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    Clinical Trial Results:
    An Extension Study to the CBAF312A2201 study to evaluate long-term safety, tolerability and efficacy of BAF312 given orally once daily in patients with relapsing-remitting multiple sclerosis

    Summary
    EudraCT number
    		 2009-014392-51
    Trial protocol
    		 ES   HU   DE   PL   IT   FI  
    Global end of trial date
    10 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Oct 2017
    First version publication date
    26 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CBAF312A2201E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01185821
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    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
    10 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate long-term safety and tolerability of siponimod in relapsing-remitting multiple sclerosis (RRMS) patients, with specific emphasis on: effects on cardiac conduction during the titration of the study drug, long-term blood pressure effects, viral infections, macular edema, dermatologic alterations
    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
    30 Aug 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    184
    EEA total number of subjects
    124
    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)
    184
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients enrolled in the Extension study had completed the Core study. All patients underwent a 10 day titration at the start of the dose blinded phase of the study

    Pre-assignment
    Screening details
    		 During the double blind phase of the extension study patients received the same dose from the Core study. Placebo patients from Core Period 1 were randomized to 0.5, 2 or 10mg, those from Period 2 were randomized to 0.25 or 1.25 mg. All patients received 2mg in Open Label phase (.5 and .25mg were titrated up to 2mg)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BAF312 10 mg/2 mg
    Arm description
    		 10 mg dose in Double Blind Phase and 2 mg in Open Label Phase
    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
    10 mg dose in Double Blind and 2 mg dose in Open Label dosed once a day

    Arm title
    		 BAF312 2 mg/2 mg
    Arm description
    		 2 mg dose in Double Blind Phase and 2 mg in Open Label Phase
    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
    2 mg dose in Double Blind and 2 mg dose in Open Label dosed once a day

    Arm title
    		 BAF312 1.25 mg/2 mg
    Arm description
    		 1.25 mg dose in Double Blind Phase and 2 mg in Open Label Phase
    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
    1.25 mg dose in Double Blind and 2 mg dose in Open Label dosed once a day

    Arm title
    		 BAF312 .5 mg/2 mg
    Arm description
    		 .5 mg dose in Double Blind Phase and 2 mg in Open Label Phase
    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
    .5 mg dose in Double Blind and 2 mg dose in Open Label dosed once a day

    Arm title
    		 BAF312 .25 mg/2 mg
    Arm description
    		 .25 mg dose in Double Blind Phase and 2 mg in Open Label Phase
    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
    .25 mg dose in Double Blind and 2 mg dose in Open Label dosed once a day

    Number of subjects in period 1
    		BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg
    Started
    33
    29
    43
    29
    50
    Patients with washout
    33
    29
    39
    29
    33
    Patients without washout
    0 [1]
    0 [2]
    4 [3]
    0 [4]
    17 [5]
    Patients on placebo in Core
    8 [6]
    7 [7]
    9 [8]
    8 [9]
    2 [10]
    Completed
    26
    20
    33
    23
    26
    Not completed
    7
    9
    10
    6
    24
         Abnormal laboratory value(s)
    1
    2
    1
    -
    -
         Adverse event, serious fatal
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    3
    2
    2
    1
    3
         Adverse event, non-fatal
    2
    3
    1
    2
    5
         Administrative problems
    -
    -
    1
    1
    2
         Lost to follow-up
    1
    1
    2
    1
    2
         Condition no longer required study drug
    -
    -
    -
    -
    1
         Abnormal test procedure result
    -
    -
    -
    -
    1
         Lack of efficacy
    -
    -
    3
    -
    9
         Protocol deviation
    -
    -
    -
    1
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.
    [10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone added to provide additional information for patients entering the Extension study from the Core study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BAF312 10 mg/2 mg
    Reporting group description
    		 10 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Reporting group title
    BAF312 2 mg/2 mg
    Reporting group description
    		 2 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Reporting group title
    BAF312 1.25 mg/2 mg
    Reporting group description
    		 1.25 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Reporting group title
    BAF312 .5 mg/2 mg
    Reporting group description
    		 .5 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Reporting group title
    BAF312 .25 mg/2 mg
    Reporting group description
    		 .25 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Reporting group values
    		 BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg Total
    Number of subjects
    		 33 29 43 29 50 184
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.8 ± 9.09 35.1 ± 9.16 34.0 ± 7.57 35.2 ± 9.10 37.2 ± 8.42 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 21 18 32 18 41 130
        Male
    		 12 11 11 11 9 54
    Study Specific Characteristic | Expanded disability status scale (EDSS)
    Disability progression was assessed based on the EDSS scores ranging from 0 (normal) to 10 (death due to MS)
    Units: Combined scores
        arithmetic mean (standard deviation)
    		 2.03 ± 0.960 2.19 ± 1.278 1.95 ± 1.096 1.88 ± 1.374 2.22 ± 1.258 -

