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    Clinical Trial Results:
    Prospective, randomized, double-blind, placebo-controlled, parallel-group multicenter study, with an extension period of dose-blinded active treatment, to investigate the efficacy and safety of two dose levels of NT 201 in treating chronic troublesome sialorrhea in various neurological conditions

    Summary
    EudraCT number
    		 2012-005539-10
    Trial protocol
    		 DE  
    Global end of trial date
    09 Nov 2016

    Results information
    Results version number
    		 v3(current)
    This version publication date
    21 Apr 2018
    First version publication date
    14 Dec 2017
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Minor editorial changes to make it match with CTgov entries

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MRZ60201_3090_1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02091739
    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
    01 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to investigate the efficacy and safety of two different dose levels of NT 201 (75 units or 100 units per cycle), compared with placebo, in reducing the salivary flow rate, and the severity and frequency of chronic troublesome sialorrhea with Parkinson’s disease or atypical parkinsonism (multiple system atrophy, corticobasal degeneration, or progressive supranuclear palsy) or after stroke or traumatic brain injury.
    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
    11 Apr 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
    Germany: 53
    Country: Number of subjects enrolled
    Poland: 131
    Worldwide total number of subjects
    184
    EEA total number of subjects
    184
    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)
    77
    From 65 to 84 years
    107
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 12 sites in Poland and Germany.

    Pre-assignment
    Screening details
    		 A total of 216 subjects were screened for the study, of which 184 subjects were randomized and treated in the Main Period (MP) of the study. A total of 173 subjects who completed the MP, entered the 2 treatment arms of the Extension Period (EP) of the study.

    Period 1
    Period 1 title
    MP: 16 Weeks
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MP: Placebo
    Arm description
    		 Subjects received 2.0 milliliter (mL) placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intraglandular use
    Dosage and administration details
    Subjects received one injection session of overall 2.0 mL placebo matched to the volume of incobotulinumtoxinA via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 in the MP.

    Arm title
    		 MP: IncobotulinumtoxinA (Xeomin) (75 units)
    Arm description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 75 units.
    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
    Intraglandular use
    Dosage and administration details
    Subjects received one injection session of overall 2.0 mL incobotulinumtoxinA containing 75 units via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 in the MP.

    Arm title
    		 MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Arm description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 100 units.
    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
    Intraglandular use
    Dosage and administration details
    Subjects received one injection session of overall 2.0 mL incobotulinumtoxinA containing 100 units via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 in the MP.

    Number of subjects in period 1
    		MP: Placebo MP: IncobotulinumtoxinA (Xeomin) (75 units) MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Started
    36
    74
    74
    Completed
    32
    69
    72
    Not completed
    4
    5
    2
         Consent withdrawn by subject
    3
    4
    -
         Lost to follow-up
    -
    -
    1
         Adverse event, non-fatal
    1
    1
    1
    Period 2
    Period 2 title
    EP: 48 Weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EP: IncobotulinumtoxinA (Xeomin) (75 units)
    Arm description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 75 units at each of the three EP injection sessions.
    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
    Intraglandular use
    Dosage and administration details
    Subjects received overall 2.0 mL incobotulinumtoxinA containing 75 units via bilateral intraglandular injection into the parotid and submandibular glands at each of the three injection sessions in the EP.

    Arm title
    		 EP: IncobotulinumtoxinA (Xeomin) (100 units)
    Arm description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 100 units at each of the three EP injection sessions
    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
    Intraglandular use
    Dosage and administration details
    Subjects received overall 2.0 mL incobotulinumtoxinA containing 100 units via bilateral intraglandular injection into the parotid and submandibular glands at each of the three injection sessions in the EP.

    Number of subjects in period 2
    		EP: IncobotulinumtoxinA (Xeomin) (75 units) EP: IncobotulinumtoxinA (Xeomin) (100 units)
    Started
    84
    89
    Completed
    76
    75
    Not completed
    8
    14
         Adverse event, serious fatal
    3
    2
         Consent withdrawn by subject
    2
    6
         Adverse event, non-fatal
    2
    6
         Other
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MP: Placebo
    Reporting group description
    		 Subjects received 2.0 milliliter (mL) placebo.

    Reporting group title
    MP: IncobotulinumtoxinA (Xeomin) (75 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 75 units.

    Reporting group title
    MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 100 units.

