per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).

    Reporting group title
    BOTOX® 4 U/kg
    Reporting group description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.

    Reporting group title
    Placebo
    Reporting group description
    Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.

    Subject analysis set title
    BOTOX® 8 U/kg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 units (U) per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).

    Subject analysis set title
    BOTOX® 4 U/kg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.

    Primary: Average Change from Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Ankle Score with Knee Extended at Weeks 4 and 6

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    End point title
    Average Change from Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Ankle Score with Knee Extended 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 mITT population, all randomized participants with a valid MAS-B baseline ankle score with knee extended and at least one post-baseline measurement at Weeks 2, 4, or 6 for the MAS-B of the ankle score with knee extended 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® 8 U/kg BOTOX® 4 U/kg Placebo
    Number of subjects analysed
    123
    119
    125
    Units: score on a scale
        least squares mean (standard error)
    -1.06 ( 0.071 )
    -1.01 ( 0.072 )
    -0.80 ( 0.071 )
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01 [1]
    Method
    Mixed Model Repeated Measures
    Parameter type
    Least Squares (LS) Mean Difference
    Point estimate
    -0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.453
         upper limit
    -0.063
    Notes
    [1] - MMRM including baseline MAS-B ankle score (knee extended) as a covariate and factors of age, treatment, visit, treatment-by-visit interaction, study center and previous botulinum toxin exposure where age is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.033 [2]
    Method
    Mixed Model Repeated Measures
    Parameter type
    LS Mean Difference
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.405
         upper limit
    -0.018
    Notes
    [2] - MMRM including baseline MAS-B ankle score (knee extended) as a covariate and factors of age, treatment, visit, treatment-by-visit interaction, study center and previous botulinum toxin exposure where age is represented by stratification 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 Mixed Model Repeated Measures (MMRM) model was used for analysis. Participants from the mITT population, all randomized participants with a valid MAS-B baseline ankle score with knee extended and at least one post-baseline measurement at Weeks 2, 4, or 6 for the MAS-B of the ankle score with knee extended and the CGI by physician, with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Weeks 4 and 6
    End point values
    BOTOX® 8 U/kg BOTOX® 4 U/kg Placebo
    Number of subjects analysed
    123
    118
    124
    Units: score on a scale
        least squares mean (standard error)
    1.65 ( 0.090 )
    1.49 ( 0.091 )
    1.36 ( 0.089 )
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.023 [3]
    Method
    Mixed Model Repeated Measures
    Parameter type
    LS Mean Difference
    Point estimate
    0.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    0.532
    Notes
    [3] - MMRM including baseline MAS-B ankle score (knee extended) as a covariate and factors of age, treatment, visit, treatment-by-visit interaction, study center and previous botulinum toxin exposure where age is represented by stratification categories.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.299 [4]
    Method
    Mixed Model Repeated Measures
    Parameter type
    LS Mean Difference
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.115
         upper limit
    0.374
    Notes
    [4] - MMRM including baseline MAS-B ankle score (knee extended) as a covariate and factors of age, treatment, visit, treatment-by-visit interaction, study center and previous botulinum toxin exposure where age 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 Analysis of Covariance (ANCOVA) model was used for analysis. The Modified ITT population includes all randomized participants with a valid MAS-B baseline ankle score with knee extended and at least one post-baseline measurement at Weeks 2, 4, or 6 for the MAS-B of the ankle score with knee extended and the CGI by physician, with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Weeks 8 and 12
    End point values
    BOTOX® 8 U/kg BOTOX® 4 U/kg Placebo
    Number of subjects analysed
    127
    125
    129
    Units: score on a scale
    least squares mean (standard error)
        Week 8, Active Goal (n=121, 121, 127)
    0.10 ( 0.108 )
    -0.03 ( 0.108 )
    -0.31 ( 0.105 )
        Week 8, Passive Goal (n=120, 121, 127)
    0.19 ( 0.115 )
    0.18 ( 0.114 )
    -0.26 ( 0.111 )
        Week 12, Active Goal (n=124, 123, 128)
    0.37 ( 0.112 )
    0.09 ( 0.113 )
    -0.12 ( 0.111 )
        Week 12, Passive Goal (n=124, 123, 128)
    0.40 ( 0.114 )
    0.27 ( 0.114 )
    0.00 ( 0.112 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 8, Active Goal
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [5]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.126
         upper limit
    0.704
    Notes
    [5] - ANCOVA model including baseline MAS-B ankle score with knee extended 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
    Statistical analysis description
    Week 8, Active Goal
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.047 [6]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.004
         upper limit
    0.573
    Notes
    [6] - ANCOVA model including baseline MAS-B ankle score with knee extended 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 3
    Statistical analysis description
    Week 8, Passive Goal
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004 [7]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.145
         upper limit
    0.756
    Notes
    [7] - ANCOVA model including baseline MAS-B ankle score with knee extended 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 4
    Statistical analysis description
    Week 8, Passive Goal
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004 [8]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.141
         upper limit
    0.74
    Notes
    [8] - ANCOVA model including baseline MAS-B ankle score with knee extended 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 5
    Statistical analysis description
    Week 12, Active Goal
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [9]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.191
         upper limit
    0.797
    Notes
    [9] - ANCOVA model including baseline MAS-B ankle score with knee extended 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 6
    Statistical analysis description
    Week 12, Active Goal
