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    Clinical Trial Results:
    A multicenter, randomized, double-blind, parallel-group, placebo-controlled variable treatment duration study evaluating the efficacy and safety of Siponimod (BAF312) in patients with secondary progressive multiple sclerosis followed by extended treatment with open-label BAF312

    Summary
    EudraCT number
    		 2012-003056-36
    Trial protocol
    		 HU   IE   DE   CZ   SK   NL   ES   GB   AT   SE   PT   IT   LV   GR   LT   EE   BE   PL   BG   FR  
    Global end of trial date
    31 Mar 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Jun 2024
    First version publication date
    12 Apr 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CBAF312A2304
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01665144
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis campus, Basel, Switzerland, CH-4056
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    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
    31 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the efficacy of BAF312 relative to placebo in delaying the time to 3-month confirmed disability progression in patients with secondary progressive multiple sclerosis (SPMS) as measured by Expanded Disability Status Scale (EDSS) in the Core Part of the study.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Dec 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 30
    Country: Number of subjects enrolled
    Australia: 36
    Country: Number of subjects enrolled
    Austria: 59
    Country: Number of subjects enrolled
    Belgium: 34
    Country: Number of subjects enrolled
    Bulgaria: 30
    Country: Number of subjects enrolled
    Canada: 47
    Country: Number of subjects enrolled
    China: 22
    Country: Number of subjects enrolled
    Czechia: 35
    Country: Number of subjects enrolled
    Estonia: 16
    Country: Number of subjects enrolled
    France: 85
    Country: Number of subjects enrolled
    Germany: 257
    Country: Number of subjects enrolled
    Greece: 14
    Country: Number of subjects enrolled
    Hungary: 60
    Country: Number of subjects enrolled
    Ireland: 11
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Italy: 89
    Country: Number of subjects enrolled
    Japan: 23
    Country: Number of subjects enrolled
    Latvia: 19
    Country: Number of subjects enrolled
    Lithuania: 25
    Country: Number of subjects enrolled
    Netherlands: 33
    Country: Number of subjects enrolled
    Poland: 109
    Country: Number of subjects enrolled
    Portugal: 33
    Country: Number of subjects enrolled
    Romania: 22
    Country: Number of subjects enrolled
    Russian Federation: 95
    Country: Number of subjects enrolled
    Slovakia: 25
    Country: Number of subjects enrolled
    Spain: 106
    Country: Number of subjects enrolled
    Sweden: 24
    Country: Number of subjects enrolled
    Switzerland: 31
    Country: Number of subjects enrolled
    Türkiye: 33
    Country: Number of subjects enrolled
    United Kingdom: 78
    Country: Number of subjects enrolled
    United States: 154
    Worldwide total number of subjects
    1651
    EEA total number of subjects
    1086
    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)
    1651
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in 294 investigative sites in 31 countries.

    Pre-assignment
    Screening details
    		 The Screening Epoch included a Screening Phase (Day -45 to Day -8) and a Baseline Phase (Day -7 to Day 1 before the first study drug administration). During the Core Part, eligible patients were randomized in a 2:1 ratio to siponimod (BAF312) or placebo. Patients who were eligible to enter the Extension Part received open label siponimod.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Siponimod (BAF312)
    Arm description
    		 Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Siponimod
    Investigational medicinal product code
    BAF312
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Following randomization in the Core Part (CP), patients underwent 6-day titration to the target maintenance dose of blinded study drug (2 mg siponimod). Patients with lymphocyte counts (at 2 consecutive visits) of <0.2 x10^9/L were to reduce the dose to 1 mg/day in a blinded fashion. Siponimod was administered orally once daily as film-coated tablets.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo to BAF312 was administered orally during the Core Part of the trial.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Following randomization in the Core Part (CP), patients underwent 6-day titration to the target maintenance dose of blinded study drug (placebo). Placebo was administered orally once daily as film-coated tablets.

    Number of subjects in period 1
    		Siponimod (BAF312) Placebo
    Started
    1105
    546
    Safety set
    1099
    546
    Full analysis set
    1099
    546
    Completed
    903
    424
    Not completed
    202
    122
         Physician decision
    13
    1
         Adverse Event
    45
    18
         Technical problems
    2
    -
         Death
    3
    1
         Non-compliance with study treatment
    5
    -
         Protocol deviation
    3
    1
         Lost to follow-up
    9
    8
         Progressive disease
    8
    4
         New therapy for study indication
    2
    1
         Withdrawal by subject
    96
    77
         Lack of efficacy
    16
    11
    Period 2
    Period 2 title
    Extension Part
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Siponimod (BAF312)
    Arm description
    		 Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Siponimod
    Investigational medicinal product code
    BAF312
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eligible patients who entered the Extension Part (EP) received open label siponimod. For the EP, treatment for patients who had completed the CP on either double-blind treatment or on the abbreviated schedule, initiated with the 6-day dose titration pack. Patients who had been on 2 mg with double-blind treatment were titrated to the 2 mg dose while patients who were taking 1 mg were titrated to the 1 mg dose. Patients who had been on open-label siponimod in the CP initiated treatment on their current dose of siponimod.

    Arm title
    		 Placebo-BAF312
    Arm description
    		 Participants who received placebo in the Core Part and switched to siponimod in the Extension Part.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Siponimod
    Investigational medicinal product code
    BAF312
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eligible patients who entered the Extension Part (EP) received open label siponimod. For the EP, treatment for patients who had completed the CP on either double-blind treatment or on the abbreviated schedule, initiated with the 6-day dose titration pack. Patients who had been on 2 mg with double-blind treatment were titrated to the 2 mg dose while patients who were taking 1 mg were titrated to the 1 mg dose. Patients who had been on open-label siponimod in the CP initiated treatment on their current dose of siponimod.