    Reporting group values
    		 MP: Placebo MP: IncobotulinumtoxinA (Xeomin) (75 units) MP: IncobotulinumtoxinA (Xeomin) (100 units) Total
    Number of subjects
    		 36 74 74 184
    Age categorical
    Units: Subjects
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 19 30 28 77
        From 65-84 years
    		 17 44 46 107
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 8 24 22 54
        Male
    		 28 50 52 130
    Race
    Units: Subjects
        White
    		 36 74 73 183
        Asian
    		 0 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 1 1
        Not Hispanic or Latino
    		 36 74 73 183
    Weight
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    		 80.6 ± 16.4 78.4 ± 17.1 79.8 ± 14 -
    Body Mass Index (BMI)
    Units: kilogram per square meter (kg/m^2)
        arithmetic mean (standard deviation)
    		 28.5 ± 6 26.7 ± 5.2 27.7 ± 3.8 -

    End points

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    End points reporting groups
    Reporting group title
    MP: Placebo
    Reporting group description
    		 Subjects received 2.0 milliliter (mL) placebo.

    Reporting group title
    MP: IncobotulinumtoxinA (Xeomin) (75 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 75 units.

    Reporting group title
    MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 100 units.
    Reporting group title
    EP: IncobotulinumtoxinA (Xeomin) (75 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 75 units at each of the three EP injection sessions.

    Reporting group title
    EP: IncobotulinumtoxinA (Xeomin) (100 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 100 units at each of the three EP injection sessions

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS is the subset of subjects who were treated and had at least the baseline value of unstimulated salivary flow (uSFR).

    Primary: MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 4

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    End point title
    		 MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 4
    End point description
    uSFR was assessed by weighing of dental rolls soaked with saliva over 5 minutes and then procedure was repeated after 30 minutes and the average of the 2 results for flow rate was calculated.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    		 MP: Placebo MP: IncobotulinumtoxinA (Xeomin) (75 units) MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Number of subjects analysed
    36 [1]
    73 [2]
    73 [3]
    Units: gram per minute (g/min)
        least squares mean (standard error)
    -0.04 ± 0.033
    -0.06 ± 0.027
    -0.13 ± 0.026
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    Statistical analysis title
    		 Week 4: IncobotulinumtoxinA 100 units v Placebo
    Statistical analysis description
    A fixed sequence test procedure was used for the confirmatory analysis of the co-primary endpoints by comparing the least square (LS) means estimates of an mixed model repeated measurement (MMRM) model (2-sided, significance level alpha=0.05) between treatment groups in the following order: 1) IncobotulinumtoxinA 100 units versus (v) Placebo 2) IncobotulinumtoxinA 75 units v Placebo
    Comparison groups
    MP: IncobotulinumtoxinA (Xeomin) (100 units) v MP: Placebo
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.031
    Statistical analysis title
    		 Week 4: IncobotulinumtoxinA 75 units v Placebo
    Statistical analysis description
    A fixed sequence test procedure was used for the confirmatory analysis of the co-primary endpoints by comparing the least square means estimates of an MMRM model (2-sided, significance level alpha=0.05) between treatment groups in the following order: 1) IncobotulinumtoxinA 100 units versus (v) Placebo 2) IncobotulinumtoxinA 75 units v Placebo
    Comparison groups
    MP: Placebo v MP: IncobotulinumtoxinA (Xeomin) (75 units)
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.542
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03

