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    Clinical Trial Results:
    Prospective, multicenter, randomized, double-blind, parallel-group, dose-response study of three doses Xeomin® (incobotulinumtoxinA, NT 201) for the treatment of lower limb spasticity in children and adolescents (age 2 - 17 years) with cerebral palsy

    Summary
    EudraCT number
    		 2012-005054-30
    Trial protocol
    		 EE   AT   DE   SK   CZ   ES   Outside EU/EEA   FR  
    Global end of trial date
    11 May 2016

    Results information
    Results version number
    		 v1
    This version publication date
    24 Nov 2016
    First version publication date
    24 Nov 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    MRZ60201_3070_1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01893411
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merz Pharmaceuticals GmbH
    Sponsor organisation address
    Eckenheimer Landstrasse 100, Frankfurt/M, Germany, 60318
    Public contact
    Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, clinicaltrials@merz.de
    Scientific contact
    Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, clinicaltrials@merz.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001039-PIP01-10
    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
    29 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to investigate the dose-response of Botulinum neurotoxin type A free from complexing proteins (NT 201) in subjects with Lower limb (LL) spasticity due toCerebral palsy (CP) after injection treatment in three parallel dose groups: 16 Units [U]/kg body weight [BW] NT 201 with a maximum total dose of 400 U in the high dose group, 12 U/kg BW NT 201 with a maximum total dose of 300 U in the mid dose group, and 4 U/kg BW NT 201 with a maximum total dose of 100 U in the low dose group. Two injection treatments were followed by 12 to 36 weeks observation each (overall duration: 24-72 weeks).
    Protection of trial subjects
    High medical and ethical standards were followed in accordance with Good Clinical Practice and other applicable regulations. In addition, an independent data monitoring committee was in charge of monitoring patient safety while the study was ongoing.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jul 2013
    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: 61
    Country: Number of subjects enrolled
    Slovakia: 14
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    Ukraine: 107
    Country: Number of subjects enrolled
    Korea, Republic of: 54
    Country: Number of subjects enrolled
    Romania: 9
    Worldwide total number of subjects
    311
    EEA total number of subjects
    113
    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)
    261
    Adolescents (12-17 years)
    50
    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
    		 A total of 338 subjects were screened and 311 subjects were randomised and treated with high dose (156 subjects), mid dose (77 subjects) and low dose (78 subjects).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin)
    Arm description
    		 Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Incobotulinumtoxin A
    Investigational medicinal product code
    NT 201
    Other name
    Xeomin; Botulinum toxin type A (150 kiloDalton) free from complexing proteins
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.

    Arm title
    		 Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin)
    Arm description
    		 Subjects received 12 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Incobotulinumtoxin A
    Investigational medicinal product code
    NT 201
    Other name
    Xeomin; Botulinum toxin type A (150 kiloDalton) free from complexing proteins
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 12 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.

    Arm title
    		 Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Arm description
    		 Subjects received 4 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Incobotulinumtoxin A
    Investigational medicinal product code
    NT 201
    Other name
    Xeomin; Botulinum toxin type A (150 kiloDalton) free from complexing proteins
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 4 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.

    Number of subjects in period 1
    		High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Started
    156
    77
    78
    Completed
    139
    70
    69
    Not completed
    17
    7
    9
         Physician decision
    1
    1
    2
         Consent withdrawn by subject
    7
    4
    3
         Adverse event, non-fatal
    1
    -
    -
         Not specified
    3
    1
    3
         Lost to follow-up
    2
    -
    1
         Lack of efficacy
    2
    1
    -
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin)
    Reporting group description
    		 Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.

    Reporting group title
    Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin)
    Reporting group description
    		 Subjects received 12 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.

    Reporting group title
    Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Reporting group description
    		 Subjects received 4 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.

    Reporting group values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin) Total
    Number of subjects
    		 156 77 78 311
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 131 67 63 261
        Adolescents (12-17 years)
    		 25 10 15 50
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.4 ( 3.9 ) 6.6 ( 3.8 ) 7.1 ( 4.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 83 44 42 169
        Male
    		 73 33 36 142

    End points

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    End points reporting groups
    Reporting group title
    High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin)
    Reporting group description
    		 Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.

    Reporting group title
    Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin)
    Reporting group description
    		 Subjects received 12 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.