    Number of subjects in period 2 [1]
    		Siponimod (BAF312) Placebo-BAF312
    Started
    821
    399
    Completed
    326
    159
    Not completed
    495
    240
         Physician decision
    29
    13
         Adverse Event
    104
    59
         Technical problems
    20
    8
         Death
    20
    4
         Protocol deviation
    3
    -
         Patient/guardian decision
    180
    98
         Study closed early
    42
    19
         Progressive disease
    36
    14
         Lost to follow-up
    9
    5
         Missing
    12
    6
         New therapy for study indication
    3
    2
         Lack of efficacy
    37
    12
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only eligible patients entered the Extension Part

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Siponimod (BAF312)
    Reporting group description
    		 Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo to BAF312 was administered orally during the Core Part of the trial.

    Reporting group values
    		 Siponimod (BAF312) Placebo Total
    Number of subjects
    		 1105 546 1651
    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)
    		 1105 546 1651
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 48.0 ( 7.84 ) 48.1 ( 7.94 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 669 323 992
        Male
    		 436 223 659
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 31 18 49
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 7 3 10
        White
    		 1050 513 1563
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 17 12 29

    End points

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    End points reporting groups
    Reporting group title
    Siponimod (BAF312)
    Reporting group description
    		 Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo to BAF312 was administered orally during the Core Part of the trial.
    Reporting group title
    Siponimod (BAF312)
    Reporting group description
    		 Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.

    Reporting group title
    Placebo-BAF312
    Reporting group description
    		 Participants who received placebo in the Core Part and switched to siponimod in the Extension Part.

    Primary: Percentage of participants with 3-month Confirmed Disability Progression (CDP) events as measured by the Expanded Disability Status Scale (EDSS)

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    End point title
    		 Percentage of participants with 3-month Confirmed Disability Progression (CDP) events as measured by the Expanded Disability Status Scale (EDSS)
    End point description
    The EDSS uses an ordinal scale to assess neurologic impairment in MS based on a neurological examination. Scores in each of 7 functional systems (Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel & Bladder, and Cerebral) and an ambulation score were combined to determine the EDSS steps, ranging from 0 (normal) to 10 (death due to MS). 3-month confirmed disability progression is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5 sustained for at least 3 months.
    End point type
    Primary
    End point timeframe
    Baseline, every 3 month up to the maximum of approximately 3 years
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1096
    545
    Units: Percentage of participants
        number (not applicable)
    26.3
    31.7
    Statistical analysis title
    		 3-month confirmed disability progression
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1641
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0134
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.95

    Secondary: Percentage of participants with 3-month confirmed worsening in T25W of at least 20% from baseline

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    End point title
    		 Percentage of participants with 3-month confirmed worsening in T25W of at least 20% from baseline
    End point description
    The Timed 25-Foot Walk Test (T25W) measured the time, in seconds, to walk 25 feet (7.62 meters). A 3-month confirmed worsening of at least 20% from baseline in the T25W was defined as an increase from baseline sustained for at least 3 months. This outcome measure was analyzed using a Cox proportional hazards model.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to the maximum of approximately 3 years
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1087
    543
    Units: Percentage of participants
        number (not applicable)
    39.7
    41.4
    Statistical analysis title
    		 3-month confirmed worsening T25W
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1630
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.4398
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.1

    Secondary: Change from baseline in T2 lesion volume

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    End point title
    		 Change from baseline in T2 lesion volume
    End point description
    Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the total volume of T2 lesions. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center. The change from baseline in T2 lesion volume was analyzed using a mixed model for repeated measures (MMRM) with visit as a categorical factor and an unstructured covariance matrix and with adjustment for baseline covariates.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12 and Month 24
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    995
    495
    Units: mm^3
    least squares mean (standard error)
        Month 12
    204.9 ( 67.47 )
    818.0 ( 87.29 )
        Month 24
    162.9 ( 73.90 )
    940.4 ( 97.20 )
        Average over Month 12 and Month 24
    183.9 ( 66.33 )
    879.2 ( 85.43 )
    Statistical analysis title
    		 Month 12
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -613.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -800.2
         upper limit
    		 -426
    Variability estimate
    Standard error of the mean
    Dispersion value
    95.39
    Statistical analysis title
    		 Average over Month 12 and Month 24
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -695.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -877.3
         upper limit
    		 -513.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    92.79
    Statistical analysis title
    		 Month 24
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -777.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -990.6
         upper limit
    		 -564.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    108.62

    Secondary: Percentage of participants with 6-month Confirmed Disability Progression (CDP) events as measured by the Expanded Disability Status Scale (EDSS)

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    End point title
    		 Percentage of participants with 6-month Confirmed Disability Progression (CDP) events as measured by the Expanded Disability Status Scale (EDSS)
    End point description
    The EDSS uses an ordinal scale to assess neurologic impairment in multiple sclerosis (MS) based on a neurological examination. Scores in each of 7 functional systems (Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel & Bladder, and Cerebral) and an ambulation score were combined to determine the EDSS steps, ranging from 0 (normal) to 10 (death due to MS). 6-month confirmed disability progression is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5 sustained for at least 6 months. This outcome measure was analyzed using a Cox proportional hazards model.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to the maximum of approximately 3 years
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1096
    545
    Units: Percentage of participants
        number (not applicable)
    19.9
    25.5
    Statistical analysis title
    		 6-month confirmed disability progression
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1641
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0058
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.92