    End points

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    End points reporting groups
    Reporting group title
    BAF312 10 mg/2 mg
    Reporting group description
    		 10 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Reporting group title
    BAF312 2 mg/2 mg
    Reporting group description
    		 2 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Reporting group title
    BAF312 1.25 mg/2 mg
    Reporting group description
    		 1.25 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Reporting group title
    BAF312 .5 mg/2 mg
    Reporting group description
    		 .5 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Reporting group title
    BAF312 .25 mg/2 mg
    Reporting group description
    		 .25 mg dose in Double Blind Phase and 2 mg in Open Label Phase

    Primary: Total number of adverse events during evaluation of long term safety and tolerability of BAF312A in Extension study.

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    End point title
    		 Total number of adverse events during evaluation of long term safety and tolerability of BAF312A in Extension study. [1]
    End point description
    Refer to adverse events for complete listing of serious adverse events and other adverse events. Adverse events of interest were presented in separate tables. There were no reports of macular edema.
    End point type
    Primary
    End point timeframe
    Baseline up to approximately 5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point
    End point values
    		 BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg
    Number of subjects analysed
    33
    29
    43
    29
    50
    Units: events
        Serious adverse events
    4
    7
    6
    6
    8
        Other adverse events
    30
    26
    42
    29
    42
    No statistical analyses for this end point

    Primary: Number of participants with cardiac conduction abnormalities during the titration phase of the study

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    End point title
    		 Number of participants with cardiac conduction abnormalities during the titration phase of the study [2]
    End point description
    Number of patients with abnormal ECG conduction findings during dose-blinded titration at any visit post-dose, by type of abnormality and treatment (Extension Set). Number analyzed represent participants who had ECG results. Washout was defined as not being on treatment drug between Core and Extension for >7 days. Abbreviations: washout = WO, Con=conduction
    End point type
    Primary
    End point timeframe
    Baseline Extension up to day 10
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point
    End point values
    		 BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg
    Number of subjects analysed
    33
    29
    39
    29
    33
    Units: participants
        With WO (33,29,39,29,33) Conduction-Prolonged QTc
    5
    2
    5
    2
    4
        With washout (33,29,39,29,33) Conduction - IVCD
    3
    8
    1
    3
    0
        With WO (33,29,39,29,33) Conduction - AV Mobitz I
    1
    0
    0
    0
    0
        With WO (33,29,39,29,33) Con:1st degree AV block
    0
    1
    1
    1
    1
        With washout (33,29,39,29,33) Conduction - WPW
    0
    0
    0
    1
    0
        Without washout (0,0,4,0,17) Conduction - IVCD
    0
    0
    0
    0
    4
    No statistical analyses for this end point

    Primary: Number of participants with changes in blood pressure for overall extension study. (Extension analysis set)

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    End point title
    		 Number of participants with changes in blood pressure for overall extension study. (Extension analysis set) [3]
    End point description
    Sitting blood pressure was measured in triplicate. The categories of notably low and high values and changes are presented for systolic (SBP) and diastolic (DBP). Multiple occurrences for a patient are counted as one occurrence in this table.
    End point type
    Primary
    End point timeframe
    Baseline Extension up to approximately 5 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point
    End point values
    		 BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg
    Number of subjects analysed
    33
    29
    43
    29
    50
    Units: participants
        SBP Low: ≤ 90
    1
    3
    2
    1
    1
        SBP ≥ 20 decrease from baseline
    8
    10
    4
    6
    10
        SBP High: ≥ 160
    1
    1
    1
    3
    3
        SBP ≥ 20 increase from baseline
    9
    8
    12
    13
    18
        DBP Low: ≤ 50
    1
    0
    1
    0
    1
        DBP ≥ 15 decrease from baseline
    14
    8
    10
    10
    10
        DBP High: ≥ 100
    4
    7
    4
    4
    4
        DBP ≥ 15 increase from baseline
    9
    13
    13
    11
    17
    No statistical analyses for this end point

    Primary: Number of participants with viral infections of interest greater or equal to 5% in any dose group (Extension Set)

