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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 upper limb spasticity alone or combined upper and lower limb spasticity in children and adolescents (age 2 - 17 years) with cerebral palsy.

    Summary
    EudraCT number
    		 2012-005496-14
    Trial protocol
    		 PL   Outside EU/EEA  
    Global end of trial date
    28 Aug 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Aug 2019
    First version publication date
    10 Mar 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Zero AEs observed replaced with zero participants analyzed for various data points in several AE-related endpoints

    Trial information

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    Trial identification
    Sponsor protocol code
    MRZ60201_3072_1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02002884
    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 6915031, clinicaltrials@merz.de
    Scientific contact
    Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 6915031, clinicaltrials@merz.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of one or both upper limbs (UL) alone or in combination with injections into one or both lower limbs (LL) are effective and safe in treating children/adolescents (age 2-17 years) with spasticity due to cerebral palsy.
    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
    28 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Mexico: 62
    Country: Number of subjects enrolled
    Argentina: 21
    Country: Number of subjects enrolled
    Russian Federation: 36
    Country: Number of subjects enrolled
    Ukraine: 122
    Country: Number of subjects enrolled
    United States: 27
    Country: Number of subjects enrolled
    Poland: 83
    Worldwide total number of subjects
    351
    EEA total number of subjects
    83
    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)
    271
    Adolescents (12-17 years)
    80
    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
    		 The study was conducted at 28 investigative sites in Mexico, Argentina, Russian federation, Ukraine, United States and Poland.

    Pre-assignment
    Screening details
    		 A total of 372 subjects were screened, 351 subjects were randomized and 350 subjects were randomized and treated in the study. 331 subjects completed the main period (MP) and moved to the open-label-extension period (OLEX) out of which 281 subjects completed the OLEX period.

    Period 1
    Period 1 title
    Main Period (MP)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MP Low Dose Group
    Arm description
    		 In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 Units per kilogram (U/kg) body weight (BW) up to a total body dose of 125 Units (U).
    Arm type
    		 Experimental

    Investigational medicinal product name
    IncobotulinumtoxinA
    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
    On Day 1 of MP, subjects randomized to low dose group received intramuscular injections of 2 U/kg NT 201 (maximum of 50 U in subjects with more than [>] 25 kilogram [kg] BW) into spastic muscles of one of the UL. Treatment with fixed doses of either flexed elbow or flexed wrist or both was mandatory. If the contralateral UL or one or both LL were also treated, subjects received additional doses of NT 201. The total body dose ranged from 2 U/kg (50 U for subjects with >25kg BW) to 5 U/kg (125 U for subjects with >25kg BW) depending on the combination of treated limbs and the subject's Gross Motor Function Classification System (GMFCS) level.

    Arm title
    		 MP Mid Dose Group
    Arm description
    		 In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IncobotulinumtoxinA
    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
    On Day 1 of MP, subjects randomized to mid dose group received intramuscular injections of 6 U/kg NT 201 (maximum of 150 U in subjects with >25kg BW) into spastic muscles of one of the UL. Treatment with fixed doses of either flexed elbow or flexed wrist or both was mandatory. If the contralateral UL or one or both LL were also treated, subjects received additional doses of NT 201. The total body dose ranged from 6 U/kg (150 U for subjects with >25kg BW) to 15 U/kg (375 U for subjects with >25kg BW) depending on the combination of treated limbs and the subject's GMFCS level.

    Arm title
    		 MP High Dose Group
    Arm description
    		 In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IncobotulinumtoxinA
    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
    On Day 1 of MP, subjects randomized to high dose group received intramuscular injections of 8 U/kg NT 201 (maximum of 200 U in subjects with >25kg BW) into spastic muscles of one of the UL. Treatment with fixed doses of either flexed elbow or flexed wrist or both was mandatory. If the contralateral UL or one or both LL were also treated, subjects received additional doses of NT 201. The total body dose ranged from 8 U/kg (200 U for subjects with >25kg BW) to 20 U/kg (500 U for subjects with >25kg BW) depending on the combination of treated limbs and the subject's GMFCS level.

