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    Clinical Trial Results:
    Prospective, Double-Blind, Placebo-Controlled, Randomized, Multi-Center Study With an Open-Label Extension Period to Investigate the Efficacy and Safety of NT 201 in the Treatment of Post-Stroke Spasticity of the Lower Limb

    Summary
    EudraCT number
    		 2010-024579-23
    Trial protocol
    		 DE   AT   CZ   ES   PL   IT   HU  
    Global end of trial date
    04 Jan 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    MRZ 60201/SP/3002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01464307
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to investigate the efficacy and safety of 400 units NT 201 compared with placebo in the first double-blind treatment cycle, and to investigate the safety of 400 units NT 201 administered in three subsequent open-label treatment cycles.
    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
    01 Feb 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 111
    Country: Number of subjects enrolled
    Russian Federation: 43
    Country: Number of subjects enrolled
    Czech Republic: 39
    Country: Number of subjects enrolled
    United States: 37
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    France: 3
    Worldwide total number of subjects
    289
    EEA total number of subjects
    201
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    203
    From 65 to 84 years
    86
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 331 individuals suffering from post-stroke lower-limb spasticity were screened and 290 were included in study at 51 sites. One ineligible subject was randomized to placebo but withdrawn from study prior to first treatment with study medication. For purpose of study analysis overall number of subjects enrolled is therefore considered 289.

    Pre-assignment
    Screening details
    		 A total of 289 subjects were enrolled in main period. All of the 269 subjects who completed the main period of the study entered the open-label extension period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IncobotulinumtoxinA (Xeomin) 400 Units
    Arm description
    		 IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9 percent (%) Sodium Chloride (NaCl), 400 units, total volume 8.0 milliliter (mL); Mode of administration: intramuscular injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NT 201
    Investigational medicinal product code
    NT 201
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received IncobotulinumtoxinA (400 Units) one intramuscular injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, 400 units, total volume 8.0 ml.

    Arm title
    		 Placebo
    Arm description
    		 Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received Placebo to IncobotulinumtoxinA one intramuscular injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, 400 units, total volume 8.0 mL.

    Number of subjects in period 1
    		IncobotulinumtoxinA (Xeomin) 400 Units Placebo
    Started
    144
    145
    Treated
    144
    145
    Completed
    129
    140
    Not completed
    15
    5
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    5
    2
         Adverse event, non-fatal
    6
    1
         Lack of efficacy
    2
    -
         Predefined discontinuation criteria
    2
    1
    Period 2
    Period 2 title
    Open-Label Extension Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IncobotulinumtoxinA (Xeomin) 400 Units
    Arm description
    		 IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): All subjects receive three injection sessions of solution, prepared by reconstitution of powder with 0.9% NaCl, 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NT 201
    Investigational medicinal product code
    NT 201
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received IncobotulinumtoxinA (400 Units) three intramuscular injection sessions of solution, prepared by reconstitution of powder with 0.9% NaCl, 400 units, total volume 8.0 ml.

    Number of subjects in period 2
    		IncobotulinumtoxinA (Xeomin) 400 Units
    Started
    269
    Treated
    269
    Completed
    218
    Not completed
    51
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    14
         Adverse event, non-fatal
    15
         Non-compliance
    9
         Lost to follow-up
    1
         Lack of efficacy
    5
         Predefined discontinuation criteria
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IncobotulinumtoxinA (Xeomin) 400 Units
    Reporting group description
    		 IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9 percent (%) Sodium Chloride (NaCl), 400 units, total volume 8.0 milliliter (mL); Mode of administration: intramuscular injection.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection

    Reporting group values
    		 IncobotulinumtoxinA (Xeomin) 400 Units Placebo Total
    Number of subjects
    		 144 145 289
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 100 103 203
        From 65-84 years
    		 44 42 86
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.3 ( 11.2 ) 57 ( 13 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 40 55 95
        Male
    		 104 90 194

    End points

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    End points reporting groups
    Reporting group title
    IncobotulinumtoxinA (Xeomin) 400 Units
    Reporting group description
    		 IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9 percent (%) Sodium Chloride (NaCl), 400 units, total volume 8.0 milliliter (mL); Mode of administration: intramuscular injection.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection
    Reporting group title
    IncobotulinumtoxinA (Xeomin) 400 Units
    Reporting group description
    		 IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): All subjects receive three injection sessions of solution, prepared by reconstitution of powder with 0.9% NaCl, 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.