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    End point title
    		 Number of participants with viral infections of interest greater or equal to 5% in any dose group (Extension Set) [4]
    End point description
    Most infections were clinical diagnoses and were not confirmed by microbiology / virologic investigations. A patient with multiple occurrences of an infection for a preferred term is counted only once in each specific category. Events identified as infections by the Investigator and defined as an AE with onset on or after the first dose of Extension Study drug up to and including 30 days after the date of the last dose
    End point type
    Primary
    End point timeframe
    Baseline Extension up to approximately 5 years
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point
    End point values
    		 BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg
    Number of subjects analysed
    33
    29
    43
    29
    50
    Units: participants
        Oral herpes
    5
    0
    4
    2
    4
        Herpes zoster
    5
    0
    3
    2
    0
        Influenza
    3
    4
    3
    6
    6
    No statistical analyses for this end point

    Primary: Number of participants with dermatologic alterations - basal cell carcinoma (Extension Set)

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    End point title
    		 Number of participants with dermatologic alterations - basal cell carcinoma (Extension Set) [5]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline Extension up to approximately 5 years
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point
    End point values
    		 BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg
    Number of subjects analysed
    33
    29
    43
    29
    50
    Units: participants
    1
    0
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of relapses in one year - annualized relapse rates for overall extension study (ARR) (Extension Set)

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    End point title
    		 Number of relapses in one year - annualized relapse rates for overall extension study (ARR) (Extension Set)
    End point description
    Group level ARR (raw) is calculated as the total number of relapses for all the patients in the treatment group divided by the total number of days on study for all patients in the group and multiplied by 365.25 to obtain the annual rate. Model estimates are based on a negative binomial regression model, adjusted for treatment group, age, baseline EDSS, baseline number of Gd-enhanced T1 lesions and number of relapses in previous 2 years as covariates, with log(time on study in years) as the offset variable, using the log link.
    End point type
    Secondary
    End point timeframe
    Baseline extension up to approximately 5 years
    End point values
    		 BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg
    Number of subjects analysed
    33
    29
    43
    29
    50
    Units: Group level ARR
        arithmetic mean (confidence interval 95%)
    0.18 (0.11 to 0.31)
    0.15 (0.08 to 0.26)
    0.16 (0.10 to 0.26)
    0.19 (0.11 to 0.33)
    0.22 (0.14 to 0.35)
    No statistical analyses for this end point

    Secondary: Percentage of participants free of Magnetic Resonance Imaging (MRI) identified disease activity at any scan during Extension Study (Extension Set)

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    End point title
    		 Percentage of participants free of Magnetic Resonance Imaging (MRI) identified disease activity at any scan during Extension Study (Extension Set)
    End point description
    Free of MRI disease activity is defined as free of Gadolinium enhanced T1 lesions at any scan; free of new or enlarging T2 lesions at any scan: free of both gadolinium enhanced T1 lesions and new or enlarging T2 lesions at any sca, N = Number of patients with at least one MRI scan during the specified time period. New lesions at a specific visit are assessed relative to the previous scheduled visit scan. No imputation of missing scans is performed. As a result missing scans can lead to an overestimation of the proportion of patients free of a specific MRI activity.
    End point type
    Secondary
    End point timeframe
    Baseline Extension up to approximately 5 years
    End point values
    		 BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg
    Number of subjects analysed
    31
    26
    43
    29
    47
    Units: percentage of participants
    number (not applicable)
        Free of Gd-enhanced T1 lesions at any scan
    58.1
    57.7
    58.1
    44.8
    66.0
        Free of new/enlarging T2 lesions at any scan
    32.3
    42.3
    46.5
    20.7
    40.4
        Free of Gd-enhanced T1 and new enlarged T2 lesions
    32.3
    42.3
    44.2
    20.7
    40.4
    No statistical analyses for this end point

    Secondary: Percentage of participants free of confirmed disability progression in Extension Study (Extension Set)

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    End point title
    		 Percentage of participants free of confirmed disability progression in Extension Study (Extension Set)
    End point description
    Six-month disability progression was defined relative to extension baseline EDSS score: 1.5 point increase in patients with baseline EDSS score of 0, 1.0 increase in patients with baseline EDSS score of between 0.5 to 5.0, inclusive and 0.5 increase in patients with baseline EDSS score of ≥ 5.5. The criteria for 6-month disability progression included detection of onset of progression and confirmation of progression for a period of at least 6 months.
    End point type
    Secondary
    End point timeframe
    Baseline Extension up to approximately 5 years
    End point values
    		 BAF312 10 mg/2 mg BAF312 2 mg/2 mg BAF312 1.25 mg/2 mg BAF312 .5 mg/2 mg BAF312 .25 mg/2 mg
    Number of subjects analysed
    33
    29
    43
    29
    50
    Units: percentage of participants
        number (confidence interval 95%)
    72.3 (56.0 to 88.7)
    82.4 (66.6 to 98.3)
    84.8 (73.5 to 96.0)
    81.4 (66.6 to 96.1)
    78.6 (65.4 to 91.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    BAF312 10/2 mg
    Reporting group description
    		 BAF312 10/2 mg