    Secondary: Percentage of participants with first relapse events as measured by time to first confirmed relapse

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    End point title
    		 Percentage of participants with first relapse events as measured by time to first confirmed relapse
    End point description
    Multiple sclerosis (MS) relapse was defined as appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. Additionally, the abnormality had to be present for at least 24 hours and occur in the absence of fever (<37.5°C) or known infection. A confirmed MS relapse was defined as accompanied by a clinically-relevant change in the EDSS, as defined in the study protocol, performed by the Independent EDSS Rater. Time to first relapse was defined as the time from Day 1 until the start of relapse symptoms. Patients without relapse were censored at the latest known date to be at risk. This outcome measure was analyzed using a Cox proportional hazards model.
    End point type
    Secondary
    End point timeframe
    Up to maximum approximately 3 years
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1061
    528
    Units: Percentage of participants
        number (not applicable)
    10.7
    18.9
    Statistical analysis title
    		 Time to first relapse
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1589
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.7

    Secondary: Annualized relapse rate (ARR) for confirmed relapses

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    End point title
    		 Annualized relapse rate (ARR) for confirmed relapses
    End point description
    Multiple sclerosis (MS) relapse was defined as appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. Additionally, the abnormality had to be present for at least 24 hours and occur in the absence of fever (<37.5°C) or known infection. A confirmed MS relapse was defined as accompanied by a clinically-relevant change in the EDSS, as defined in the study protocol, performed by the Independent EDSS Rater. ARR was defined as the average number of confirmed relapses per year. ARR was analyzed using a negative binomial regression model.
    End point type
    Secondary
    End point timeframe
    Up to maximum approximately 3 years
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1099
    546
    Units: relapses/year
        arithmetic mean (confidence interval 95%)
    0.071 (0.055 to 0.092)
    0.160 (0.123 to 0.207)
    Statistical analysis title
    		 ARR for confirmed relapses
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Negative binomial regression model
    Parameter type
    		 ARR ratio
    Point estimate
    0.445
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.337
         upper limit
    		 0.587

    Secondary: Percentage of patients with relapse (confirmed relapse and any relapse)

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    End point title
    		 Percentage of patients with relapse (confirmed relapse and any relapse)
    End point description
    Multiple sclerosis (MS) relapse was defined as appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. Additionally, the abnormality had to be present for at least 24 hours and occur in the absence of fever (<37.5°C) or known infection. A confirmed MS relapse was defined as accompanied by a clinically-relevant change in the EDSS, as defined in the study protocol, performed by the Independent EDSS Rater.
    End point type
    Secondary
    End point timeframe
    Up to maximum approximately 3 years
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1099
    546
    Units: Percentage of participants
    number (not applicable)
        Any relapse (confirmed or unconfirmed)
    16.7
    26.0
        Confirmed relapse
    10.3
    18.7
    No statistical analyses for this end point

    Secondary: Change from baseline in MSWS-12 converted score

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    End point title
    		 Change from baseline in MSWS-12 converted score
    End point description
    The Multiple Sclerosis Walking Scale (MSWS-12) version 2 is a patient-rated measure of walking consisting of 12 items. Walking limitations were reported by the patients using categories, generating a total transformed score ranging from 0-100. Higher scores reflected greater impairment. The change from baseline in MSWS-12 converted score was analyzed using a repeated measures model.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12 and Month 24
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1022
    516
    Units: score on a scale
    least squares mean (standard error)
        Month 12
    1.53 ( 0.678 )
    3.36 ( 0.908 )
        Month 24
    4.16 ( 0.848 )
    5.38 ( 1.167 )
    Statistical analysis title
    		 Month 12
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1538
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0764
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.85
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.03
    Statistical analysis title
    		 Month 24
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1538
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3671
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.89
         upper limit
    		 1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.359

    Secondary: Number of T1 Gd-enhancing lesions per patient per scan

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    End point title
    		 Number of T1 Gd-enhancing lesions per patient per scan
    End point description
    Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the number of T1 gadolinium (Gd)-enhancing lesions. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center. The number of T1 Gd-enhancing lesions per patient per scan was analyzed using a negative binomial regression model.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12 and Month 24
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    996
    496
    Units: T1 Gd-enhancing lesions/patient/scan
    least squares mean (confidence interval 95%)
        Month 12
    0.080 (0.058 to 0.111)
    0.640 (0.488 to 0.839)
        Month 24
    0.074 (0.040 to 0.138)
    0.418 (0.288 to 0.607)
    Statistical analysis title
    		 Month 24
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Negative binomial regression model
    Parameter type
    		 Rate ratio
    Point estimate
    0.178
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.087
         upper limit
    		 0.362
    Statistical analysis title
    		 Month 12
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Negative binomial regression model
    Parameter type
    		 Rate ratio
    Point estimate
    0.126
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.083
         upper limit
    		 0.191