    Number of subjects in period 1
    		MP Low Dose Group MP Mid Dose Group MP High Dose Group
    Started
    87
    88
    176
    Treated
    87
    87
    176
    Completed
    81
    82
    168
    Not completed
    6
    6
    8
         Consent withdrawn by subject
    6
    2
    2
         Adverse event, non-fatal
    -
    1
    1
         Other
    -
    3
    3
         Lost to follow-up
    -
    -
    2
    Period 2
    Period 2 title
    Open-Label Extension Period (OLEX)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 OLEX (3 Injections)
    Arm description
    		 Subjects who completed MP and qualified for further participation in the study were treated with doses of NT 201 between 8 and 20 U/kg (maximum body dose of 500 U in subjects with >25kg BW) in each of the three injection cycles in OLEX.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IncobotulinumtoxinA
    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
    On Day 1 of each of the three injection cycles of OLEX, subjects who qualified for further participation in the study received intramuscular injections of 8 U/kg NT 201 (maximum of 200 U in subjects with >25kg BW) into spastic muscles of the UL selected for treatment in MP. Treatment with fixed doses of either flexed elbow or flexed wrist or both was mandatory. If the contralateral UL or one or both LL were also treated, subjects received additional doses of NT 201. The total body dose ranged from 8 U/kg (200 U for subjects with >25kg BW) to 20 U/kg (500 U for subjects with >25kg BW) depending on the combination of treated limbs and the subject's GMFCS level.

    Number of subjects in period 2
    		OLEX (3 Injections)
    Started
    331
    Completed
    281
    Not completed
    50
         Consent withdrawn by subject
    10
         Physician decision
    1
         Adverse event, non-fatal
    5
         Other
    24
         Lost to follow-up
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MP Low Dose Group
    Reporting group description
    		 In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 Units per kilogram (U/kg) body weight (BW) up to a total body dose of 125 Units (U).

    Reporting group title
    MP Mid Dose Group
    Reporting group description
    		 In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.

    Reporting group title
    MP High Dose Group
    Reporting group description
    		 In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.

    Reporting group values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group Total
    Number of subjects
    		 87 88 176 351
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 64 71 136 271
        Adolescents (12-17 years)
    		 23 17 40 80
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.2 ( 4.70 ) 7.4 ( 4.13 ) 7.3 ( 4.40 ) -
    Gender categorical
    Units: Subjects
        Female
    		 38 31 62 131
        Male
    		 49 57 114 220
    Ethnicity characteristic
    Units: Subjects
        Hispanic or Latino
    		 16 26 45 87
        Not Hispanic or Latino
    		 71 62 131 264
    Race characteristic
    Units: Subjects
        White
    		 81 75 160 316
        Black or African American
    		 3 2 2 7
        Other
    		 3 11 14 28

    End points

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    End points reporting groups
    Reporting group title
    MP Low Dose Group
    Reporting group description
    		 In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 Units per kilogram (U/kg) body weight (BW) up to a total body dose of 125 Units (U).

    Reporting group title
    MP Mid Dose Group
    Reporting group description
    		 In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.

    Reporting group title
    MP High Dose Group
    Reporting group description
    		 In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.
    Reporting group title
    OLEX (3 Injections)
    Reporting group description
    		 Subjects who completed MP and qualified for further participation in the study were treated with doses of NT 201 between 8 and 20 U/kg (maximum body dose of 500 U in subjects with >25kg BW) in each of the three injection cycles in OLEX.

    Subject analysis set title
    MP: Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was the subset in the safety analysis set (SES) of the MP for whom the primary efficacy variable or co-primary efficacy variable were available (that is, all subjects who had at least an AS score in the clinical pattern flexed elbow or flexed wrist at baseline [Day 1] or the Investigator’s global impression of change scales [GICS] at Day 29 [Week 4]).

    Subject analysis set title
    Safety Evaluation Set (SES)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once.

    Subject analysis set title
    MP Low Dose Group
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 U/kg BW up to a total body dose of 125 U.

    Subject analysis set title
    MP Mid Dose Group
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.

    Subject analysis set title
    MP High Dose Group
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.

    Subject analysis set title
    OLEX (3 Injections)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who completed MP and qualified for further participation in the study were treated with doses of NT 201 between 8 and 20 U/kg (maximum body dose of 500 U in subjects with >25kg BW) in each of the three injection cycles in OLEX.