    Reporting group title
    BAF312 2/2 mg
    Reporting group description
    		 BAF312 2/2 mg

    Reporting group title
    BAF312 1.25/2 mg
    Reporting group description
    		 BAF312 1.25/2 mg

    Reporting group title
    BAF312 0.5/2 mg
    Reporting group description
    		 BAF312 0.5/2 mg

    Reporting group title
    BAF312 0.25/2 mg
    Reporting group description
    		 BAF312 0.25/2 mg

    Reporting group title
    All patients
    Reporting group description
    		 All patients

    Serious adverse events
    		 BAF312 10/2 mg BAF312 2/2 mg BAF312 1.25/2 mg BAF312 0.5/2 mg BAF312 0.25/2 mg All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 33 (12.12%)
    7 / 29 (24.14%)
    6 / 43 (13.95%)
    6 / 29 (20.69%)
    8 / 50 (16.00%)
    31 / 184 (16.85%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Submandibular mass
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine cervical metaplasia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Smear cervix abnormal
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Femur fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dysaesthesia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    3 / 184 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenic cyst
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Otosclerosis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Stress urinary incontinence
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 BAF312 10/2 mg BAF312 2/2 mg BAF312 1.25/2 mg BAF312 0.5/2 mg BAF312 0.25/2 mg All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 33 (90.91%)
    26 / 29 (89.66%)
    42 / 43 (97.67%)
    29 / 29 (100.00%)
    42 / 50 (84.00%)
    169 / 184 (91.85%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibrous histiocytoma
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    3 / 43 (6.98%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    5 / 184 (2.72%)
         occurrences all number
    0
    1
    3
    1
    0
    5
    Melanocytic naevus
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    6 / 43 (13.95%)
    2 / 29 (6.90%)
    7 / 50 (14.00%)
    18 / 184 (9.78%)
         occurrences all number
    2
    1
    8
    3
    8
    22
    Seborrhoeic keratosis
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    4 / 50 (8.00%)
    7 / 184 (3.80%)
         occurrences all number
    2
    1
    0
    0
    4
    7
    Skin papilloma
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 29 (10.34%)
    1 / 43 (2.33%)
    2 / 29 (6.90%)
    2 / 50 (4.00%)
    10 / 184 (5.43%)
         occurrences all number
    2
    3
    1
    2
    4
    12
    Uterine leiomyoma
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    2
    0
    0
    1
    0
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    3 / 43 (6.98%)
    3 / 29 (10.34%)
    8 / 50 (16.00%)
    16 / 184 (8.70%)
         occurrences all number
    2
    1
    3
    3
    8
    17
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    4 / 184 (2.17%)
         occurrences all number
    0
    1
    2
    0
    2
    5
    Fatigue
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 29 (13.79%)
    5 / 43 (11.63%)
    2 / 29 (6.90%)
    6 / 50 (12.00%)
    18 / 184 (9.78%)
         occurrences all number
    1
    6
    5
    2
    6
    20
    Gait disturbance
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    4 / 184 (2.17%)
         occurrences all number
    3
    0
    0
    1
    0
    4
    Influenza like illness
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    1 / 29 (3.45%)
    1 / 50 (2.00%)
    5 / 184 (2.72%)
         occurrences all number
    1
    0
    2
    2
    1
    6
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    6 / 184 (3.26%)
         occurrences all number
    3
    0
    1
    0
    3
    7
    Oedema peripheral
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    2
    0
    1
    0
    3
    Pyrexia
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    4 / 43 (9.30%)
    3 / 29 (10.34%)
    5 / 50 (10.00%)
    15 / 184 (8.15%)
         occurrences all number
    3
    1
    5
    5
    6
    20
    Respiratory, thoracic and mediastinal disorders
    Catarrh
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    4 / 184 (2.17%)
         occurrences all number
    1
    0
    2
    5
    0
    8
    Cough
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 29 (10.34%)
    3 / 43 (6.98%)
    4 / 29 (13.79%)
    2 / 50 (4.00%)
    15 / 184 (8.15%)
         occurrences all number
    3
    6
    3
    9
    2
    23
    Dyspnoea
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    0
    2
    0
    1
    3
    Epistaxis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 29 (3.45%)
    3 / 43 (6.98%)
    0 / 29 (0.00%)
    3 / 50 (6.00%)
    10 / 184 (5.43%)
         occurrences all number
    3
    1
    3
    0
    4
    11
    Rhinitis allergic
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    4 / 184 (2.17%)
         occurrences all number
    0
    0
    4
    0
    2
    6
    Wheezing