    Reporting group title
    Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Reporting group description
    		 Subjects received 4 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS) population is subset in the Safety evaluation set (SES) for whom the primary efficacy variable (for all subjects who had at least an AS score of plantar flexor at baseline [Day 1 of the first injection cycle] or the investigator’s Global Impression of Change of Plantar Flexor Spasticity Scale (GICS-PF) [for subjects with bilateral treatment on same body side as chosen for the primary efficacy variable] at Day 29 [Week 4] of the first injection cycle) were available as part of end points reporting groups

    Primary: Change From Baseline in the Ashworth Scale (AS) Score of Plantar Flexors of the primary body side at Day 29 (week 4) of the 1st Injection Cycle

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    End point title
    		 Change From Baseline in the Ashworth Scale (AS) Score of Plantar Flexors of the primary body side at Day 29 (week 4) of the 1st Injection Cycle
    End point description
    The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spasticmuscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (=noincrease in tone) to 4 (=limb rigid in flexion or extension). For subjects with bilateral pes equinus, the body side for primary efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. For subjects with unilateral treatment, the treated body side was kept throughout the entire study. '1st IC' indicates 1st injection cycle. Values represent least square (LS) means resulting from MMRM models comparing high versus low and mid versus low. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Primary
    End point timeframe
    Baseline to week 4
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        Week 4 of 1st IC (high versus low; n=156, 78)
    -0.7 ( 0.061 )
    999 ( 999 )
    -0.66 ( 0.084 )
        Week 4 of 1st IC (mid versus low; n=77, n=78)
    999 ( 999 )
    -0.7 ( 0.089 )
    -0.66 ( 0.088 )
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) v Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 Mixed Model Repeated Measure
    Parameter type
    		 LS-Mean difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.14
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) v Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.741
    Method
    		 Mixed Model Repeated Measure
    Parameter type
    		 LS-Mean difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.18

    Primary: Co-primary Variable: Investigator's Global Impression of Change of Plantar Flexor Spasticity Scale (GICS-PF) of the primary body side at Day 29 (week 4) of the 1st Injection Cycle

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    End point title
    		 Co-primary Variable: Investigator's Global Impression of Change of Plantar Flexor Spasticity Scale (GICS-PF) of the primary body side at Day 29 (week 4) of the 1st Injection Cycle
    End point description
    This variable is classified as co-primary to satisfy a FDA request. The GICS-PF scale is a 7-Point Likert Scale for the assessment of the functional change due to treatmentof plantar flexor spasticity only. Ranges from +3 (very much improved function) to -3 (very much worsefunction). For subjects with bilateral pes equinus, the body side for primary efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. For subjects with unilateral treatment, the treated body side was kept throughout the entire study. '1st IC' indicates 1st injection cycle. Values represent least square (LS) means resulting from ANCOVA models comparing high versus low and mid versus low. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Primary
    End point timeframe
    Baseline to week 4
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        Week 4 of 1st IC (high versus low; n=156, 78)
    1.53 ( 0.059 )
    999 ( 999 )
    1.37 ( 0.081 )
        Week 4 of 1st IC (mid versus low; n=77, n=78)
    999 ( 999 )
    1.38 ( 0.092 )
    1.32 ( 0.09 )
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) v Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.075
    Method
    		 Mixed Model Repeated Measure
    Parameter type
    		 LS-Mean difference
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.34
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) v Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.603
    Method
    		 Mixed Model Repeated Measure
    Parameter type
    		 LS-Mean difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.27

    Secondary: Change From Baseline in the AS Score of Plantar Flexors of the non-primary body side in subjects with bilateral treatment at Day 29 (week 4) of the 1st and 2nd Injection Cycle

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    End point title
    		 Change From Baseline in the AS Score of Plantar Flexors of the non-primary body side in subjects with bilateral treatment at Day 29 (week 4) of the 1st and 2nd Injection Cycle
    End point description
    The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spasticmuscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). '1st IC' and '2nd IC' indicates 1st and 2nd injection cycle. Values represent least square (LS) means resulting from MMRM models comparing high versus low and mid versus low. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline to week 4 of 1st IC and 2nd IC (week 16-40)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        Week 4 of 1st IC (high versus low; n=114, 54)
    -0.76 ( 0.073 )
    999 ( 999 )
    -0.61 ( 0.104 )
        Week 4 of 1st IC (mid versus low; n=58, 54)
    999 ( 999 )
    -0.6 ( 0.105 )
    -0.58 ( 0.108 )
        Week 4 of 2nd IC (high versus low; n=104, 53)
    -0.95 ( 0.077 )
    999 ( 999 )
    -0.74 ( 0.106 )
        Week 4 of 2nd IC (mid versus low; n=53, 53)
    999 ( 999 )
    -0.85 ( 0.124 )
    -0.76 ( 0.123 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the AS Score of Plantar Flexors of the primary body side at Day 29 (week 4) of the 2nd Injection Cycle