    Primary: MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4

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    End point title
    		 MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4
    End point description
    The AS categorizes severity of spasticity by judging resistance to passive movement. Spasticity was assessed by using the 5-point AS with:0 (no increase in tone); 1 (slight increase in tone giving a “catch” when the limb was moved in flexion or extension); 2 (more marked increase in tone, but limb easily flexed); 3 (considerable increase in tone -passive movements difficult); 4 (limb rigid in flexion or extension). Values represent least square (LS) mean differences between baseline and Week 4 resulting from Mixed Model Repeated Measurement (MMRM) models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. Here “n” was the number of subjects who were evaluable for this measure at a given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group
    Number of subjects analysed
    87 [1]
    87 [2]
    176 [3]
    Units: unit on a scale
    least squares mean (standard error)
        High (n=172) versus Low (n=85)
    -0.93 ( 0.078 )
    999 ( 999 )
    -1.15 ( 0.056 )
        Mid (n=86) versus Low (n=85)
    -0.96 ( 0.082 )
    -1.02 ( 0.082 )
    999 ( 999 )
    Notes
    [1] - MP-FAS
    [2] - MP-FAS
    [3] - MP-FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS-Means are from mixed model with treatment group, pooled site and pre-treatment status included as fixed factors and AS at baseline, Gross Motor Function Classification System–Extended and Revised (GMFCS-E&R) level at screening included as covariates. For MMRM visit*treatment is interaction term repeated factor.
    Comparison groups
    MP Low Dose Group v MP High Dose Group
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 MMRM
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.04
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS-Means are from mixed model with treatment group, pooled site and pre-treatment status included as fixed factors and AS at baseline, GMFCS-E&R level at screening included as covariates. For MMRM visit*treatment is interaction term repeated factor.
    Comparison groups
    MP Low Dose Group v MP Mid Dose Group
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.546
    Method
    		 MMRM
    Parameter type
    		 LS-Mean difference
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.15

    Primary: Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4

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    End point title
    		 Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4
    End point description
    The GICS was used to measure independently the investigator’s impression of change due to treatment. The response option was a common 7-point Likert scale, that ranges from +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse). Values represent LS mean differences between baseline and Week 4 resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. Here “n” was the number of subjects who were evaluable for this measure at given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Primary
    End point timeframe
    Week 4
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group
    Number of subjects analysed
    87 [4]
    87 [5]
    176 [6]
    Units: unit on a scale
    least squares mean (standard error)
        High (n=176) versus Low (n=87)
    1.55 ( 0.083 )
    999 ( 999 )
    1.64 ( 0.062 )
        Mid (n=87) versus Low (n=87)
    1.57 ( 0.089 )
    1.44 ( 0.092 )
    999 ( 999 )
    Notes
    [4] - MP-FAS
    [5] - MP-FAS
    [6] - MP-FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS-Means are from analysis of covariance (ANCOVA) with treatment group, pooled site and pretreatment status included as fixed factors and maximum AS score of the two possible primary target patterns flexed elbow or flexed wrist baseline, GMFCS-E&R level at screening included as covariates.
    Comparison groups
    MP Low Dose Group v MP High Dose Group
    Number of subjects included in analysis
    263
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 ANCOVA
    Parameter type
    		 LS-Mean difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.28
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS-Means are from ANCOVA with treatment group, pooled site and pre-treatment status included as fixed factors and maximum AS score of the two possible primary target patterns flexed elbow or flexed wrist baseline, GMFCS-E&R level at screening included as covariates.
    Comparison groups
    MP Low Dose Group v MP Mid Dose Group
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.297
    Method
    		 ANCOVA
    Parameter type
    		 LS-Mean difference
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.11

    Secondary: MP: Change From Baseline in AS score of the Other Treated UL Main Clinical Target Pattern at Week 4

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    End point title
    		 MP: Change From Baseline in AS score of the Other Treated UL Main Clinical Target Pattern at Week 4
    End point description
    The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 0 (no increase in tone); 1(slight increase in tone giving a “catch” when the limb was moved in flexion or extension); 2(more marked increase in tone, but limb easily flexed); 3(considerable increase in tone - passive movements difficult); 4(limb rigid in flexion or extension). Values represent LS mean differences between baseline and Week 4 resulting from MMRM models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. Here “n” was the number of subjects who were evaluable for this measure at given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group
    Number of subjects analysed
    87 [7]
    88 [8]
    176 [9]
    Units: unit on a scale
    least squares mean (standard error)
        High (n=143) versus Low (n=67)
    -1.03 ( 0.083 )
    999 ( 999 )
    -1.13 ( 0.061 )
        Mid (n=69) versus Low (n=67)
    -1.08 ( 0.087 )
    -1.22 ( 0.090 )
    999 ( 999 )
    Notes
    [7] - MP-FAS
    [8] - MP-FAS
    [9] - MP-FAS
    No statistical analyses for this end point

    Secondary: MP: Change From Baseline in AS score in UL Treated Clenched Fist With Flexed Wrist at Week 4