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 29 (3.45%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    4 / 50 (8.00%)
    9 / 184 (4.89%)
         occurrences all number
    3
    2
    1
    0
    4
    10
    Depression
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    6 / 43 (13.95%)
    3 / 29 (10.34%)
    7 / 50 (14.00%)
    18 / 184 (9.78%)
         occurrences all number
    1
    1
    6
    3
    11
    22
    Insomnia
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    8 / 43 (18.60%)
    3 / 29 (10.34%)
    6 / 50 (12.00%)
    20 / 184 (10.87%)
         occurrences all number
    2
    2
    8
    3
    8
    23
    Sleep disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    1
    0
    4
    0
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 29 (17.24%)
    3 / 43 (6.98%)
    2 / 29 (6.90%)
    2 / 50 (4.00%)
    15 / 184 (8.15%)
         occurrences all number
    5
    6
    3
    3
    2
    19
    Blood bilirubin increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    Blood cholesterol increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    2 / 29 (6.90%)
    1 / 50 (2.00%)
    4 / 184 (2.17%)
         occurrences all number
    0
    0
    1
    2
    2
    5
    C-reactive protein increased
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    3 / 50 (6.00%)
    5 / 184 (2.72%)
         occurrences all number
    1
    1
    0
    0
    4
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 29 (10.34%)
    2 / 43 (4.65%)
    3 / 29 (10.34%)
    2 / 50 (4.00%)
    13 / 184 (7.07%)
         occurrences all number
    4
    4
    2
    3
    2
    15
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    5 / 184 (2.72%)
         occurrences all number
    2
    1
    1
    0
    1
    5
    Lymphocyte count decreased
         subjects affected / exposed
    4 / 33 (12.12%)
    2 / 29 (6.90%)
    4 / 43 (9.30%)
    2 / 29 (6.90%)
    3 / 50 (6.00%)
    15 / 184 (8.15%)
         occurrences all number
    4
    2
    11
    3
    6
    26
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 29 (6.90%)
    0 / 43 (0.00%)
    3 / 29 (10.34%)
    1 / 50 (2.00%)
    8 / 184 (4.35%)
         occurrences all number
    5
    3
    0
    5
    1
    14
    Fall
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 29 (10.34%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    1 / 50 (2.00%)
    9 / 184 (4.89%)
         occurrences all number
    3
    4
    0
    3
    8
    18
    Joint injury
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    1
    0
    2
    0
    0
    3
    Ligament sprain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    2 / 29 (6.90%)
    1 / 50 (2.00%)
    7 / 184 (3.80%)
         occurrences all number
    2
    0
    2
    2
    1
    7
    Limb injury
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    2 / 50 (4.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    0
    0
    1
    2
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    2
    0
    0
    1
    3
    Tachycardia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    0
    1
    0
    3
    4
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    0
    1
    0
    2
    3
    Dizziness
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    1 / 43 (2.33%)
    1 / 29 (3.45%)
    4 / 50 (8.00%)
    8 / 184 (4.35%)
         occurrences all number
    1
    1
    1
    1
    4
    8
    Headache
         subjects affected / exposed
    9 / 33 (27.27%)
    4 / 29 (13.79%)
    9 / 43 (20.93%)
    4 / 29 (13.79%)
    10 / 50 (20.00%)
    36 / 184 (19.57%)
         occurrences all number
    14
    7
    9
    12
    14
    56
    Hypoaesthesia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    2 / 50 (4.00%)
    4 / 184 (2.17%)
         occurrences all number
    3
    0
    0
    2
    2
    7
    Migraine
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    3 / 43 (6.98%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    6 / 184 (3.26%)
         occurrences all number
    2
    0
    3
    1
    0
    6
    Muscle spasticity
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 43 (0.00%)
    3 / 29 (10.34%)
    0 / 50 (0.00%)
    5 / 184 (2.72%)
         occurrences all number
    0
    2
    0
    3
    0
    5
    Neuralgia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    4 / 43 (9.30%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    5 / 184 (2.72%)
         occurrences all number
    1
    0
    6
    0
    0
    7
    Paraesthesia
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    3 / 50 (6.00%)
    9 / 184 (4.89%)
         occurrences all number
    5
    0
    0
    3
    3
    11
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    1
    0
    2
    0
    3
    Lymphadenitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Lymphopenia
         subjects affected / exposed
    6 / 33 (18.18%)
    5 / 29 (17.24%)
    4 / 43 (9.30%)
    6 / 29 (20.69%)
    3 / 50 (6.00%)
    24 / 184 (13.04%)
         occurrences all number
    9
    7
    4
    9
    3
    32
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    4 / 184 (2.17%)