    Primary: MP: Subjects's Global Impression of Change Scale (GICS) at Week 4

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    End point title
    		 MP: Subjects's Global Impression of Change Scale (GICS) at Week 4
    End point description
    The GICS was used to measure the impression of change due to treatment. The response option was a common 7-point Likert scale that ranged from -3 = very much worse to +3 = very much improved and was applicable for subject and caregiver. If the subject was not able to answer then carer's rating was to be recorded instead of subject's rating and the subject's rating was left blank.
    End point type
    Primary
    End point timeframe
    Week 4
    End point values
    		 MP: Placebo MP: IncobotulinumtoxinA (Xeomin) (75 units) MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Number of subjects analysed
    36 [4]
    74 [5]
    74 [6]
    Units: units on scale
        least squares mean (standard error)
    0.67 ± 0.186
    1.02 ± 0.148
    1.25 ± 0.144
    Notes
    [4] - FAS
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    		 Week 4: IncobotulinumtoxinA 100 units v Placebo
    Statistical analysis description
    A fixed sequence test procedure was used for the confirmatory analysis of the co-primary endpoints by comparing the least square means estimates of an MMRM model (2-sided, significance level alpha=0.05) between treatment groups in the following order: 1) IncobotulinumtoxinA 100 units versus (v) Placebo 2) IncobotulinumtoxinA 75 Units v Placebo
    Comparison groups
    MP: Placebo v MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.183
    Statistical analysis title
    		 Week 4: IncobotulinumtoxinA 75 units v Placebo
    Statistical analysis description
    A fixed sequence test procedure was used for the confirmatory analysis of the co-primary endpoints by comparing the least square means estimates of an MMRM model (2-sided, significance level alpha=0.05) between treatment groups in the following order: 1) IncobotulinumtoxinA 100 units versus (v) Placebo 2) IncobotulinumtoxinA 75 units v Placebo
    Comparison groups
    MP: Placebo v MP: IncobotulinumtoxinA (Xeomin) (75 units)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.055
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.181

    Secondary: MP: Change From Baseline in uSFR Rate at Week 8 and 12

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    End point title
    		 MP: Change From Baseline in uSFR Rate at Week 8 and 12
    End point description
    uSFR was assessed by weighing of dental rolls soaked with saliva over 5 minutes and then procedure was repeated after 30 minutes and the average of the 2 results for flow rate was calculated.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8 and 12
    End point values
    		 MP: Placebo MP: IncobotulinumtoxinA (Xeomin) (75 units) MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Number of subjects analysed
    36 [7]
    73 [8]
    73 [9]
    Units: g/min
    least squares mean (standard error)
        Week 8
    -0.02 ± 0.033
    -0.08 ± 0.027
    -0.13 ± 0.026
        Week 12
    -0.03 ± 0.033
    -0.1 ± 0.027
    -0.12 ± 0.026
    Notes
    [7] - FAS
    [8] - FAS
    [9] - FAS
    No statistical analyses for this end point

    Secondary: MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12

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    End point title
    		 MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12
    End point description
    The GICS was used to measure the investigator's impression of change due to treatment. The response option was a common 7-point Likert scale that ranged from -3 = very much worse to +3 = very much improved and was applicable for subject and caregiver. If the subject was not able to answer then carer's rating was to be recorded instead of subject's rating and the subject's rating was left blank.
    End point type
    Secondary
    End point timeframe
    Week 1, 2, 8, and 12
    End point values
    		 MP: Placebo MP: IncobotulinumtoxinA (Xeomin) (75 units) MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Number of subjects analysed
    36 [10]
    74 [11]
    74 [12]
    Units: units on scale
    least squares mean (standard error)
        Week 1
    0.67 ± 0.17
    0.73 ± 0.138
    0.96 ± 0.133
        Week 2
    0.83 ± 0.178
    0.91 ± 0.143
    1.11 ± 0.139
        Week 8
    0.47 ± 0.192
    1.07 ± 0.151
    1.3 ± 0.148
        Week 12
    0.56 ± 0.197
    0.98 ± 0.156
    1.21 ± 0.152
    Notes
    [10] - FAS
    [11] - FAS
    [12] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    MP: From first injection up to first injection in EP (week 16). EP: From first injection in EP (week 16) up to end of study (week 64).
    Adverse event reporting additional description
    The investigator asked the subject for adverse events systematically at each visit. Two subjects received the wrong or no dose in single EP cycles due to procedural reasons and hence were not included in the safety analyses that cover the complete EP: IncobotulinumtoxinA (Xeomin) (75 Units) arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    MP: Placebo
    Reporting group description
    		 Subjects received 2.0 mL placebo.

    Reporting group title
    MP: IncobotulinumtoxinA (Xeomin) (75 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 75 units.

    Reporting group title
    MP: IncobotulinumtoxinA (Xeomin) (100 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 100 units.

    Reporting group title
    EP: IncobotulinumtoxinA (Xeomin) (75 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 75 units at each of the three EP injection sessions.

    Reporting group title
    EP: IncobotulinumtoxinA (Xeomin) (100 units)
    Reporting group description
    		 Subjects received 2.0 mL incobotulinumtoxinA containing 100 units at each of the three EP injection sessions.