    Primary: Change from Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4

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    End point title
    		 Change from Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4
    End point description
    The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). Full Analysis Set: Subset of subjects in the Safety Evaluation Set (SES) of the main period for whom the primary efficacy variable was available, whereby SES is the subset of all subjects who were exposed to IP in the main period at least once.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    		 IncobotulinumtoxinA (Xeomin) 400 Units Placebo
    Number of subjects analysed
    144
    145
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    2.8 ( 0.7 )
    2.8 ( 0.7 )
        Change at Week 4
    -0.4 ( 0.7 )
    -0.4 ( 0.7 )
    Statistical analysis title
    		 IncobotulinumtoxinA (Xeomin) Vs Placebo
    Statistical analysis description
    The number of subjects included in the MMRM analysis was only 286 because a covariate was missing for 3 subjects.
    Comparison groups
    IncobotulinumtoxinA (Xeomin) 400 Units v Placebo
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.777
    Method
    		 Mixed-Model Repeated Measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.2

    Primary: Co-primary variable: Investigator's Global Assessment of Efficacy at Week 12

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    End point title
    		 Co-primary variable: Investigator's Global Assessment of Efficacy at Week 12
    End point description
    A 4-point Likert scale was used with the ratings 1 = very good, 2 = good, 3 = moderate, and 4 = poor. Investigator's Global Assessment of Efficacy at Week 12 was co-primary outcome measure to fulfill post marketing commitments for U.S. regulatory authorities only. Elsewhere, it would be a secondary outcome measure. Full Analysis Set: Subset of subjects in the Safety Evaluation Set (SES) of the main period for whom the primary efficacy variable was available, whereby SES is the subset of all subjects who were exposed to IP in the main period at least once.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 IncobotulinumtoxinA (Xeomin) 400 Units Placebo
    Number of subjects analysed
    144
    145
    Units: Percentage of Participants
    number (not applicable)
        Very good
    3.5
    4.8
        Good
    28.5
    22.8
        Moderate
    22.2
    26.9
        Poor
    45.8
    45.5
    Statistical analysis title
    		 IncobotulinumtoxinA (Xeomin) Vs Placebo
    Comparison groups
    IncobotulinumtoxinA (Xeomin) 400 Units v Placebo
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.804 [1]
    Method
    		 Wilcoxon's Rank-Sum Test
    Confidence interval
    Notes
    [1] - worst-case analysis.

    Secondary: Response Rate for Plantar Flexors at all Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS)

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    End point title
    		 Response Rate for Plantar Flexors at all Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS)
    End point description
    Response is defined as an improvement (reduction) of the plantar flexor Ashworth Score by at least one score point. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). Here, ‘n’ specifies those subjects who were evaluated for this outcome measure at given time point. Full Analysis Set: Subset of subjects in the Safety Evaluation Set (SES) of the main period for whom the primary efficacy variable was available, whereby SES is the subset of all subjects who were exposed to IP in the main period at least once.
    End point type
    Secondary
    End point timeframe
    Week 4, 8, and 12
    End point values
    		 IncobotulinumtoxinA (Xeomin) 400 Units Placebo
    Number of subjects analysed
    142
    144
    Units: Percentage of Participants
    number (not applicable)
        Week 4 (n=142, 144)
    37.3
    35.4
        Week 8 (n=140, 142)
    39.3
    33.8
        Week 12 (n=135, 141)
    20
    17
    Statistical analysis title
    		 IncobotulinumtoxinA (Xeomin) Vs Placebo
    Statistical analysis description
    Week 4. Number of subjects included in analysis was three less than the observed cases because of a missing covariate for the logistic regression analysis, that is, n=283 for week 4.
    Comparison groups
    IncobotulinumtoxinA (Xeomin) 400 Units v Placebo
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.845 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.74
    Notes
    [2] - observed cases analysis.
    Statistical analysis title
    		 IncobotulinumtoxinA (Xeomin) Vs Placebo
    Statistical analysis description
    Week 8. Number of subjects included in analysis was three less than the observed cases because of a missing covariate for the logistic regression analysis, that is, n=279 for week 8.
    Comparison groups
    IncobotulinumtoxinA (Xeomin) 400 Units v Placebo
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.437 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 2.04
    Notes
    [3] - observed cases analysis.
    Statistical analysis title
    		 IncobotulinumtoxinA (Xeomin) Vs Placebo
    Statistical analysis description
    Week 12. Number of subjects included in analysis was three less than the observed cases because of a missing covariate for the logistic regression analysis, that is, n=273 for week 12.
    Comparison groups
    IncobotulinumtoxinA (Xeomin) 400 Units v Placebo
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.698 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 2.21
    Notes
    [4] - observed cases analysis.