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.153 [10]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.081
         upper limit
    0.541
    Notes
    [10] - ANCOVA model including baseline MAS-B ankle score with knee extended 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 7
    Statistical analysis description
    Week 12, Passive Goal
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01 [11]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    0.711
    Notes
    [11] - ANCOVA model including baseline MAS-B ankle score with knee extended 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 8
    Statistical analysis description
    Week 12, Passive Goal
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.078 [12]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.031
         upper limit
    0.571
    Notes
    [12] - ANCOVA model including baseline MAS-B ankle score with knee extended 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: Change from Baseline in Severity of Spasticity of the Ankle with Knee Extended and Knee Flexed (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 Ankle with Knee Extended and Knee Flexed (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 determined 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 fast velocity passive stretch determining the dynamic component of the muscle contracture for the joint. The investigator measured 2 joint angles by goniometer: the R1 angle which is the angle of catch after a V3 stretch and the R2 angle defined as the passive joint range of movement following a V1 stretch. The R2–R1 value indicated the level of the dynamic component of spasticity in the joint. The difference between R2 and R1 range of motion and respective change from baseline to each posttreatment office visit on the MTS was derived. An Analysis of Covariance (ANCOVA) model was used for analysis. The mITT population was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Weeks 2, 4, 6, 8 and 12
    End point values
    BOTOX® 8 U/kg BOTOX® 4 U/kg Placebo
    Number of subjects analysed
    127
    125
    129
    Units: angle
    least squares mean (standard error)
        Change from Baseline to Week 2 (n=126, 124, 129)
    -4.44 ( 1.023 )
    -5.69 ( 1.024 )
    -2.44 ( 1.0101 )
        Change from Baseline to Week 4 (n-124, 121, 126)
    -6.11 ( 1.134 )
    -6.80 ( 1.135 )
    -4.69 ( 1.121 )
        Change from Baseline to Week 6 (n=126, 121, 126)
    -6.65 ( 1.029 )
    -7.23 ( 1.049 )
    -3.32 ( 1.029 )
        Change from Baseline to Week 8 (n=122, 123, 127)
    -5.42 ( 1.317 )
    -5.82 ( 1.308 )
    -3.36 ( 1.291 )
        Change from Baseline to Week 12 (n=125, 123, 128)
    -4.59 ( 1.070 )
    -3.07 ( 1.074 )
    -1.98 ( 1.057 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change from Baseline to Week 2
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.158 [13]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -1.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.768
         upper limit
    0.779
    Notes
    [13] - ANCOVA model including baseline MTS ankle score with knee extended 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
    Statistical analysis description
    Change from Baseline to Week 2
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02 [14]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -3.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.974
         upper limit
    -0.524
    Notes
    [14] - ANCOVA model including baseline MTS ankle score with knee extended 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 3
    Statistical analysis description
    Change from Baseline to Week 4
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.363 [15]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -1.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.489
         upper limit
    1.648
    Notes
    [15] - ANCOVA model including baseline MTS ankle score with knee extended 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 4
    Statistical analysis description
    Change from Baseline to Week 4
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.171 [16]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.127
         upper limit
    0.914
    Notes
    [16] - ANCOVA model including baseline MTS ankle score with knee extended 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 5
    Statistical analysis description
    Change from Baseline to Week 6
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02 [17]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -3.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.143
         upper limit
    -0.525
    Notes
    [17] - ANCOVA model including baseline MTS ankle score with knee extended 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 6
    Statistical analysis description
    Change from Baseline to Week 6
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006 [18]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -3.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.688
         upper limit
    -1.148
    Notes
    [18] - ANCOVA model including baseline MTS ankle score with knee extended 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 7
    Statistical analysis description
    Change from Baseline to Week 8
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.254 [19]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.621
         upper limit
    1.491
    Notes
    [19] - ANCOVA model including baseline MTS ankle score with knee extended 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 8
    Statistical analysis description
    Change from Baseline to Week 8
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.165 [20]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.935
         upper limit
    1.014
    Notes
    [20] - ANCOVA model including baseline MTS ankle score with knee extended 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 9
    Statistical analysis description
    Change from Baseline to Week 12
    Comparison groups
    BOTOX® 8 U/kg v Placebo
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.078 [21]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.517
         upper limit
    0.296
    Notes
    [21] - ANCOVA model including baseline MTS ankle score with knee extended 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 10
    Statistical analysis description
    Change from Baseline to Week 12
    Comparison groups
    BOTOX® 4 U/kg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.451 [22]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.944
         upper limit
    1.758
    Notes
    [22] - ANCOVA model including baseline MTS ankle score with knee extended 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.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) to the end of 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® 8 U/kg
    Reporting group description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT).