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    End point title
    		 MP: Change From Baseline in AS score in UL Treated Clenched Fist With Flexed Wrist at Week 4
    End point description
    The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 0 (no increase in tone); 1(slight increase in tone giving a “catch” when the limb was moved in flexion or extension); 2(more marked increase in tone, but limb easily flexed); 3(considerable increase in tone - passive movements difficult); 4(limb rigid in flexion or extension). Values represent LS mean differences between baseline and Week 4 resulting from MMRM models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. Here “n” was the number of subjects who were evaluable for this measure at given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group
    Number of subjects analysed
    87 [10]
    88 [11]
    176 [12]
    Units: unit on a scale
    least squares mean (standard error)
        High (n=45) versus Low (n=18)
    -0.53 ( 0.212 )
    999 ( 999 )
    -1.00 ( 0.133 )
        Mid (n=20) versus Low (n=18)
    -0.070 ( 0.202 )
    -1.04 ( 0.176 )
    999 ( 999 )
    Notes
    [10] - MP-FAS
    [11] - MP-FAS
    [12] - MP-FAS
    No statistical analyses for this end point

    Secondary: MP: Change From Baseline in AS score for Each Treated Clinical Pattern of the UL at Week 4

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    End point title
    		 MP: Change From Baseline in AS score for Each Treated Clinical Pattern of the UL at Week 4
    End point description
    The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 0 (no increase in tone); 1(slight increase in tone giving a “catch” when the limb was moved in flexion or extension); 2(more marked increase in tone, but limb easily flexed); 3(considerable increase in tone - passive movements difficult); 4(limb rigid in flexion or extension). Values represent LS mean differences between baseline and Week 4 resulting from MMRM models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. Here “n” was the number of subjects who were evaluable for this measure at given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group
    Number of subjects analysed
    87 [13]
    88 [14]
    176 [15]
    Units: unit on a scale
    least squares mean (standard error)
        Flexed elbow: High (n=166) versus Low (n=83)
    -0.99 ( 0.076 )
    999 ( 999 )
    -1.18 ( 0.056 )
        Flexed elbow: Mid (n=82) versus Low (n=83)
    -1.01 ( 0.081 )
    -1.17 ( 0.082 )
    999 ( 999 )
        Flexed wrist: High (n=149) versus Low (n=69)
    -0.96 ( 0.085 )
    999 ( 999 )
    -1.08 ( 0.061 )
        Flexed wrist: Mid (n=73) versus Low (n=69)
    -1.01 ( 0.087 )
    -1.05 ( 0.087 )
    999 ( 999 )
        Clenched fist: High (n=64) versus Low (n=34)
    -0.64 ( 0.136 )
    999 ( 999 )
    -1.09 ( 0.096 )
        Clenched fist: Mid (n=30) versus Low (n=34)
    -0.58 ( 0.145 )
    -0.87 ( 0.141 )
    999 ( 999 )
        Thumb in palm: High (n=98) versus Low (n=49)
    -0.88 ( 0.116 )
    999 ( 999 )
    -1.11 ( 0.083 )
        Thumb in palm: Mid (n=44) versus Low (n=49)
    -0.93 ( 0.131 )
    -1.14 ( 0.123 )
    999 ( 999 )
        Pronated forearm: High (n=150) versus Low (n=72)
    -0.88 ( 0.080 )
    999 ( 999 )
    -1.02 ( 0.058 )
        Pronated forearm: Mid (n=73) versus Low (n=72)
    -0.87 ( 0.086 )
    -0.94 ( 0.088 )
    999 ( 999 )
    Notes
    [13] - MP-FAS
    [14] - MP-FAS
    [15] - MP-FAS
    No statistical analyses for this end point

    Secondary: MP: Change From Baseline in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) Assessed With 'Questionnaire on Pain caused by Spasticity (QPS)'