         occurrences all number
    0
    1
    2
    0
    1
    4
    Tinnitus
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    3 / 184 (1.63%)
         occurrences all number
    1
    0
    0
    0
    2
    3
    Vertigo
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 29 (3.45%)
    3 / 43 (6.98%)
    2 / 29 (6.90%)
    6 / 50 (12.00%)
    16 / 184 (8.70%)
         occurrences all number
    4
    1
    4
    2
    6
    17
    Vertigo positional
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    1 / 50 (2.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    0
    0
    2
    1
    3
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    1 / 29 (3.45%)
    1 / 50 (2.00%)
    5 / 184 (2.72%)
         occurrences all number
    1
    0
    3
    1
    1
    6
    Eye pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    2
    0
    0
    1
    0
    3
    Iridocyclitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    5
    0
    0
    5
    Vision blurred
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    3 / 43 (6.98%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    5 / 184 (2.72%)
         occurrences all number
    2
    0
    3
    0
    0
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    2 / 43 (4.65%)
    1 / 29 (3.45%)
    3 / 50 (6.00%)
    7 / 184 (3.80%)
         occurrences all number
    0
    1
    2
    2
    3
    8
    Abdominal pain upper
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    3 / 43 (6.98%)
    5 / 29 (17.24%)
    3 / 50 (6.00%)
    12 / 184 (6.52%)
         occurrences all number
    0
    1
    3
    5
    3
    12
    Aphthous ulcer
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    0
    1
    3
    0
    4
    Constipation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    3 / 50 (6.00%)
    4 / 184 (2.17%)
         occurrences all number
    1
    0
    0
    0
    3
    4
    Diarrhoea
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    7 / 43 (16.28%)
    3 / 29 (10.34%)
    6 / 50 (12.00%)
    19 / 184 (10.33%)
         occurrences all number
    1
    2
    9
    3
    7
    22
    Dyspepsia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    5 / 184 (2.72%)
         occurrences all number
    1
    1
    1
    0
    2
    5
    Enteritis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    3
    0
    0
    0
    3
    Gastritis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    3
    0
    2
    0
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    3 / 29 (10.34%)
    1 / 50 (2.00%)
    6 / 184 (3.26%)
         occurrences all number
    1
    0
    2
    3
    1
    7
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    Nausea
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    3 / 29 (10.34%)
    4 / 50 (8.00%)
    8 / 184 (4.35%)
         occurrences all number
    2
    0
    0
    5
    6
    13
    Toothache
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    4 / 43 (9.30%)
    1 / 29 (3.45%)
    4 / 50 (8.00%)
    11 / 184 (5.98%)
         occurrences all number
    0
    6
    5
    1
    6
    18
    Vomiting
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 29 (10.34%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    3 / 50 (6.00%)
    7 / 184 (3.80%)
         occurrences all number
    2
    3
    0
    0
    3
    8
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    Alopecia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    5 / 184 (2.72%)
         occurrences all number
    2
    0
    2
    0
    1
    5
    Dermal cyst
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    1
    0
    0
    2
    0
    3
    Dermatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Dermatitis allergic
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    2 / 50 (4.00%)
    4 / 184 (2.17%)
         occurrences all number
    0
    0
    0
    2
    2
    4
    Dermatitis contact
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    1
    0
    0
    2
    0
    3
    Eczema
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    8 / 184 (4.35%)
         occurrences all number
    3
    3
    2
    0
    1
    9
    Hyperkeratosis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    Pigmentation disorder
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 29 (6.90%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    5 / 184 (2.72%)
         occurrences all number
    2
    2
    1
    0
    0
    5
    Pruritus
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    1 / 29 (3.45%)
    3 / 50 (6.00%)
    7 / 184 (3.80%)
         occurrences all number
    1
    0
    2
    1
    4
    8
    Urticaria
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    3 / 43 (6.98%)
    1 / 29 (3.45%)
    1 / 50 (2.00%)
    5 / 184 (2.72%)
         occurrences all number
    0
    0
    3
    1
    1
    5
    Renal and urinary disorders
    Bladder dysfunction
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    Micturition urgency
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    5 / 184 (2.72%)