    Serious adverse events
    		 MP: Placebo MP: IncobotulinumtoxinA (Xeomin) (75 units) MP: IncobotulinumtoxinA (Xeomin) (100 units) EP: IncobotulinumtoxinA (Xeomin) (75 units) EP: IncobotulinumtoxinA (Xeomin) (100 units)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 36 (8.33%)
    6 / 74 (8.11%)
    9 / 74 (12.16%)
    15 / 82 (18.29%)
    14 / 89 (15.73%)
         number of deaths (all causes)
    0
    0
    0
    3
    2
         number of deaths resulting from adverse events
    0
    0
    0
    3
    2
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Hypertensive crisis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
     Coronary arterial stent insertion
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical device battery replacement
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical device change
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rehabilitation therapy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angioplasty
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicectomy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterostomy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Explorative laparotomy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Laparotomy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrectomy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal stone removal
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureter dilation procedure
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteral stent insertion
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Pyrexia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
     Asthma
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Lower respiratory tract inflammation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dopamine dysregulation syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Suicidal ideation
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
     Device occlusion
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
     Angiogram
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Femur fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Lumbar vertebral fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Rib fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Skin abrasion
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Spinal column injury
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Aortic valve stenosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Bradycardia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
     Parkinson's disease
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    1 / 74 (1.35%)
    6 / 82 (7.32%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Drop attacks
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Freezing phenomenon
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Akinesia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Movement disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac pacemaker insertion
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
     Coagulopathy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
     Vertigo
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    2 / 82 (2.44%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecal vomiting
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Giant cell epulis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Megacolon
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal food impaction
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
     Drug-induced liver injury
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
     Skin ulcer
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
     Hydronephrosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extravasation of urine
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
      Back pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Pyuria
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    2 / 82 (2.44%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
     Cellulitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 82 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 82 (1.22%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MP: Placebo MP: IncobotulinumtoxinA (Xeomin) (75 units) MP: IncobotulinumtoxinA (Xeomin) (100 units) EP: IncobotulinumtoxinA (Xeomin) (75 units) EP: IncobotulinumtoxinA (Xeomin) (100 units)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 36 (5.56%)
    14 / 74 (18.92%)
    10 / 74 (13.51%)
    22 / 82 (26.83%)
    22 / 89 (24.72%)
    Injury, poisoning and procedural complications
     Fall
         subjects affected / exposed
    0 / 36 (0.00%)
    6 / 74 (8.11%)
    2 / 74 (2.70%)
    5 / 82 (6.10%)
    4 / 89 (4.49%)
         occurrences all number
    0
    8
    5
    9
    5
    Contusion
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 74 (5.41%)
    0 / 74 (0.00%)
    3 / 82 (3.66%)
    1 / 89 (1.12%)
         occurrences all number
    0
    5
    0
    3
    1
    Vascular disorders
     Hypertension
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 74 (2.70%)
    3 / 74 (4.05%)
    5 / 82 (6.10%)
    2 / 89 (2.25%)
         occurrences all number
    1
    2
    3
    5
    2
    Surgical and medical procedures
     Tooth extraction
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 74 (0.00%)
    4 / 74 (5.41%)
    3 / 82 (3.66%)
    4 / 89 (4.49%)
         occurrences all number
    0
    0
    4
    4
    5
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 74 (5.41%)
    3 / 74 (4.05%)
    3 / 82 (3.66%)
    10 / 89 (11.24%)
         occurrences all number
    0
    5
    3
    4
    13
    Infections and infestations
     Nasopharyngitis
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 74 (2.70%)
    2 / 74 (2.70%)
    1 / 82 (1.22%)
    6 / 89 (6.74%)
         occurrences all number
    1
    2
    2
    1
    6
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 74 (2.70%)
    0 / 74 (0.00%)
    5 / 82 (6.10%)
    0 / 89 (0.00%)
         occurrences all number
    0
    2
    0
    6
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2014
    Main Changes: 1. Addition of a new safety assessment to prospectively monitor suicidality in order to comply with FDA guidance on suicidality testing in all clinical trials investigating neurological indications: Columbia Suicide Severity Rating Scale (C-SSRS). 2. Addition of detailed immunogenicity assessment. 3. Addition of dental examination by a dentist at week 32 4. Legally acceptable representative was replaced by impartial witness 5. Dental examinations and mROAG assessment concerning AE reporting were explicitly explained.

    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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