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    End point title
    		 MP: Change From Baseline in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) Assessed With 'Questionnaire on Pain caused by Spasticity (QPS)'
    End point description
    Pain intensity (from subjects) and pain frequency (from parent/caregiver) to be assessed with 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). Values represent LS mean differences between baseline and Week 4 resulting from MMRM models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. Here “n” was the number of subjects who were evaluable for this measure at given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model. P/C = Parent/Caregiver.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, and 14
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group
    Number of subjects analysed
    87 [16]
    88 [17]
    176 [18]
    Units: unit on a scale
    least squares mean (standard error)
        UL, Subject, Week 4 High (n=52) versus low (n=30)
    -0.42 ( 0.217 )
    999 ( 999 )
    -0.75 ( 0.199 )
        UL, Subject, Week 4 Mid (n=34) versus low (n=30)
    -0.39 ( 0.256 )
    -0.67 ( 0.289 )
    999 ( 999 )
        UL, Subject, Week 8 High (n=52) versus low (n=29)
    -0.52 ( 0.206 )
    999 ( 999 )
    -0.64 ( 0.188 )
        UL, Subject, Week 8 Mid (n=34) versus low (n=29)
    -0.63 ( 0.259 )
    -0.55 ( 0.290 )
    999 ( 999 )
        UL, Subject, Week 14 High (n=52) versus low (n=27)
    -0.56 ( 0.217 )
    999 ( 999 )
    -0.59 ( 0.202 )
        UL, Subject, Week 14 Mid (n=32) versus low (n=27)
    -0.66 ( 0.327 )
    -0.59 ( 0.361 )
    999 ( 999 )
        UL, P/C, Week 4 High (n=133) versus low (n=64)
    -0.46 ( 0.102 )
    999 ( 999 )
    -0.44 ( 0.076 )
        UL, P/C, Week 4 Mid (n=65) versus low (n=64)
    -0.43 ( 0.106 )
    -0.28 ( 0.115 )
    999 ( 999 )
        UL, P/C, Week 8 High (n=138) versus low (n=67)
    -0.40 ( 0.095 )
    999 ( 999 )
    -0.44 ( 0.070 )
        UL, P/C, Week 8 Mid (n=66) versus low (n=67)
    -0.43 ( 0.100 )
    -0.34 ( 0.109 )
    999 ( 999 )
        UL, P/C, Week 14 High (n=137) versus low (n=58)
    -0.23 ( 0.105 )
    999 ( 999 )
    -0.24 ( 0.071 )
        UL, P/C, Week 14 Mid (n=61) versus low (n=58)
    -0.31 ( 0.100 )
    -0.25 ( 0.107 )
    999 ( 999 )
        LL, Subject, Week 4 High (n=43) versus low (n=24)
    -0.74 ( 0.282 )
    999 ( 999 )
    -0.62 ( 0.250 )
        LL, Subject, Week 4 Mid (n=29) versus low (n=24)
    -0.46 ( 0.305 )
    -0.55 ( 0.321 )
    999 ( 999 )
        LL, Subject, Week 8 High (n=44) versus low (n=25)
    -1.04 ( 0.241 )
    999 ( 999 )
    -0.69 ( 0.218 )
        LL, Subject, Week 8 Mid (n=28) versus low (n=25)
    -0.90 ( 0.261 )
    -0.81 ( 0.284 )
    999 ( 999 )
        LL, Subject, Week 14 High (n=43) versus low (n=23)
    -0.71 ( 0.275 )
    999 ( 999 )
    -0.57 ( 0.245 )
        LL, Subject, Week 14 Mid (n=28) versus low (n=23)
    -0.67 ( 0.315 )
    -0.63 ( 0.335 )
    999 ( 999 )
        LL, P/C, Week 4 High (n=110) versus low (n=56)
    -0.50 ( 0.105 )
    999 ( 999 )
    -0.52 ( 0.077 )
        LL, P/C, Week 4 Mid (n=54) versus low (n=56)
    -0.46 ( 0.103 )
    -0.42 ( 0.111 )
    999 ( 999 )
        LL, P/C, Week 8 High (n=113) versus low (n=59)
    -0.56 ( 0.098 )
    999 ( 999 )
    -0.51 ( 0.074 )
        LL, P/C, Week 8 Mid (n=54) versus low (n=59)
    -0.52 ( 0.102 )
    -0.36 ( 0.111 )
    999 ( 999 )
        LL, P/C, Week 14 High (n=110) versus low (n=53)
    -0.33 ( 0.108 )
    999 ( 999 )
    -0.32 ( 0.078 )
        LL, P/C, Week 14 Mid (n=53) versus low (n=53)
    -0.37 ( 0.086 )
    -0.31 ( 0.090 )
    999 ( 999 )
    Notes
    [16] - MP-FAS
    [17] - MP-FAS
    [18] - MP-FAS
    No statistical analyses for this end point