         occurrences all number
    3
    1
    1
    0
    1
    6
    Nephrolithiasis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 29 (6.90%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    5 / 184 (2.72%)
         occurrences all number
    2
    2
    0
    1
    0
    5
    Urinary retention
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    1
    0
    0
    3
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 33 (12.12%)
    3 / 29 (10.34%)
    2 / 43 (4.65%)
    2 / 29 (6.90%)
    3 / 50 (6.00%)
    14 / 184 (7.61%)
         occurrences all number
    5
    3
    2
    2
    3
    15
    Back pain
         subjects affected / exposed
    6 / 33 (18.18%)
    2 / 29 (6.90%)
    5 / 43 (11.63%)
    3 / 29 (10.34%)
    3 / 50 (6.00%)
    19 / 184 (10.33%)
         occurrences all number
    7
    2
    7
    3
    3
    22
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    Joint swelling
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    3 / 184 (1.63%)
         occurrences all number
    2
    0
    0
    0
    1
    3
    Muscle spasms
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    1 / 29 (3.45%)
    1 / 50 (2.00%)
    5 / 184 (2.72%)
         occurrences all number
    1
    0
    2
    1
    1
    5
    Muscular weakness
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    4 / 184 (2.17%)
         occurrences all number
    2
    0
    2
    0
    0
    4
    Musculoskeletal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    4 / 43 (9.30%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    9 / 184 (4.89%)
         occurrences all number
    1
    3
    4
    0
    2
    10
    Myalgia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    3 / 50 (6.00%)
    4 / 184 (2.17%)
         occurrences all number
    0
    0
    1
    0
    4
    5
    Neck pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    6 / 184 (3.26%)
         occurrences all number
    1
    4
    1
    0
    2
    8
    Pain in extremity
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    4 / 29 (13.79%)
    5 / 50 (10.00%)
    12 / 184 (6.52%)
         occurrences all number
    2
    1
    0
    4
    9
    16
    Tendonitis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 43 (0.00%)
    2 / 29 (6.90%)
    2 / 50 (4.00%)
    6 / 184 (3.26%)
         occurrences all number
    0
    2
    0
    2
    2
    6
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    3 / 50 (6.00%)
    3 / 184 (1.63%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    Bronchitis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    5 / 43 (11.63%)
    3 / 29 (10.34%)
    6 / 50 (12.00%)
    16 / 184 (8.70%)
         occurrences all number
    0
    4
    9
    3
    7
    23
    Conjunctivitis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    3 / 184 (1.63%)
         occurrences all number
    2
    0
    1
    0
    0
    3
    Cystitis
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 29 (3.45%)
    2 / 43 (4.65%)
    1 / 29 (3.45%)
    1 / 50 (2.00%)
    8 / 184 (4.35%)
         occurrences all number
    13
    1
    2
    1
    4
    21
    Fungal infection
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    1 / 29 (3.45%)
    1 / 50 (2.00%)
    6 / 184 (3.26%)
         occurrences all number
    3
    1
    0
    1
    3
    8
    Fungal skin infection
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    3
    0
    0
    0
    0
    3
    Gastroenteritis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    1 / 43 (2.33%)
    3 / 29 (10.34%)
    4 / 50 (8.00%)
    10 / 184 (5.43%)
         occurrences all number
    0
    2
    2
    4
    5
    13
    Gastroenteritis viral
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    3 / 43 (6.98%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    5 / 184 (2.72%)
         occurrences all number
    0
    0
    3
    0
    2
    5
    Herpes zoster
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 29 (0.00%)
    3 / 43 (6.98%)
    2 / 29 (6.90%)
    0 / 50 (0.00%)
    10 / 184 (5.43%)
         occurrences all number
    5
    0
    3
    2
    0
    10
    Influenza
         subjects affected / exposed
    4 / 33 (12.12%)
    4 / 29 (13.79%)
    5 / 43 (11.63%)
    7 / 29 (24.14%)
    7 / 50 (14.00%)
    27 / 184 (14.67%)
         occurrences all number
    4
    4
    8
    9
    11
    36
    Nasopharyngitis
         subjects affected / exposed
    10 / 33 (30.30%)
    8 / 29 (27.59%)
    17 / 43 (39.53%)
    11 / 29 (37.93%)
    18 / 50 (36.00%)
    64 / 184 (34.78%)
         occurrences all number
    27
    13
    29
    27
    49
    145
    Onychomycosis
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    3 / 50 (6.00%)
    5 / 184 (2.72%)
         occurrences all number
    1
    1
    0
    0
    3
    5
    Oral herpes
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 29 (0.00%)
    4 / 43 (9.30%)
    2 / 29 (6.90%)
    4 / 50 (8.00%)
    15 / 184 (8.15%)
         occurrences all number
    9
    0
    6
    19
    11
    45
    Otitis media