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    End point title
    		 Change From Baseline in the AS Score of Plantar Flexors of the primary body side at Day 29 (week 4) of the 2nd Injection Cycle
    End point description
    The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spasticmuscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). For subjects with bilateral pes equinus, the body side for primary efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. For subjects with unilateral treatment, the treated body side was kept throughout the entire study. '2nd IC' indicates 2nd injection cycle. Values represent least square (LS) means resulting from MMRM models comparing high versus low and mid versus low. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline to week 4 of 2nd IC (week 16-40)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        Week 4 of 1st IC (high versus low; n=143, 73)
    -0.89 ( 0.061 )
    999 ( 999 )
    -0.82 ( 0.082 )
        Week 4 of 1st IC (mid versus low; n=71, n=73)
    999 ( 999 )
    -1.03 ( 0.094 )
    -0.85 ( 0.091 )
    No statistical analyses for this end point

    Secondary: Changes From Baseline in AS Score of Plantar Flexors of the primary body side at Day 57 (week 8) and Day 85 (week 12) of the 1st and of the 2nd Injection Cycle

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    End point title
    		 Changes From Baseline in AS Score of Plantar Flexors of the primary body side at Day 57 (week 8) and Day 85 (week 12) of the 1st and of the 2nd Injection Cycle
    End point description
    The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spasticmuscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). For subjects with bilateral pes equinus, the body side for primary efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. For subjects with unilateral treatment, the treated body side was kept throughout the entire study. '1st IC' and '2nd IC' indicates 1st and 2nd injection cycle. Values represent least square (LS) means resulting from MMRM models comparing high versus low and mid versus low. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline to week 8 and 12 of 1st IC and 2nd IC (week 20-44 and 24-48)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        Week 8 of 1st IC (high versus low; n=156, 78)
    -0.62 ( 0.059 )
    999 ( 999 )
    -0.69 ( 0.08 )
        Week 8 of 1st IC (mid versus low; n=77, n=78)
    999 ( 999 )
    -0.74 ( 0.088 )
    -0.69 ( 0.086 )
        Week 12 of 1st IC (high versus low; n=156, 78)
    -0.43 ( 0.056 )
    999 ( 999 )
    -0.58 ( 0.077 )
        Week 12 of 1st IC (mid versus low; n=77, n=78)
    999 ( 999 )
    -0.45 ( 0.086 )
    -0.59 ( 0.085 )
        Week 8 of 2nd IC (high versus low; n=143, 73)
    -0.76 ( 0.058 )
    999 ( 999 )
    -0.76 ( 0.079 )
        Week 8 of 2nd IC (mid versus low; n=71, 73)
    999 ( 999 )
    -0.92 ( 0.092 )
    -0.79 ( 0.09 )
        Week 12 of 2nd IC (high versus low; n=143, 73)
    -0.57 ( 0.058 )
    999 ( 999 )
    -0.65 ( 0.079 )
        Week 12 of 2nd IC (mid versus low; n=71, 73)
    999 ( 999 )
    -0.64 ( 0.088 )
    -0.68 ( 0.085 )
    No statistical analyses for this end point

    Secondary: Changes From Baseline in AS Score of Knee Flexors or Thigh Adductors in subjects with unilateral treatment at Day 29 (week 4) of the 1st and of the 2nd Injection Cycle

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    End point title
    		 Changes From Baseline in AS Score of Knee Flexors or Thigh Adductors in subjects with unilateral treatment at Day 29 (week 4) of the 1st and of the 2nd Injection Cycle
    End point description
    The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spasticmuscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). '1st IC' and '2nd IC' indicates 1st and 2nd injection cycle. Values represent least square (LS) means resulting from MMRM models comparing high versus low and mid versus low. KF = Knee Flexors; TA = Thigh Adductors; w = week. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline to week 4 of 1st IC and 2nd IC (week 16-40)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        KF, w 4 of 1st IC (high versus low; n=30, 19)
    -0.6 ( 0.18 )
    999 ( 999 )
    -0.39 ( 0.214 )
        KF, w 4 of 1st IC (mid versus low; n=11, 19)
    999 ( 999 )
    -0.07 ( 0.285 )
    -0.32 ( 0.204 )
        KF, w 4 of 2nd IC (high versus low; n=27, 16)
    -0.64 ( 0.173 )
    999 ( 999 )
    -0.79 ( 0.2 )
        KF, w 4 of 2nd IC (mid versus low; n=10, 16)
    999 ( 999 )
    -0.31 ( 0.269 )
    -0.67 ( 0.19 )
        TA, w 4 of 1st IC (high versus low; n=12, 5)
    -0.61 ( 0.287 )
    999 ( 999 )
    -0.76 ( 0.506 )
        TA, w 4 of 1st IC (mid versus low; n=12, 5)
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        TA, w 4 of 2nd IC (high versus low; n=11, 4)
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        TA, w 4 of 2nd IC (mid versus low; n=8, 4)
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Modified Tardieu Scale [MTS] of plantar flexors of primary body side at Day 29 (week 4), Day 57 (week 8), and Day 85 (week 12) of the 1st and of the 2nd Injection Cycle