    Secondary: Number of new or enlarging T2 lesions per patient per year

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    End point title
    		 Number of new or enlarging T2 lesions per patient per year
    End point description
    Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the number of new or enlarging T2 lesions. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center. The number of new or enlarging T2 lesions compared to previous scan was analyzed using a repeated measures negative binomial regression model.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12 and Month 24
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    997
    496
    Units: T2 lesions/patient/year
    least squares mean (confidence interval 95%)
        Month 12
    1.003 (0.858 to 1.172)
    3.776 (3.148 to 4.528)
        Month 24
    0.489 (0.371 to 0.644)
    3.437 (2.800 to 4.220)
    Statistical analysis title
    		 Month 24
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression model
    Parameter type
    		 Rate ratio
    Point estimate
    0.142
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.103
         upper limit
    		 0.196
    Statistical analysis title
    		 Month 12
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression model
    Parameter type
    		 Rate ratio
    Point estimate
    0.266
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.215
         upper limit
    		 0.328

    Secondary: Percent brain volume change (PBVC) relative to baseline

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    End point title
    		 Percent brain volume change (PBVC) relative to baseline
    End point description
    Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the percentage change in brain volume. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center. PBVC relative to baseline was analyzed using a repeated measures model (for normally distributed data) with visit as a categorical factor.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12 and Month 24
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    894
    436
    Units: % change from baseline in brain volume
    least squares mean (standard error)
        Month 12
    -0.283 ( 0.0264 )
    -0.458 ( 0.0341 )
        Month 24
    -0.711 ( 0.0356 )
    -0.839 ( 0.0476 )
    Statistical analysis title
    		 Month 12
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1330
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.175
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.103
         upper limit
    		 0.247
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0367
    Statistical analysis title
    		 Month 24
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1330
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0196
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.021
         upper limit
    		 0.236
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0549

    Secondary: Number of participants with 3-month CDP events as measured by EDSS in the subgroup of SPMS patients with/without superimposed relapses

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    End point title
    		 Number of participants with 3-month CDP events as measured by EDSS in the subgroup of SPMS patients with/without superimposed relapses
    End point description
    The Expanded Disability Status Scale (EDSS) assesses neurologic impairment in multiple sclerosis (MS). EDSS scale ranges from 0 (normal) to 10 (death due to MS). Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5. The definition of 3-month confirmed disability progression (CDP) was an increase from baseline in EDSS as defined before sustained for at least 3 months. The following secondary progressive multiple sclerosis (SPMS) groups were defined for the analysis of this endpoint: • Without superimposed relapses in the 2 years prior to study start (baseline definition) • With superimposed relapses in the 2 years prior to study start (baseline definition) • Without superimposed relapses during the Core Part of study (post-treatment) • With superimposed relapses during the Core Part of study (post-treatment) Data was analyzed using a Cox proportional hazard model.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to the maximum of approximately 3 years
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1099
    546
    Units: Participants
        W/O superimposed relapses at baseline (n=708, 343)
    190
    101
        W/ superimposed relapses at baseline (n=388, 202)
    98
    72
        W/O superimposed relapses post-treat. (n=986, 444)
    237
    122
        W/ superimposed relapses post-treat. (n=113, 102)
    51
    51
    Statistical analysis title
    		 Without superimposed relapses at baseline
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.11
    Statistical analysis title
    		 With superimposed relapses post-treatment
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.19
    Statistical analysis title
    		 Without superimposed relapses post-treatment
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.06
    Statistical analysis title
    		 With superimposed relapses at baseline
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.91

    Secondary: Number of participants with 3-month CDP events as measured by EDSS in the subgroup of rapidly and not rapidly evolving patients

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    End point title
    		 Number of participants with 3-month CDP events as measured by EDSS in the subgroup of rapidly and not rapidly evolving patients
    End point description
    The Expanded Disability Status Scale (EDSS) assesses neurologic impairment in multiple sclerosis (MS). EDSS scale ranges from 0 (normal) to 10 (death due to MS). Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5. The definition of 3-month confirmed disability progression (CDP) was an increase from baseline in EDSS as defined before sustained for at least 3 months. Rapidly evolving patients are defined as subjects with 1.5 or greater EDSS change in the 2 years prior to or at study start and disability progression in the 2 years prior to study start was not adjudicated. Data was analyzed using a Cox proportional hazard model.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to the maximum of approximately 3 years
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1099
    546
    Units: Participants
        Rapidly evolving patients (n=264, 145)
    82
    60
        Not rapidly evolving patients (n=835, 401)
    206
    113
    Statistical analysis title
    		 Rapidly evolving patients
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.91
    Statistical analysis title
    		 Not rapidly evolving patients
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.09

    Secondary: Number of participants with 3-month CDP events as measured by EDSS in the subgroup of patients with and without moderate/severe disease course

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    End point title
    		 Number of participants with 3-month CDP events as measured by EDSS in the subgroup of patients with and without moderate/severe disease course
    End point description
    The Expanded Disability Status Scale (EDSS) assesses neurologic impairment in multiple sclerosis (MS). EDSS scale ranges from 0 (normal) to 10 (death due to MS). Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5. The definition of 3-month confirmed disability progression (CDP) was an increase from baseline in EDSS as defined before sustained for at least 3 months. Moderate or severe course of disease is defined as global Multiple Sclerosis Severity Score (MSSS) of 4 or more at baseline. Data was analyzed using a Cox proportional hazard model.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to the maximum of approximately 3 years
    End point values
    		 Siponimod (BAF312) Placebo
    Number of subjects analysed
    1099
    546
    Units: Participants
        With moderate or severe disease (n=904, 459)
    232
    141
        Without moderate or severe disease (n=195, 87)
    56
    32
    Statistical analysis title
    		 Without moderate or severe course of disease
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.13
    Statistical analysis title
    		 With moderate or severe course of disease
    Comparison groups
    Siponimod (BAF312) v Placebo
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.99