    Secondary: MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4

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    End point title
    		 MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4
    End point description
    The GICS was used to measure independently the child’s/adolescent’s, and parent’s or caregiver’s impression of change due to treatment. The response option was a common 7-point Likert scale, that ranges from: +3(very much improved); +2(much improved); +1(minimally improved); 0(no change); -1(minimally worse); -2(much worse); -3(very much worse). Values represent LS mean differences between baseline and Week 4 resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. Here “n” was the number of subjects who were evaluable for this measure at a given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group
    Number of subjects analysed
    87 [19]
    88 [20]
    176 [21]
    Units: unit on a scale
    least squares mean (standard error)
        Subject: High (n=55) versus Low (n=31)
    1.51 ( 0.153 )
    999 ( 999 )
    1.63 ( 0.139 )
        Subject: Mid (n=38) versus Low (n=31)
    1.53 ( 0.180 )
    1.48 ( 0.190 )
    999 ( 999 )
        Parent/Caregiver: High (n=176) versus Low (n=87)
    1.41 ( 0.087 )
    999 ( 999 )
    1.60 ( 0.065 )
        Parent/Caregiver: Mid (n=87) versus Low (n=87)
    1.36 ( 0.094 )
    1.29 ( 0.097 )
    999 ( 999 )
    Notes
    [19] - MP-FAS
    [20] - MP-FAS
    [21] - MP-FAS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Treatment Cycle

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    End point title
    		 Number of Subjects With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Treatment Cycle
    End point description
    The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 66
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group OLEX (3 Injections)
    Number of subjects analysed
    87 [22]
    87 [23]
    176 [24]
    331 [25]
    Units: Subjects
        Overall
    21
    13
    42
    114
        First injection cycle (MP) (n=87,87,176,0)
    21
    13
    42
    0
        Second injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    64
        Third injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    43
        Fourth injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    48
    Notes
    [22] - SES
    [23] - SES
    [24] - SES
    [25] - SES
    No statistical analyses for this end point

    Secondary: Number of Subjects With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and per Treatment Cycle

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    End point title
    		 Number of Subjects With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and per Treatment Cycle
    End point description
    The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 66
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group OLEX (3 Injections)
    Number of subjects analysed
    87 [26]
    87 [27]
    176 [28]
    331 [29]
    Units: subjects
        Overall
    1
    1
    1
    5
        First injection cycle (MP) (n=87,87,176,0)
    1
    1
    1
    0
        Second injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    2
        Third injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    3
        Fourth injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    1
    Notes
    [26] - SES
    [27] - SES
    [28] - SES
    [29] - SES
    No statistical analyses for this end point

    Secondary: Number of Subjects With Occurrence of Serious TEAEs (TESAEs) Overall and per Treatment Cycle

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    End point title
    		 Number of Subjects With Occurrence of Serious TEAEs (TESAEs) Overall and per Treatment Cycle
    End point description
    The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 66
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group OLEX (3 Injections)
    Number of subjects analysed
    87 [30]
    87 [31]
    176 [32]
    331 [33]
    Units: subjects
        Overall
    2
    1
    2
    16
        First injection cycle (MP) (n=87,87,176,0)
    2
    1
    2
    0
        Second injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    7
        Third injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    9
        Fourth injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    3
    Notes
    [30] - SES
    [31] - SES
    [32] - SES
    [33] - SES
    No statistical analyses for this end point

    Secondary: Number of Subjects With Occurrence of TEAEs Related to Treatment Overall and per Treatment Cycle

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    End point title
    		 Number of Subjects With Occurrence of TEAEs Related to Treatment Overall and per Treatment Cycle
    End point description
    The SES was the subset of all subjects treated in MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 66
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group OLEX (3 Injections)
    Number of subjects analysed
    87 [34]
    87 [35]
    176 [36]
    331 [37]
    Units: subjects
        Overall
    0
    0
    3
    5
        First injection cycle (MP) (n=87,87,176,0)
    0
    0
    3
    0
        Second injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    2
        Third injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    2
        Fourth injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    1
    Notes
    [34] - SES
    [35] - SES
    [36] - SES
    [37] - SES
    No statistical analyses for this end point

    Secondary: Number of Subjects With Occurrence of TEAEs by Worst Intensity Overall and per Treatment Cycle