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    End point title
    		 Changes From Baseline in Modified Tardieu Scale [MTS] of plantar flexors of primary body side at Day 29 (week 4), Day 57 (week 8), and Day 85 (week 12) of the 1st and of the 2nd Injection Cycle
    End point description
    The Modified Tardieu Scale (MTS) assesses spastic muscle tone by subtraction of two angles measuredat different conditions of passive muscle stretch. R2 is the angle of passive range of motion with apassive movement at slow speed. R1 is the angle where a "catch-and-release" or clonus can betriggered at the fastest possible speed. For subjects with bilateral pes equinus, the body side for primary efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. For subjects with unilateral treatment, the treated body side was kept throughout the entire study. '1st IC' and '2nd IC' indicates 1st and 2nd injection cycle. Values represent least square (LS) means resulting from ANCOVA models comparing high versus low and mid versus low. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline to week 4, 8, and 12 of 1st IC and 2nd IC (week 16-40, 20-44 and 24-48)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        Week 4 of 1st IC (high versus low; n=156, 78)
    -2.38 ( 0.897 )
    999 ( 999 )
    -2.56 ( 1.231 )
        Week 4 of 1st IC (mid versus low; n=77, 78)
    999 ( 999 )
    -0.88 ( 1.389 )
    -2.47 ( 1.367 )
        Week 8 of 1st IC (high versus low; n=156, 78)
    -3.15 ( 0.921 )
    999 ( 999 )
    -2.63 ( 1.267 )
        Week 8 of 1st IC (mid versus low; n=77, 78)
    999 ( 999 )
    -1.74 ( 1.393 )
    -2.56 ( 1.372 )
        Week 12 of 1st IC (high versus low; n=156, 78)
    -3.1 ( 0.848 )
    999 ( 999 )
    -2.67 ( 1.157 )
        Week 12 of 1st IC (mid versus low; n=77, 78)
    999 ( 999 )
    -0.07 ( 1.231 )
    -2.59 ( 1.213 )
        Week 4 of 2nd IC (high versus low; n=143, 73)
    -4.72 ( 1.173 )
    999 ( 999 )
    -3.83 ( 1.594 )
        Week 4 of 2nd IC (mid versus low; n=71, 73)
    999 ( 999 )
    -3.24 ( 1.773 )
    -3.6 ( 1.713 )
        Week 8 of 2nd IC (high versus low; n=143, 73)
    -4.72 ( 1.065 )
    999 ( 999 )
    -4.25 ( 1.44 )
        Week 8 of 2nd IC (mid versus low; n=71, 73)
    999 ( 999 )
    -2.97 ( 1.634 )
    -4.04 ( 1.575 )
        Week 12 of 2nd IC (high versus low; n=143, 73)
    -4.27 ( 0.968 )
    999 ( 999 )
    -5.68 ( 1.298 )
        Week 12 of 2nd IC (mid versus low; n=71, 73)
    999 ( 999 )
    -2.12 ( 1.519 )
    -5.45 ( 1.455 )
    No statistical analyses for this end point

    Secondary: Investigator's, Child's/Adolescent's, and Parent's/Caregiver's Global Impression of Change Scale [GICS] at Day 29 (week 4) of the 1st and 2nd Injection Cycle