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    3 / 50 (6.00%)
    5 / 184 (2.72%)
         occurrences all number
    1
    1
    0
    0
    3
    5
    Pharyngitis
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 29 (13.79%)
    3 / 43 (6.98%)
    6 / 29 (20.69%)
    3 / 50 (6.00%)
    17 / 184 (9.24%)
         occurrences all number
    1
    4
    4
    6
    3
    18
    Pneumonia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    4 / 184 (2.17%)
         occurrences all number
    1
    1
    0
    0
    2
    4
    Respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 29 (3.45%)
    1 / 43 (2.33%)
    1 / 29 (3.45%)
    2 / 50 (4.00%)
    5 / 184 (2.72%)
         occurrences all number
    0
    1
    1
    1
    4
    7
    Rhinitis
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    1 / 43 (2.33%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    7 / 184 (3.80%)
         occurrences all number
    3
    2
    1
    0
    6
    12
    Sinusitis
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 29 (6.90%)
    3 / 43 (6.98%)
    5 / 29 (17.24%)
    5 / 50 (10.00%)
    18 / 184 (9.78%)
         occurrences all number
    4
    2
    5
    8
    6
    25
    Subcutaneous abscess
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    0 / 50 (0.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    Tinea versicolour
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 29 (6.90%)
    2 / 43 (4.65%)
    0 / 29 (0.00%)
    1 / 50 (2.00%)
    5 / 184 (2.72%)
         occurrences all number
    0
    2
    2
    0
    1
    5
    Tonsillitis
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 29 (3.45%)
    5 / 43 (11.63%)
    2 / 29 (6.90%)
    1 / 50 (2.00%)
    10 / 184 (5.43%)
         occurrences all number
    1
    1
    5
    2
    1
    10
    Tooth infection
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 29 (6.90%)
    1 / 43 (2.33%)
    1 / 29 (3.45%)
    0 / 50 (0.00%)
    5 / 184 (2.72%)
         occurrences all number
    1
    4
    1
    2
    0
    8
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 33 (12.12%)
    6 / 29 (20.69%)
    4 / 43 (9.30%)
    7 / 29 (24.14%)
    9 / 50 (18.00%)
    30 / 184 (16.30%)
         occurrences all number
    11
    10
    7
    14
    11
    53
    Urinary tract infection
         subjects affected / exposed
    6 / 33 (18.18%)
    4 / 29 (13.79%)
    2 / 43 (4.65%)
    4 / 29 (13.79%)
    4 / 50 (8.00%)
    20 / 184 (10.87%)
         occurrences all number
    9
    5
    2
    7
    12
    35
    Vaginal infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    2 / 29 (6.90%)
    2 / 50 (4.00%)
    5 / 184 (2.72%)
         occurrences all number
    0
    0
    1
    2
    2
    5
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    1 / 43 (2.33%)
    1 / 29 (3.45%)
    2 / 50 (4.00%)
    4 / 184 (2.17%)
         occurrences all number
    0
    0
    3
    1
    2
    6
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 29 (13.79%)
    2 / 43 (4.65%)
    1 / 29 (3.45%)
    3 / 50 (6.00%)
    12 / 184 (6.52%)
         occurrences all number
    2
    4
    3
    1
    10
    20
    Hypoglycaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 29 (0.00%)
    0 / 43 (0.00%)
    0 / 29 (0.00%)
    2 / 50 (4.00%)
    2 / 184 (1.09%)
         occurrences all number
    0
    0
    0
    0
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2010
    The amendment was to introduce measures to mitigate observed bradyarrhythmic effects by means of dose titration and an enhanced monitoring to identify and to manage patients at risk. Further, the amendment introduced the need for re-screening of patients who had study drug interruptions of more than 4 weeks between completing the Core Study and starting the participation in the Extension Study. Corresponding changes were made to the study design and dose titration content as well as in-house monitoring and cardiac exclusion criteria.
    05 Nov 2010
    Introduced an interim analysis to evaluate the safety of the dose-titration scheme used during the first 10 days of the study. Data of interest included heart rate, ECG parameters, and AEs.
    13 Jun 2012
    Incorporated the OL Phase into the study design and changed siponimod dosing from 5 separate fixed-dose groups to a 2 mg/day fixed dose. Study was extended from 2 years up to 5 years
    19 Mar 2014
    Key changes were adding an abbreviated visit schedule option for patients who stopped taking study medication and continued in the study, allowed concomitant treatment with beta blockers, provided updated details on potent inhibitors/inducers of CYP2C9 and further extended the study duration (beyond 5 years)

    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.
    This study was prematurely discontinued after approximately 5 years. The decision to prematurely discontinue the study was not taken due to safety-related concerns, but a decision to focus the development of siponimod in MS on a different population
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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