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Core Part: from first dose of double-blind study treatment until end of Core Part (up to approximately 3 years). Core and Extension: from first dose of siponimod until end of study (up to approximately 10 years).
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Core-BAF312
    Reporting group description
    		 Participants who were randomized to siponimod (BAF312) during the Core Part

    Reporting group title
    All BAF312
    Reporting group description
    		 All participants who received at least one dose of siponimod (BAF312) during the Core Part and/or the Extension Part

    Reporting group title
    Core-Placebo
    Reporting group description
    		 Participants who were randomized to placebo during the Core Part

    Serious adverse events
    		 Core-BAF312 All BAF312 Core-Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    196 / 1099 (17.83%)
    610 / 1517 (40.21%)
    83 / 546 (15.20%)
         number of deaths (all causes)
    4
    33
    4
         number of deaths resulting from adverse events
    2
    7
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Astrocytoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    11 / 1099 (1.00%)
    68 / 1517 (4.48%)
    7 / 546 (1.28%)
         occurrences causally related to treatment / all
    5 / 12
    68 / 102
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Cervix carcinoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1099 (0.09%)
    7 / 1517 (0.46%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm malignant
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 1099 (0.09%)
    18 / 1517 (1.19%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    14 / 19
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign renal neoplasm
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer stage IV
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lip squamous cell carcinoma
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Endometrial cancer
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysplastic naevus
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal melanoma
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Lung neoplasm
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Malignant melanoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    6 / 1517 (0.40%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    2 / 1099 (0.18%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melanocytic naevus
         subjects affected / exposed
    1 / 1099 (0.09%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal oncocytoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seminoma
         subjects affected / exposed
    2 / 1099 (0.18%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurofibroma
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 1099 (0.09%)
    8 / 1517 (0.53%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 1099 (0.00%)
    10 / 1517 (0.66%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the vagina
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testis cancer
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulval cancer stage 0
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 1099 (0.09%)
    6 / 1517 (0.40%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 1099 (0.09%)
    5 / 1517 (0.33%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Haematoma
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Hypotension
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Orthostatic hypotension
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Vasculitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Internal haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 1099 (0.18%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Accidental death
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    General physical health deterioration
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Granuloma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Malaise
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Impaired healing
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Hyperpyrexia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Oedema peripheral
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Pyrexia
         subjects affected / exposed
    2 / 1099 (0.18%)
    11 / 1517 (0.73%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Sudden death
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune reconstitution inflammatory syndrome
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Immobile
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Walking disability
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical polyp
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heavy menstrual bleeding
         subjects affected / exposed
    2 / 1099 (0.18%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intermenstrual bleeding
         subjects affected / exposed
    2 / 1099 (0.18%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian disorder
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Testicular atrophy
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Ovarian cyst
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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 respiratory failure
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Nasal polyps
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Pneumothorax
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory paralysis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Pulmonary hypertension
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Respiratory depression
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 1099 (0.00%)
    5 / 1517 (0.33%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 1099 (0.09%)
    8 / 1517 (0.53%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Adjustment disorder
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Anxiety
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety disorder due to a general medical condition
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 1099 (0.00%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    1 / 1099 (0.09%)
    0 / 1517 (0.00%)
    0 / 546 (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
    Depression
         subjects affected / exposed
    3 / 1099 (0.27%)
    3 / 1517 (0.20%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Depression suicidal
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressive symptom
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Drug abuse
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Euphoric mood
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Suicidal ideation
         subjects affected / exposed
    3 / 1099 (0.27%)
    8 / 1517 (0.53%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mixed anxiety and depressive disorder
         subjects affected / exposed
    2 / 1099 (0.18%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    3 / 1099 (0.27%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    4 / 1099 (0.36%)
    8 / 1517 (0.53%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Cholelithiasis
         subjects affected / exposed
    1 / 1099 (0.09%)
    5 / 1517 (0.33%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 1099 (0.09%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Hepatic steatosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Hepatitis acute
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Non-alcoholic steatohepatitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 1099 (0.91%)
    19 / 1517 (1.25%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    10 / 11
    16 / 22
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood pressure decreased
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 1099 (0.18%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 1099 (0.45%)
    9 / 1517 (0.59%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    4 / 5
    7 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CD4 lymphocytes decreased
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Columbia suicide severity rating scale abnormal
         subjects affected / exposed
    2 / 1099 (0.18%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate decreased
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 1099 (0.09%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CD8 lymphocytes decreased
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung diffusion test decreased
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Magnetic resonance imaging abnormal
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Walking distance test abnormal
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain contusion
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Burns third degree