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    End point title
    		 Number of Subjects With Occurrence of TEAEs by Worst Intensity Overall and per Treatment Cycle
    End point description
    The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 66
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group OLEX (3 Injections)
    Number of subjects analysed
    87 [38]
    87 [39]
    176 [40]
    331 [41]
    Units: subjects
        Overall: Mild
    15
    10
    33
    62
        Overall: Moderate
    6
    2
    7
    44
        Overall: Severe
    0
    1
    2
    8
        First injection cycle (MP): Mild (n=87,87,176,0)
    15
    10
    33
    0
        First injection cycle (MP):Moderate(n=87,87,176,0)
    6
    2
    7
    0
        First injection cycle (MP): Severe (n=87,87,176,0)
    0
    1
    2
    0
        Second injection cycle (OLEX): Mild (n=0,0,0,331)
    0
    0
    0
    43
        Second injection cycle(OLEX):Moderate(n=0,0,0,331)
    0
    0
    0
    18
        Second injection cycle (OLEX): Severe(n=0,0,0,331)
    0
    0
    0
    3
        Third injection cycle (OLEX): Mild (n=0,0,0,331)
    0
    0
    0
    23
        Third injection cycle (OLEX):Moderate(n=0,0,0,331)
    0
    0
    0
    15
        Third injection cycle (OLEX): Severe (n=0,0,0,331)
    0
    0
    0
    4
        Fourth injection cycle (OLEX): Mild (n=0,0,0,331)
    0
    0
    0
    28
        Fourth injection cycle(OLEX):Moderate(n=0,0,0,331)
    0
    0
    0
    19
        Fourth injection cycle (OLEX): Severe(n=0,0,0,331)
    0
    0
    0
    1
    Notes
    [38] - SES
    [39] - SES
    [40] - SES
    [41] - SES
    No statistical analyses for this end point

    Secondary: Number of Subjects With Occurrence of TEAEs by Worst Causal Relationship Overall and per Treatment Cycle

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    End point title
    		 Number of Subjects With Occurrence of TEAEs by Worst Causal Relationship Overall and per Treatment Cycle
    End point description
    The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 66
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group OLEX (3 Injections)
    Number of subjects analysed
    87 [42]
    87 [43]
    176 [44]
    331 [45]
    Units: subjects
        Overall: Related
    0
    0
    3
    5
        Overall: Not related
    21
    13
    39
    109
        First cycle (MP): Related (n=87,87,176,0)
    0
    0
    3
    0
        First cycle (MP): Not related (n=87,87,176,0)
    21
    13
    39
    0
        Second cycle (OLEX): Related (n=0,0,0,331)
    0
    0
    0
    2
        Second cycle (OLEX): Not related (n=0,0,0,331)
    0
    0
    0
    62
        Third cycle (OLEX): Related (n=0,0,0,331)
    0
    0
    0
    2
        Third cycle (OLEX): Not related (n=0,0,0,331)
    0
    0
    0
    40
        Fourth cycle (OLEX): Related (n=0,0,0,331)
    0
    0
    0
    1
        Fourth cycle (OLEX): Not related (n=0,0,0,331)
    0
    0
    0
    47
    Notes
    [42] - SES
    [43] - SES
    [44] - SES
    [45] - SES
    No statistical analyses for this end point

    Secondary: Number of Subjects With Occurrence of TEAEs by Final Outcome Overall and per Treatment Cycle

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    End point title
    		 Number of Subjects With Occurrence of TEAEs by Final Outcome Overall and per Treatment Cycle
    End point description
    The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 66
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group OLEX (3 Injections)
    Number of subjects analysed
    87 [46]
    87 [47]
    176 [48]
    331 [49]
    Units: subjects
        Overall: Resolved
    18
    10
    39
    96
        Overall: Resolved with sequelae
    1
    0
    0
    1
        Overall: Resolving
    0
    2
    1
    7
        Overall: Not resolved
    2
    1
    1
    8
        Overall: Unknown
    0
    0
    1
    2
        Overall: Fatal
    0
    0
    0
    0
        First cycle (MP): Resolved (n=87,87,176,0)
    18
    10
    39
    0
        Firstcycle(MP):Resolvedwithsequelae(n=87,87,176,0)
    1
    0
    0
    0
        First cycle (MP): Resolving(n=87,87,176,0)
    0
    2
    1
    0
        First cycle (MP): Not resolved(n=87,87,176,0)
    2
    1
    1
    0
        First cycle (MP): Unknown(n=87,87,176,0)
    0
    0
    1
    0
        First cycle (MP): Fatal(n=87,87,176,0)
    0
    0
    0
    0
        Second cycle (OLEX): Resolved(n=0,0,0,331)
    0
    0
    0
    57
        Secondcycle(OLEX):Resolvedwithsequelae(n=0,0,0,331
    0
    0
    0
    0
        Second cycle (OLEX): Resolving(n=0,0,0,331)
    0
    0
    0
    3
        Second cycle (OLEX): Not resolved(n=0,0,0,331)
    0
    0
    0
    4
        Second cycle (OLEX): Unknown(n=0,0,0,331)
    0
    0
    0
    0
        Second cycle (OLEX): Fatal(n=0,0,0,331)
    0
    0
    0
    0
        Third cycle (OLEX): Resolved(n=0,0,0,331)
    0
    0
    0
    37
        Thirdcycle(OLEX):Resolvedwithsequelae(n=0,0,0,331)
    0
    0
    0
    0
        Third cycle (OLEX): Resolving(n=0,0,0,331)
    0
    0
    0
    0
        Third cycle (OLEX): Not resolved(n=0,0,0,331)
    0
    0
    0
    4
        Third cycle (OLEX): Unknown(n=0,0,0,331)
    0
    0
    0
    1
        Third cycle (OLEX): Fatal(n=0,0,0,331)
    0
    0
    0
    0
        Fourth cycle (OLEX): Resolved(n=0,0,0,331)
    0
    0
    0
    39
        Fourthcycle(OLEX):Resolvedwithsequelae(n=0,0,0,331
    0
    0
    0
    1
        Fourth cycle (OLEX): Resolving(n=0,0,0,331)
    0
    0
    0
    4
        Fourth cycle (OLEX): Not resolved(n=0,0,0,331)
    0
    0
    0
    2
        Fourth cycle (OLEX): Unknown(n=0,0,0,331)
    0
    0
    0
    2
        Fourth cycle (OLEX): Fatal(n=0,0,0,331)
    0
    0
    0
    0
    Notes
    [46] - SES
    [47] - SES
    [48] - SES
    [49] - SES
    No statistical analyses for this end point