    Secondary: Ashworth Scale (AS) for Plantar Flexors at all Post-Baseline Visits

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    End point title
    		 Ashworth Scale (AS) for Plantar Flexors at all Post-Baseline Visits
    End point description
    The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). Here, ‘n’ specifies those subjects who were evaluated for this outcome measure at given time point. Full Analysis Set: Subset of subjects in the Safety Evaluation Set (SES) of the main period for whom the primary efficacy variable was available, whereby SES is the subset of all subjects who were exposed to IP in the main period at least once.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, and 12
    End point values
    		 IncobotulinumtoxinA (Xeomin) 400 Units Placebo
    Number of subjects analysed
    144
    145
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=144, 145)
    2.8 ( 0.7 )
    2.8 ( 0.7 )
        Week 4 (n= 142, 144)
    2.4 ( 0.9 )
    2.4 ( 0.8 )
        Week 8 (n=140, 142)
    2.4 ( 0.9 )
    2.5 ( 0.7 )
        Week 12 (n= 135, 141)
    2.7 ( 0.8 )
    2.7 ( 0.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time point of first injection until 120 +/- 7 days after last administration of injection
    Adverse event reporting additional description
    The investigator asked the subject for adverse events systematically at each visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Main Period: IncobotulinumtoxinA (Xeomin) 400 Units
    Reporting group description
    		 IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.

    Reporting group title
    Main Period: Placebo
    Reporting group description
    		 Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection

    Reporting group title
    Open-Label Extension: IncobotulinumtoxinA (Xeomin) 400 Units
    Reporting group description
    		 IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Open-Label Extension Period: All subjects receive three injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.

    Serious adverse events
    		 Main Period: IncobotulinumtoxinA (Xeomin) 400 Units Main Period: Placebo Open-Label Extension: IncobotulinumtoxinA (Xeomin) 400 Units
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 144 (4.17%)
    5 / 145 (3.45%)
    22 / 269 (8.18%)
         number of deaths (all causes)
    0
    1
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic neoplasm
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Desmoid tumour
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cranioplasty
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical induction of coma
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Skin lesion excision
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheostomy
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Limb operation
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rehabilitation therapy
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Immobile
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 145 (0.69%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Personality disorder
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper-limb fracture
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial haematoma
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 145 (0.69%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice cholestatic
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 145 (0.69%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Mobility decreased
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 145 (0.69%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 145 (0.69%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 145 (0.69%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 145 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Main Period: IncobotulinumtoxinA (Xeomin) 400 Units Main Period: Placebo Open-Label Extension: IncobotulinumtoxinA (Xeomin) 400 Units
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 144 (9.03%)
    13 / 145 (8.97%)
    31 / 269 (11.52%)
    Investigations
    γ-glutamyltransferase increased
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    7 / 269 (2.60%)
         occurrences all number
    0
    0
    7
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 144 (0.00%)
    2 / 145 (1.38%)
    11 / 269 (4.09%)
         occurrences all number
    0
    3
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 144 (0.69%)
    3 / 145 (2.07%)
    2 / 269 (0.74%)
         occurrences all number
    1
    4
    2
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 144 (0.00%)
    3 / 145 (2.07%)
    3 / 269 (1.12%)
         occurrences all number
    0
    3
    3
    Eye disorders
    Vision blurred
         subjects affected / exposed
    3 / 144 (2.08%)
    0 / 145 (0.00%)
    1 / 269 (0.37%)
         occurrences all number
    4
    0
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    7 / 144 (4.86%)
    7 / 145 (4.83%)
    10 / 269 (3.72%)
         occurrences all number
    8
    9
    10
    Back pain
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 145 (0.00%)
    6 / 269 (2.23%)
         occurrences all number
    0
    0
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 144 (2.08%)
    1 / 145 (0.69%)
    4 / 269 (1.49%)
         occurrences all number
    3
    1
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2011
    The overall reason for the amendment was to fulfil a post marketing commitment (PMC) for Xeomin in the United States. A co-primary endpoint was added, the ‘Investigator’s Global Assessment of Efficacy’. This scale had been part of the Study Protocol as tertiary outcome measure before. Accordingly, details on the analyses of the primary endpoint(s) were updated. The Ashworth Scale (AS) and the co-primary endpoint were only to be co-analyzed for United States submission and both had to show significant treatment differences.
    16 May 2014
    The overall reason for the amendment was to implement a revision of sample-size calculation and to implement current updates of approval status, safety information and statistical methods.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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