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Bursa injury
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    2 / 1099 (0.18%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone contusion
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Ankle fracture
         subjects affected / exposed
    2 / 1099 (0.18%)
    8 / 1517 (0.53%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    5 / 1099 (0.45%)
    8 / 1517 (0.53%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye contusion
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 1099 (0.18%)
    11 / 1517 (0.73%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 13
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    3 / 1099 (0.27%)
    13 / 1517 (0.86%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 15
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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 fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Fracture displacement
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    5 / 1517 (0.33%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injection related reaction
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Injury corneal
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve root injury cervical
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Post-traumatic pain
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Post procedural haematoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Procedural pain
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Maisonneuve fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Joint dislocation
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Shoulder fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Rib fracture
         subjects affected / exposed
    1 / 1099 (0.09%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reactive gastropathy
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Skin abrasion
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Subarachnoid haematoma
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic injury
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Splenic rupture
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Stress fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Skin laceration
         subjects affected / exposed
    4 / 1099 (0.36%)
    8 / 1517 (0.53%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Wound
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Traumatic haemothorax
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic liver injury
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemorrhage
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Tibia fracture
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 1099 (0.09%)
    6 / 1517 (0.40%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Malformation venous
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Corneal dystrophy
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Brugada syndrome
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    2 / 1099 (0.18%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    3 / 1099 (0.27%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Cardiac failure
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Cardiac failure acute
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Coronary artery disease
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Myocarditis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Palpitations
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Autoimmune demyelinating disease
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Allodynia
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Aphasia
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Cerebral haematoma
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysaesthesia
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         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
    2 / 1099 (0.18%)
    7 / 1517 (0.46%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clonic convulsion
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Cognitive disorder
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Dysarthria
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    5 / 1099 (0.45%)
    22 / 1517 (1.45%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 29
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Febrile infection-related epilepsy syndrome
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head titubation
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    3 / 1099 (0.27%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokinesia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intention tremor
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    1 / 1099 (0.09%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Lacunar stroke
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Meralgia paraesthetica
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Multiple sclerosis
         subjects affected / exposed
    2 / 1099 (0.18%)
    17 / 1517 (1.12%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 19
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis pseudo relapse
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 1099 (0.18%)
    7 / 1517 (0.46%)
    7 / 546 (1.28%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 7
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    2 / 1099 (0.18%)
    9 / 1517 (0.59%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 12
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Partial seizures
         subjects affected / exposed
    2 / 1099 (0.18%)
    6 / 1517 (0.40%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postictal paralysis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Presyncope
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudobulbar palsy
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Putamen haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Quadriplegia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Radiculopathy
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Progressive multiple sclerosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Secondary progressive multiple sclerosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Seizure
         subjects affected / exposed
    4 / 1099 (0.36%)
    7 / 1517 (0.46%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 13
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 1099 (0.00%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status migrainosus
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Syncope
         subjects affected / exposed
    4 / 1099 (0.36%)
    6 / 1517 (0.40%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1099 (0.09%)
    6 / 1517 (0.40%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    3 / 1099 (0.27%)
    12 / 1517 (0.79%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uhthoff's phenomenon
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Subdural hygroma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Amnestic disorder
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         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
    Anaemia
         subjects affected / exposed
    0 / 1099 (0.00%)
    4 / 1517 (0.26%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Leukopenia
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 1099 (0.00%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocytic infiltration
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Ear and labyrinth disorders
    Deafness transitory
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Vertigo
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoacusis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blindness
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Retinoschisis
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Photophobia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular oedema
         subjects affected / exposed
    3 / 1099 (0.27%)
    6 / 1517 (0.40%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Gastrointestinal disorders
    Anal haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Anal fissure
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acquired oesophageal web
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Abdominal pain upper
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 1099 (0.18%)
    6 / 1517 (0.40%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Gastric haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Gastric perforation
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Gastritis erosive
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Dysphagia
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Ileus
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Impaired gastric emptying