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    End point title
    		 Investigator's, Child's/Adolescent's, and Parent's/Caregiver's Global Impression of Change Scale [GICS] at Day 29 (week 4) of the 1st and 2nd Injection Cycle
    End point description
    The Global Impression of Change Scales (GICS) are global outcomes to assess the impression of change due to treatment. GICS will be assessed by the investigator, by the subject (if feasible) and by parents'/caregiver (if applicable). GICS are 7-Point Likert Scales ranging from +3 (very much improved function) to -3 (very much worse function). '1st IC' and '2nd IC' indicates 1st and 2nd injection cycle. Values represent least square (LS) means resulting from MMRM models comparing high versus low and mid versus low. Inv = Investigator; S = Subject; P/C = Parent/Caregiver. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline to week 4 of 1st IC and 2nd IC (week 16-40)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        Inv, 1st IC (high versus low; n=156, 78)
    1.5 ( 0.056 )
    999 ( 999 )
    1.35 ( 0.076 )
        Inv, 1st IC (mid versus low; n=77, 78)
    999 ( 999 )
    1.36 ( 0.087 )
    1.33 ( 0.086 )
        S, 1st IC (high versus low; n=67, 41)
    1.72 ( 0.205 )
    999 ( 999 )
    1.64 ( 0.223 )
        S, 1st IC (mid versus low; n=42, 41)
    999 ( 999 )
    1.17 ( 0.203 )
    1.3 ( 0.216 )
        P/C, 1st IC (high versus low; n=156, 78)
    1.53 ( 0.068 )
    999 ( 999 )
    1.43 ( 0.092 )
        P/C, 1st IC (mid versus low; n=77, 78)
    999 ( 999 )
    1.26 ( 0.107 )
    1.39 ( 0.105 )
        Inv, 2nd IC (high versus low; n=143, 73)
    1.46 ( 0.071 )
    999 ( 999 )
    1.38 ( 0.096 )
        Inv, 2nd IC (mid versus low; n=77, 73)
    999 ( 999 )
    1.56 ( 0.11 )
    1.46 ( 0.104 )
        S, 2nd IC (high versus low; n=60, 36)
    1.53 ( 0.21 )
    999 ( 999 )
    1.66 ( 0.224 )
        S, 2nd IC (mid versus low; n=39, 36)
    999 ( 999 )
    1.44 ( 0.276 )
    1.53 ( 0.283 )
        P/C, 2nd IC (high versus low; n=143, 73)
    1.45 ( 0.076 )
    999 ( 999 )
    1.34 ( 0.101 )
        P/C, 2nd IC (mid versus low; n=71, 73)
    999 ( 999 )
    1.67 ( 0.115 )
    1.4 ( 0.109 )
    No statistical analyses for this end point

    Secondary: Investigator's Global Impression of Change of GICS-Plantar-Flexor of Primary Body Side at Day 29 (Week 4) of the 1st and 2nd Injection Cycle

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    End point title
    		 Investigator's Global Impression of Change of GICS-Plantar-Flexor of Primary Body Side at Day 29 (Week 4) of the 1st and 2nd Injection Cycle
    End point description
    The Global Impression of Change Scales (GICS) are global outcomes to assess the impression of changedue to treatment. GICS will be assessed by the investigator, by the subject (if feasible) and byparents'/caregiver (if applicable). GICS are 7-Point Likert Scales ranging from +3 (very much improved function) to -3 (very much worse function). For subjects with bilateral pes equinus, the body side for primary efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. For subjects with unilateral treatment, the treated body side was kept throughout the entire study. '1st IC' and '2nd IC' indicates 1st and 2nd injection cycle. The 1st IC data represent the co-primary variable. Values represent least square (LS) means resulting from ANCOVA models comparing high versus low and mid versus low. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline to week 4 of 1st IC and 2nd IC (week 16-40)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        Week 4 of 1st IC (high versus low; n=156, 78)
    1.53 ( 0.059 )
    999 ( 999 )
    1.37 ( 0.081 )
        Week 4 of 1st IC (mid versus low; n=77, 78)
    999 ( 999 )
    1.38 ( 0.092 )
    1.32 ( 0.09 )
        Week 4 of 2nd IC (high versus low; n=143, 73)
    1.43 ( 0.073 )
    999 ( 999 )
    1.38 ( 0.098 )
        Week 4 of 2nd IC (mid versus low; n=71, 73)
    999 ( 999 )
    1.54 ( 0.11 )
    1.48 ( 0.103 )
    No statistical analyses for this end point

    Secondary: Changes from Baseline in Gross Motor Function Measure [GMFM]-66 Score at the End of 1st Cycle and at the End of Study Visit

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    End point title
    		 Changes from Baseline in Gross Motor Function Measure [GMFM]-66 Score at the End of 1st Cycle and at the End of Study Visit
    End point description
    The GMFM-66 is a standardized observational 66-item instrument designed and validated to measurechange in gross motor function over time in subjects with cerebral palsy.'1st IC' indicates 1st injection cycle. Values represent least square (LS) means resulting from ANCOVA models comparing high versus low and mid versus low. W = week. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12-36 of 1st IC and 2nd IC (End of study = week 24-72)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        W 12-36 of 1st IC (high versus low; n=155, 77)
    1.23 ( 0.288 )
    999 ( 999 )
    1.64 ( 0.392 )
        W 12-36 of 1st IC (mid versus low; n=77, 77)
    999 ( 999 )
    1.14 ( 0.448 )
    1.49 ( 0.445 )
        W 12-36 of 2nd IC (high versus low; n=155, 77)
    2.31 ( 0.359 )
    999 ( 999 )
    2.46 ( 0.488 )
        W 12-36 of 2nd IC (mid versus low; n=77, 77)
    999 ( 999 )
    3.1 ( 0.542 )
    2.59 ( 0.539 )
    No statistical analyses for this end point

    Secondary: Change in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) to all Post Baseline Visits of the 1st and of the 2nd Injection Cycle