    Secondary: Number of Subjects With Occurrence of TEAEs Leading to Discontinuation Overall and per Treatment Cycle

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    End point title
    		 Number of Subjects With Occurrence of TEAEs Leading to Discontinuation Overall and per Treatment Cycle
    End point description
    The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 66
    End point values
    		 MP Low Dose Group MP Mid Dose Group MP High Dose Group OLEX (3 Injections)
    Number of subjects analysed
    87 [50]
    87 [51]
    176 [52]
    331 [53]
    Units: subjects
        Overall
    0
    1
    1
    5
        First injection cycle (MP) (n=87,87,176,0)
    0
    1
    1
    0
        Second injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    3
        Third injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    2
        Fourth injection cycle (OLEX) (n=0,0,0,331)
    0
    0
    0
    0
    Notes
    [50] - SES
    [51] - SES
    [52] - SES
    [53] - SES
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 66
    Adverse event reporting additional description
    The investigator asked the participant for adverse events (AEs) systematically at each visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    MP: Low Dose Group
    Reporting group description
    		 In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 U/kg BW up to a total body dose of 125 U.

    Reporting group title
    MP: Mid Dose Group
    Reporting group description
    		 In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.

    Reporting group title
    MP: High Dose Group
    Reporting group description
    		 In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.

    Reporting group title
    OLEX (3 Injections)
    Reporting group description
    		 Subjects who completed MP and qualified for further participation in the study were treated with doses of NT 201 between 8 and 20 U/kg (maximum body dose of 500 U in subjects with >25kg BW) in each of the three injection cycles in OLEX.

    Serious adverse events
    		 MP: Low Dose Group MP: Mid Dose Group MP: High Dose Group OLEX (3 Injections)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 87 (1.15%)
    2 / 176 (1.14%)
    16 / 331 (4.83%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Electroencephalogram
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Spinal cord neoplasm
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Shunt malfunction
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    CSF shunt operation
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 87 (1.15%)
    0 / 176 (0.00%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Hiatus hernia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cyclic vomiting syndrome
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 87 (1.15%)
    0 / 176 (0.00%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 87 (1.15%)
    0 / 176 (0.00%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 87 (0.00%)
    1 / 176 (0.57%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    2 / 176 (1.14%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    1 / 176 (0.57%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 87 (0.00%)
    0 / 176 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MP: Low Dose Group MP: Mid Dose Group MP: High Dose Group OLEX (3 Injections)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 87 (5.75%)
    3 / 87 (3.45%)
    6 / 176 (3.41%)
    18 / 331 (5.44%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 87 (5.75%)
    3 / 87 (3.45%)
    6 / 176 (3.41%)
    18 / 331 (5.44%)
         occurrences all number
    5
    5
    6
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Apr 2015
    Incorporated FDA recommendations based on the draft FDA Guidance for Industry, 'Suicidal ideation and behavior: prospective assessment of occurrence in clinical trials'.

    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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