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 1099 (0.09%)
    7 / 1517 (0.46%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Rectal polyp
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Rectal haemorrhage
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal adhesions
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Toothache
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Umbilical hernia, obstructive
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Vomiting
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Skin and subcutaneous tissue disorders
    Actinic elastosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Actinic keratosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    1 / 1099 (0.09%)
    4 / 1517 (0.26%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermal cyst
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Rash
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 1099 (0.09%)
    5 / 1517 (0.33%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder dysfunction
         subjects affected / exposed
    2 / 1099 (0.18%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder hypertrophy
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder leukoplakia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 1099 (0.09%)
    4 / 1517 (0.26%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis noninfective
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Dysuria
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Haematuria
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 1099 (0.18%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Calculus urinary
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Renal cyst
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Single functional kidney
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive nephropathy
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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 incontinence
         subjects affected / exposed
    2 / 1099 (0.18%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    3 / 1099 (0.27%)
    9 / 1517 (0.59%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Nephrotic syndrome
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Neurogenic bladder
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urge incontinence
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Graves' disease
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Goitre
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Musculoskeletal and connective tissue disorders
    Ligament disorder
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoroacetabular impingement
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Bursitis
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 1099 (0.09%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Arthralgia
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 1099 (0.09%)
    0 / 1517 (0.00%)
    0 / 546 (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
    Spondylolisthesis
         subjects affected / exposed
    0 / 1099 (0.00%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Spinal deformity
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Patellofemoral pain syndrome
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 1099 (0.09%)
    9 / 1517 (0.59%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         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 pain
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    3 / 1099 (0.27%)
    7 / 1517 (0.46%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Appendiceal abscess
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 1099 (0.27%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 1099 (0.00%)
    6 / 1517 (0.40%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 1099 (0.18%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Chorioretinitis
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    COVID-19
         subjects affected / exposed
    0 / 1099 (0.00%)
    14 / 1517 (0.92%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Bacterial infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Bronchitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Burn infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Complicated appendicitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Diverticulitis
         subjects affected / exposed
    1 / 1099 (0.09%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis viral
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 1099 (0.09%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 1099 (0.09%)
    5 / 1517 (0.33%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis proteus
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Groin abscess
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 1099 (0.18%)
    7 / 1517 (0.46%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster meningitis
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1099 (0.09%)
    6 / 1517 (0.40%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis cryptococcal
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal abscess
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 1099 (0.09%)
    28 / 1517 (1.85%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 31
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Oral viral infection
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otosalpingitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 1099 (0.09%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Pneumonia influenzal
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Postoperative wound infection
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 1099 (0.09%)
    15 / 1517 (0.99%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 1099 (0.00%)
    9 / 1517 (0.59%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic encephalopathy
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Septic shock
         subjects affected / exposed
    2 / 1099 (0.18%)
    7 / 1517 (0.46%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 7
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 1099 (0.27%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 1099 (0.00%)
    3 / 1517 (0.20%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    5 / 1099 (0.45%)
    13 / 1517 (0.86%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 5
    3 / 15
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Viral infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    15 / 1099 (1.36%)
    67 / 1517 (4.42%)
    7 / 546 (1.28%)
         occurrences causally related to treatment / all
    9 / 32
    25 / 109
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 1099 (0.00%)
    2 / 1517 (0.13%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 1099 (0.18%)
    4 / 1517 (0.26%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemochromatosis
         subjects affected / exposed
    1 / 1099 (0.09%)
    1 / 1517 (0.07%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic crisis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Hyperkalaemia
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Shock hypoglycaemic
         subjects affected / exposed
    0 / 1099 (0.00%)
    0 / 1517 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Iron deficiency
         subjects affected / exposed
    0 / 1099 (0.00%)
    1 / 1517 (0.07%)
    0 / 546 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Core-BAF312 All BAF312 Core-Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    778 / 1099 (70.79%)
    1267 / 1517 (83.52%)
    348 / 546 (63.74%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    45 / 1099 (4.09%)
    130 / 1517 (8.57%)
    15 / 546 (2.75%)
         occurrences all number
    53
    167
    17
    Vascular disorders
    Hypertension
         subjects affected / exposed
    114 / 1099 (10.37%)
    294 / 1517 (19.38%)
    41 / 546 (7.51%)
         occurrences all number
    126
    328
    41
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    50 / 1099 (4.55%)
    107 / 1517 (7.05%)
    13 / 546 (2.38%)
         occurrences all number
    53
    123
    14
    Fatigue
         subjects affected / exposed
    100 / 1099 (9.10%)
    171 / 1517 (11.27%)
    51 / 546 (9.34%)
         occurrences all number
    112
    191
    54
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    35 / 1099 (3.18%)
    90 / 1517 (5.93%)
    18 / 546 (3.30%)
         occurrences all number
    40
    102
    23
    Psychiatric disorders
    Depression
         subjects affected / exposed
    43 / 1099 (3.91%)
    134 / 1517 (8.83%)
    28 / 546 (5.13%)
         occurrences all number
    44
    143
    31
    Insomnia
         subjects affected / exposed
    37 / 1099 (3.37%)
    84 / 1517 (5.54%)
    19 / 546 (3.48%)