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    End point title
    		 Change in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) to all Post Baseline Visits of the 1st and of the 2nd Injection Cycle
    End point description
    The QPS is a patient-reported outcome for children and adolescents (2-17 years) with cerebral palsy on spasticity-related pain. Pain intensity (from subjects) and pain frequency (from parent/caregiver) to be assessed with 'Questionnaire on Pain caused by Spasticity [QPS]'. The QPS Total Score for pain intensity ranges from 0 ('No Hurt') to 10 ('Hurt Worst'). The QPS Total Score for the observed pain frequency ranges from 0 (Never) to 4 (Always). '1st IC' and '2nd IC' indicates 1st and 2nd injection cycle. Values represent least square (LS) means resulting from ANCOVA models comparing high versus low and mid versus low. S = Subject; P/C = Parent/Caregiver; w = week. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline to week 4, 8, and 12 of 1st IC and 2nd IC (week 16-40, 20-44 and 24-48)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Units on a scale
    least squares mean (standard error)
        S, w 4 of 1st IC (high versus low; n=72, 42)
    -0.66 ( 0.198 )
    999 ( 999 )
    -1.32 ( 0.23 )
        S, w 4 of 1st IC (mid versus low; n=42, 42)
    999 ( 999 )
    -1.02 ( 0.301 )
    -1.61 ( 0.31 )
        S, w 8 of 1st IC (high versus low; n=72, 42)
    -0.6 ( 0.228 )
    999 ( 999 )
    -0.93 ( 0.265 )
        S, w 8 of 1st IC (mid versus low; n=42, 42)
    999 ( 999 )
    -0.94 ( 0.299 )
    -1.06 ( 0.308 )
        S, w 12 of 1st IC (high versus low; n=72, 42)
    -0.42 ( 0.207 )
    999 ( 999 )
    -1.13 ( 0.241 )
        S, w 12 of 1st IC (mid versus low; n=42, 42)
    999 ( 999 )
    -1.14 ( 0.253 )
    -1.47 ( 0.261 )
        P/C, w 4 of 1st IC (high versus low; n=64, 39)
    -0.44 ( 0.067 )
    999 ( 999 )
    -0.49 ( 0.089 )
        P/C, w 4 of 1st IC (mid versus low; n=39, 39)
    999 ( 999 )
    -0.31 ( 0.094 )
    -0.34 ( 0.093 )
        P/C, w 8 of 1st IC (high versus low; n=64, 39)
    -0.48 ( 0.069 )
    999 ( 999 )
    -0.47 ( 0.092 )
        P/C, w 8 of 1st IC (mid versus low; n=39, 39)
    999 ( 999 )
    -0.29 ( 0.092 )
    -0.33 ( 0.091 )
        P/C, w 12, 1st IC (high versus low; n=64, 39)
    -0.44 ( 0.071 )
    999 ( 999 )
    -0.37 ( 0.095 )
        P/C, w 12, 1st IC (mid versus low; n=39, 39)
    999 ( 999 )
    -0.21 ( 0.095 )
    -0.3 ( 0.095 )
        S, w 4 of 2nd IC (high versus low; n=72, 42)
    -0.53 ( 0.26 )
    999 ( 999 )
    -1.03 ( 0.289 )
        S, w 4 of 2nd IC (mid versus low; n=42, 42)
    999 ( 999 )
    -1.36 ( 0.347 )
    -1.53 ( 0.351 )
        S, w 8 of 2nd IC (high versus low; n=72, 42)
    -0.78 ( 0.272 )
    999 ( 999 )
    -1.16 ( 0.302 )
        S, w 8 of 2nd IC (mid versus low; n=42, 42)
    999 ( 999 )
    -1.56 ( 0.312 )
    -1.61 ( 0.315 )
        S, w 12 of 2nd IC (high versus low; n=72, 42)
    -0.34 ( 0.299 )
    999 ( 999 )
    -0.97 ( 0.333 )
        S, w 12 of 2nd IC (mid versus low; n=72, 42)
    999 ( 999 )
    -1.37 ( 0.333 )
    -1.4 ( 0.336 )
        P/C, w 4 of 2nd IC (high versus low; n=64, 39)
    -0.54 ( 0.078 )
    999 ( 999 )
    -0.47 ( 0.102 )
        P/C, w 4 of 2nd IC (mid versus low; n=39, 39)
    999 ( 999 )
    -0.59 ( 0.111 )
    -0.46 ( 0.105 )
        P/C, w 8 of 2nd IC (high versus low; n=64, 39)
    -0.55 ( 0.08 )
    999 ( 999 )
    -0.47 ( 0.104 )
        P/C, w 8 of 2nd IC (mid versus low; n=39, 39)
    999 ( 999 )
    -0.54 ( 0.119 )
    -0.44 ( 0.113 )
        P/C, w 12, 2nd IC (high versus low; n=64, 39)
    -0.49 ( 0.085 )
    999 ( 999 )
    -0.4 ( 0.112 )
        P/C, w 12, 2nd IC (mid versus low; n=39, 39)
    999 ( 999 )
    -0.52 ( 0.128 )
    -0.33 ( 0.121 )
    No statistical analyses for this end point