    Reporting group title
    Placebo
    Reporting group description
    Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb. Participants received weekly PT.

    Reporting group title
    BOTOX® 4 U/kg
    Reporting group description
    Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT.

    Serious adverse events
    BOTOX® 8 U/kg Placebo BOTOX® 4 U/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 128 (0.00%)
    4 / 128 (3.13%)
    3 / 126 (2.38%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Extrasystoles
         subjects affected / exposed
    0 / 128 (0.00%)
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 128 (0.00%)
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 128 (0.00%)
    2 / 128 (1.56%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radicular Pain
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 128 (0.00%)
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastoeneteritis
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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® 8 U/kg Placebo BOTOX® 4 U/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 128 (18.75%)
    35 / 128 (27.34%)
    26 / 126 (20.63%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 128 (3.91%)
    7 / 128 (5.47%)
    8 / 126 (6.35%)
         occurrences all number
    5
    14
    8
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    12 / 128 (9.38%)
    22 / 128 (17.19%)
    14 / 126 (11.11%)
         occurrences all number
    12
    56
    19
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 128 (6.25%)
    9 / 128 (7.03%)
    10 / 126 (7.94%)
         occurrences all number
    9
    20
    19

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2012
    -The primary efficacy analyses were reworded to specify that 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. -Addition of Section 7.7 Additional Analysis/Inference for US FDA to clarify when dose effectiveness would be concluded. This change addressed US FDA (United States Food and Drug Administration) comments during Special Protocol Assessment review. -Revised approximate volume of blood collection for hematology and chemistry laboratory assessments from 5 to 7 mL (milliliters) (participants weighing < 15 kg) and from 12 to 14 mL (participants weighing ≥ 15 kg) to meet revised central laboratory requirements. -Revised participant-reported onset of spasticity symptom relief question from “have you noticed any treatment effect…” to “have you noticed any effect…” to minimize potential bias based on central IRB requirement.
    28 Jan 2014
    -Amended primarily to add assessment of suicidal ideation/behavior using the C-SSRS as a standard safety measure required by the US FDA’s Division of Neurology Products. -Added distinction between US FDA and non-US FDA clinical hypotheses and analyses. -Added participant-reported benefit of injection as an efficacy measure. -Specified that C-SSRS 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. Request from US FDA. -Revised Inclusion Criterion and screening procedure to remove requirement of true equinus foot deformity referenced in Rodda and Graham. Clarified gait pattern analysis not required to confirm equinus foot deformity. -Revised Exclusion Criterion to remove definition of significant knee spasticity. -Modified Exclusion Criterion regarding seizure frequency for exclusion. -Added Exclusion Criterion to exclude participants with significant suicidality from treatment so as to avoid data confounding. -Clarified that participants could stay in the study even if prohibited medication was administered -Clarified MTS scale description by adding “with knee extended and knee flexed”. -Changed multiple testing procedure to gatekeeping procedure to control type I error rate -Removed pairwise comparison for higher dose versus lower dose to incorporate US FDA recommendation. -Removed overall test for among group comparison. Gatekeeping procedure sufficient to control type I error rate -Removed subgroup efficacy analyses by type of anesthesia. -Revised sample size calculation to base the calculation on 2 sample t test as the overall test for among group comparison was removed. -Removed requirement that urine pregnancy test must be performed prior to study treatment. -Updated serious adverse event reporting procedures -Revised MAS-B description so the assessment could be performed by other qualified site personnel.
    25 Jul 2016
    -Protocol amended primarily to modify the statistical methods (introduction of the Hochberg procedure, change in imputation methods, and sensitivity analyses) to reflect the simultaneous changes being made to Protocol 191622-101. -The ITT population was replaced with the mITT population (defined as all randomized participants with a valid MAS-B at baseline of the principal muscle group and ≥ 1 postbaseline measurement at Weeks 2, 4, or 6 for the MAS-B of the principal muscle group and CGI by Physician). Revised based on US FDA recommendation. -Added a responder status based on +1 score of CGI by Physician. -Changed sensitivity analyses of MAS-B and CGI by Physician to use the MI method for missing values instead of observed cases and deleted sensitivity analyses using LOCF. Revised to address US FDA feedback. -Changed primary MAS-B analysis and coprimary MAS-B and CGI by Physician (for US FDA) analyses to use MMRM with observed data; ANCOVA with MI and observed data was used as sensitivity analyses. Revised to address US FDA feedback. -Deleted subgroup analyses of adverse events because deemed unnecessary. -Changed multiple testing procedure (gatekeeping procedure) to Hochberg procedure for the coprimary analysis (for US FDA) to control type I error rate.

    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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