         occurrences all number
    39
    89
    20
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    43 / 1099 (3.91%)
    120 / 1517 (7.91%)
    6 / 546 (1.10%)
         occurrences all number
    51
    156
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    58 / 1099 (5.28%)
    108 / 1517 (7.12%)
    8 / 546 (1.47%)
         occurrences all number
    70
    141
    10
    Lymphocyte count decreased
         subjects affected / exposed
    4 / 1099 (0.36%)
    84 / 1517 (5.54%)
    0 / 546 (0.00%)
         occurrences all number
    6
    112
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    34 / 1099 (3.09%)
    96 / 1517 (6.33%)
    15 / 546 (2.75%)
         occurrences all number
    41
    127
    15
    Fall
         subjects affected / exposed
    126 / 1099 (11.46%)
    295 / 1517 (19.45%)
    59 / 546 (10.81%)
         occurrences all number
    205
    670
    93
    Nervous system disorders
    Headache
         subjects affected / exposed
    158 / 1099 (14.38%)
    249 / 1517 (16.41%)
    71 / 546 (13.00%)
         occurrences all number
    244
    388
    93
    Muscle spasticity
         subjects affected / exposed
    41 / 1099 (3.73%)
    89 / 1517 (5.87%)
    23 / 546 (4.21%)
         occurrences all number
    47
    107
    23
    Dizziness
         subjects affected / exposed
    74 / 1099 (6.73%)
    145 / 1517 (9.56%)
    26 / 546 (4.76%)
         occurrences all number
    89
    184
    31
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    9 / 1099 (0.82%)
    137 / 1517 (9.03%)
    0 / 546 (0.00%)
         occurrences all number
    9
    173
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    69 / 1099 (6.28%)
    119 / 1517 (7.84%)
    22 / 546 (4.03%)
         occurrences all number
    82
    169
    24
    Constipation
         subjects affected / exposed
    39 / 1099 (3.55%)
    103 / 1517 (6.79%)
    21 / 546 (3.85%)
         occurrences all number
    43
    119
    29
    Nausea
         subjects affected / exposed
    73 / 1099 (6.64%)
    119 / 1517 (7.84%)
    19 / 546 (3.48%)
         occurrences all number
    84
    143
    22
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    15 / 1099 (1.36%)
    80 / 1517 (5.27%)
    6 / 546 (1.10%)
         occurrences all number
    16
    113
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    69 / 1099 (6.28%)
    184 / 1517 (12.13%)
    42 / 546 (7.69%)
         occurrences all number
    83
    248
    54
    Back pain
         subjects affected / exposed
    65 / 1099 (5.91%)
    186 / 1517 (12.26%)
    43 / 546 (7.88%)
         occurrences all number
    77
    228
    47
    Pain in extremity
         subjects affected / exposed
    60 / 1099 (5.46%)
    113 / 1517 (7.45%)
    21 / 546 (3.85%)
         occurrences all number
    75
    154
    28
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    89 / 1099 (8.10%)
    165 / 1517 (10.88%)
    41 / 546 (7.51%)
         occurrences all number
    107
    244
    55
    Urinary tract infection
         subjects affected / exposed
    128 / 1099 (11.65%)
    369 / 1517 (24.32%)
    75 / 546 (13.74%)
         occurrences all number
    209
    900
    130
    Nasopharyngitis
         subjects affected / exposed
    149 / 1099 (13.56%)
    325 / 1517 (21.42%)
    79 / 546 (14.47%)
         occurrences all number
    215
    620
    128
    Influenza
         subjects affected / exposed
    72 / 1099 (6.55%)
    152 / 1517 (10.02%)
    40 / 546 (7.33%)
         occurrences all number
    87
    194
    46
    Herpes zoster
         subjects affected / exposed
    24 / 1099 (2.18%)
    92 / 1517 (6.06%)
    4 / 546 (0.73%)
         occurrences all number
    25
    97
    4
    Cystitis
         subjects affected / exposed
    28 / 1099 (2.55%)
    79 / 1517 (5.21%)
    13 / 546 (2.38%)
         occurrences all number
    43
    135
    18
    COVID-19
         subjects affected / exposed
    0 / 1099 (0.00%)
    189 / 1517 (12.46%)
    0 / 546 (0.00%)
         occurrences all number
    0
    206
    0
    Bronchitis
         subjects affected / exposed
    36 / 1099 (3.28%)
    94 / 1517 (6.20%)
    16 / 546 (2.93%)
         occurrences all number
    42
    115
    18
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    28 / 1099 (2.55%)
    99 / 1517 (6.53%)
    11 / 546 (2.01%)
         occurrences all number
    31
    102
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 May 2014
    • Based on the available treatment initiation cardiac monitoring results, the 6 hour post-dose first dose observation (Day 1 and 7) in subjects with normal cardiovascular status could be discontinued. Continued data capture with mobile cardiac telemetry (MCT) and Holter in all patients was supported, to facilitate the assessment of any relevant events occurring during treatment initiation. • To harmonize the Treatment Epoch between the protocol and eCRF. • To allow the use of beta-blockers. • To modify inclusion/exclusion criteria on use of contraception, and to provide exclusion criteria for 2 additional medications that had been approved for the treatment of MS (dimethyl fumarate and teriflunomide) after the original protocol was written. • To update details on potent CYP2C9 inhibitors. • To require any patient who missed any dose during the titration phase to restart dose titration.
    05 Mar 2015
    • To update the rule and the timing for the planned futility analysis. • To add clarity and specific considerations for concomitant treatment, regarding potential interruption of beta-blocker treatment in patients with resting heart rate ≤50 bpm before introducing siponimod/placebo treatment. • Details on “emergency breaking of treatment assignment” were updated. • Completion of the blinded data review for sample size re-estimation was mentioned, specifically confirming that the number of patients to be enrolled would not increase.
    06 Oct 2015
    • An Extension Part was incorporated into the study design. • Designations of Core Part and Extension Part were added in the descriptions of protocol elements, as applicable. • The stopping criterion for the Core Part of the study was updated. Specifically, the Core Part of the study was to be stopped approximately 3 years after the randomization of the first patient.
    23 Mar 2016
    • To specify and justify the overall study duration in the protocol to accommodate the different regulations applicable in various countries. • To make the Month 1 extension visit optional for patients who had been on open-label siponimod in the Core Part for at least 6 continuous months immediately before starting the Extension Part of the study, to avoid repeat procedures for these patients • To clarify that the Day 4 extension visit was only for patients who required first-dose monitoring and for whom this was conducted with a Holter monitor. Collection of vital signs became optional. • To clarify that the Day 7 extension visit was not needed for patients who were entering the Extension Part from open-label siponimod treatment without a break of 4 days of treatment, as no first dose monitoring was needed for these patients. • Reference to the Extension Part continuing “for at least 1 year after approval in major markets for the treatment of SPMS” was removed to provide consistency with the 84 month Schedule of Assessments. • Month 84 visit was removed from the Schedule of Assessments and designated as the end of study (EOS) visit. • Changes to the SAE language section and an addition to the ethical considerations section of the protocol were made to comply with the latest guidelines a new protocol template. • The Early Study Termination section was updated to include reasons of risk/benefit, regulatory or medical reasons to comply with current template language. • The reference to electronic EDSS was removed to allow the Sponsor to switch to other EDSS methodologies. • Changes were made to statistical sections to include baseline as a covariate for the T25W analysis (to be consistent with other analyses).
    28 Jul 2020
    ● To change cardiac assessments and monitoring requirements during dose titration for dose re-start. ● To add an additional pulmonary function test (PFT) assessment to the follow-up (FU) visit to provide additional PFT data after patients discontinued treatment with siponimod. ● To introduce the consideration of reduction in maintenance dose from 2.0 mg/ day to 1.0 mg/ day for patients with *1/*3 or *2/*3 CYP2C9 genotype. ● To introduce the possibility to collect safety information remotely and ship investigational medicinal product (IMP) directly to patients’ home, in situation it is not safe for them to attend on-site visit, in response to the COVID-19 pandemics (or similar pandemics).

    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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