    Secondary: Time to Reinjection for Each of the Three Dose Groups for the 1st and 2nd Injection Cycle

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    End point title
    		 Time to Reinjection for Each of the Three Dose Groups for the 1st and 2nd Injection Cycle
    End point description
    The 1st (IC) indicates 1st Injection Cycle and 2nd (IC) is 2nd Injection Cycle.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 24-72
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Weeks
    arithmetic mean (standard deviation)
        1st Injection cycle (n=143, 77, 73)
    15.3 ( 4.6 )
    15.9 ( 5.7 )
    15.7 ( 5.9 )
        2nd Injection Cycle (n= 110, 51, 57)
    17 ( 6.5 )
    17.9 ( 7.8 )
    15.5 ( 4.9 )
    No statistical analyses for this end point

    Secondary: Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Injection Cycle

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    End point title
    		 Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Injection Cycle
    End point description
    Treatment-emergent Adverse Events (TEAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of subjects affected.
    End point type
    Secondary
    End point timeframe
    Up to end of study visit (Week 24-72)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Subjects
        1st Injection Cycle
    53
    15
    18
        2nd Injection Cycle
    44
    15
    21
        Overall Period
    77
    26
    30
    No statistical analyses for this end point

    Secondary: Occurrence of Subjects with TEAEs of Special Interest (TEAESIs) Overall and per Injection Cycle

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    End point title
    		 Occurrence of Subjects with TEAEs of Special Interest (TEAESIs) Overall and per Injection Cycle
    End point description
    Adverse Events (AE's) occurring after treatment that were thought to possibly indicate toxin spread throughout the trial conduct are defined as AE's of Special Interests. Values reported here refer to the number of subjects affected.
    End point type
    Secondary
    End point timeframe
    Up to end of study visit (Week 24-72)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Subjects
        1st Injection Cycle
    4
    1
    0
        2nd Injection Cycle
    2
    0
    1
        Overall Period
    5
    1
    1
    No statistical analyses for this end point

    Secondary: Occurrence of Serious TEAEs (TESAEs) Overall and per Injection Cycle

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    End point title
    		 Occurrence of Serious TEAEs (TESAEs) Overall and per Injection Cycle
    End point description
    Treatment-emergent Serious Adverse Events (TESAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of subjects affected.
    End point type
    Secondary
    End point timeframe
    Up to end of study visit (Week 24-72)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Subjects
        1st Injection Cycle
    4
    0
    3
        2nd Injection Cycle
    3
    1
    3
        Overall Period
    7
    1
    6
    No statistical analyses for this end point

    Secondary: Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and per Injection Cycle

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    End point title
    		 Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and per Injection Cycle
    End point description
    Treatment-emergent Adverse Events (TEAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of subjects affected.
    End point type
    Secondary
    End point timeframe
    Up to end of study visit (Week 24-72)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Subjects
        1st Injection Cycle
    7
    1
    2
        2 nd Injection Cycle
    4
    1
    1
        Overall Period
    11
    2
    2
    No statistical analyses for this end point

    Secondary: Occurrence of TEAEs by Worst Intensity Overall and per Injection Cycle

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    End point title
    		 Occurrence of TEAEs by Worst Intensity Overall and per Injection Cycle
    End point description
    Treatment-emergent Adverse Events (TEAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of subjects affected.
    End point type
    Secondary
    End point timeframe
    Up to end of study visit (Week 24-72)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Subjects
        1st Injection Cycle: Mild AE’s
    35
    6
    14
        1st Injection Cycle: Moderate AE’s
    17
    9
    4
        1st Injection Cycle: Severe AE’s
    1
    0
    0
        2nd Injection Cycle: Mild AE’s
    24
    9
    11
        2nd Injection Cycle: Moderate AE’s
    18
    5
    9
        2nd Injection Cycle: Severe AE’s
    2
    1
    1
        Overall: Mild AE’s
    41
    14
    19
        Overall: Moderate AE’s
    33
    11
    10
        Overall: Severe AE’s
    3
    1
    1
    No statistical analyses for this end point

    Secondary: Occurrence of TEAEs by Final Outcome Overall and per Injection Cycle

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    End point title
    		 Occurrence of TEAEs by Final Outcome Overall and per Injection Cycle
    End point description
    Treatment-emergent Adverse Events (TEAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of subjects affected.
    End point type
    Secondary
    End point timeframe
    Up to end of study visit (Week 24-72)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Subjects
        1st Injection Cycle: recovered/resolved
    52
    15
    17
        1st Injection Cycle: recovering/resolving
    0
    0
    0
        1st Injection Cycle: not recovered/ not resolved
    3
    0
    1
        1st Injection Cycle: recovered/resolved w/ sequela
    1
    0
    0
        1st Injection Cycle: fatal
    0
    0
    0
        1st Injection Cycle: unknown
    1
    0
    0
        2nd Injection Cycle: recovered/resolved
    42
    14
    20
        2nd Injection Cycle: recovering/resolving
    2
    1
    0
        2nd Injection Cycle: not recovered/ not resolved
    3
    2
    2
        2nd Injection Cycle: recovered/resolved w/ sequela
    0
    0
    0
        2nd Injection Cycle: fatal
    0
    0
    0
        2nd Injection Cycle: unknown
    0
    0
    0
        Overall: recovered/resolved
    74
    25
    28
        Overall: recovering/resolving
    2
    1
    0
        Overall: not recovered/ not resolved
    6
    2
    3
        Overall: recovered/resolved w/ sequelae
    1
    0
    0
        Overall: fatal
    0
    0
    0
        Overall: unknown
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Occurrence of TEAEs leading to Discontinuation Overall and per Injection Cycle

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    End point title
    		 Occurrence of TEAEs leading to Discontinuation Overall and per Injection Cycle
    End point description
    Treatment-emergent Adverse Events (TEASs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of subjects affected.
    End point type
    Secondary
    End point timeframe
    Up to end of study visit (Week 24-72)
    End point values
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Number of subjects analysed
    156
    77
    78
    Units: Subjects
        1st Injection Cycle
    1
    0
    0
        2nd Injection Cycle
    0
    0
    0
        Overall Period
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the timepoint of first injection until end of study visit (week 24-72)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin)
    Reporting group description
    		 Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.

    Reporting group title
    Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin)
    Reporting group description
    		 Subjects received 12 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.

    Reporting group title
    Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Reporting group description
    		 Subjects received 4 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.

    Serious adverse events
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 156 (4.49%)
    1 / 77 (1.30%)
    6 / 78 (7.69%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Brain contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Strabismus correction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis reactive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Borrelia infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    		 High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin) Mid Dose: 12 U/kg body weight Incobotulinumtoxin A (Xeomin) Low Dose: 4U/kg body weight Incobotulinumtoxin A (Xeomin)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 156 (14.74%)
    10 / 77 (12.99%)
    15 / 78 (19.23%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 156 (1.92%)
    1 / 77 (1.30%)
    4 / 78 (5.13%)
         occurrences all number
    5
    1
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    17 / 156 (10.90%)
    8 / 77 (10.39%)
    9 / 78 (11.54%)
         occurrences all number
    32
    15
    11
    Bronchitis
         subjects affected / exposed
    3 / 156 (1.92%)
    1 / 77 (1.30%)
    7 / 78 (8.97%)
         occurrences all number
    6
    1
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2013
    This amendment includes clarification that occurrence of severe Adverse event of special interest (AESI) of respiratory function or severe swallowing disorders were criteria for premature study discontinuation of subjects without any further re-exposure to Investigational product (IP). Addition of swallowing disorders to respiratory disorders as AESI category that could lead to premature discontinuation of the study. Clarification that an End of Study Visit was to be conducted whenever possible at any time point, if a subject discontinued study participation, not only after the first injection cycle. Clarification that hospitalization for analgosedation starting one day before or on the day of injection treatments was not regarded as an Serious adverse event (SAE), if performed for organizational reasons only. Addition of estimated Glomerular filtration rate (GFR) to assess subject’s renal function based on the height and creatinine levels. Clarification of regulation to keep clinical patterns of spasticity treatment throughout participation in this trial and to keep these patterns also in subjects rolling over to the open-label study. Clarification of the calculation of the visit window in case of visits where the Gross Motor Function Measure (GMFM) was performed one day prior to all other assessments. Correction of ranges for injection sites for the gastrocnemius muscle and for all other muscles in the Gross Motor Function Measure (CSP) to be in line with the regulation of maximum of 25 units (U) per injection site in subjects less than (<) 25 kilogram (kg) body weight (BW) and maximum of 50 U in subjects with BW greater than or equal to (≥) 25 kg. Description how confidential data were handled on the GMFM-66 source form. Change in order of appearance of assessments in overview of study activities were aligned with descriptions in separate outcome manual for the study.

    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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