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    Clinical Trial Results:
    A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Followed by an Active Treatment Period, to Evaluate the Efficacy, Safety, and Tolerability of Two Doses of Oral Administration of Laquinimod (0.6 mg/day or 1.2 mg/day) in Patients with Relapsing Remitting Multiple Sclerosis

    Summary
    EudraCT number
    2012-003647-30
    Trial protocol
    BE   GB   LV   DE   HU   ES   GR   EE   CZ   IT   AT   PL   BG   SK  
    Global end of trial date
    04 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Mar 2019
    First version publication date
    08 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LAQ-MS-305
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01707992
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study Name: CONCERTO
    Sponsors
    Sponsor organisation name
    Teva Pharmaceutical Industries Ltd
    Sponsor organisation address
    5 Basel Street, Petach Tiqva, Israel, 49131
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., +01 215-591-3000, info.era-clinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., +01 215-591-3000, info.era-clinical@teva.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy, safety, and tolerability of a daily dose of 0.6 and 1.2 milligrams (mg) of laquinimod as compared to placebo in participants with relapsing-remitting multiple sclerosis (RRMS).
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (example, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; European Union Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical studies on medicinal products for human use). The investigator at each study site was responsible for the conduct and administration of the study at that site and for contacts with study site management, with the Independent Ethics Committee (IEC)/Institutional Review Board (IRB), and with local authorities. Written and/or oral information about the study was provided to all participants in a language understandable by the participants. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each participants before any study procedures or assessments were done. It was explained to the participants that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each participant's willingness to participate in the study was documented in writing in a consent form that was signed by the participants with the date of that signature indicated.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Feb 2013
    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
    United States: 44
    Country: Number of subjects enrolled
    Czech Republic: 42
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Moldova, Republic of: 36
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    France: 28
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Austria: 26
    Country: Number of subjects enrolled
    Estonia: 25
    Country: Number of subjects enrolled
    Montenegro: 24
    Country: Number of subjects enrolled
    Croatia: 18
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Latvia: 11
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 50
    Country: Number of subjects enrolled
    Russian Federation: 447
    Country: Number of subjects enrolled
    Ukraine: 411
    Country: Number of subjects enrolled
    Bulgaria: 205
    Country: Number of subjects enrolled
    Poland: 164
    Country: Number of subjects enrolled
    Romania: 137
    Country: Number of subjects enrolled
    Belarus: 111
    Country: Number of subjects enrolled
    Georgia: 106
    Country: Number of subjects enrolled
    Serbia: 98
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 68
    Worldwide total number of subjects
    2199
    EEA total number of subjects
    787
    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)
    2199
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study was conducted at 215 sites in 29 countries.

    Period 1
    Period 1 title
    Placebo-Controlled Phase (24 Months)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo-Controlled Phase: Placebo
    Arm description
    Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to laquinimod as per the schedule specified in the respective arms.

    Arm title
    Placebo-Controlled Phase: Laquinimod 0.6 mg
    Arm description
    Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Laquinimod
    Investigational medicinal product code
    TV-5600
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Laquinimod as per the dose and schedule specified in the respective arms.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to laquinimod as per the schedule specified in the respective arms.

    Arm title
    Placebo-Controlled Phase: Laquinimod 1.2 mg
    Arm description
    Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Laquinimod
    Investigational medicinal product code
    TV-5600
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Laquinimod as per the dose and schedule specified in the respective arms.

    Number of subjects in period 1
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Started
    740
    727
    732
    Completed
    596
    623
    532
    Not completed
    144
    104
    200
         Adverse event, serious fatal
    2
    1
    1
         Consent withdrawn by subject
    88
    68
    154
         Adverse event, non-fatal
    8
    13
    9
         Pregnancy
    12
    5
    9
         Other than specified
    11
    9
    10
         Lost to follow-up
    10
    4
    9
         Noncompliance with drug administration
    2
    1
    6
         Lack of efficacy
    10
    3
    2
         Protocol deviation
    1
    -
    -
    Period 2
    Period 2 title
    Active Treatment Phase (24 Months)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Active Treatment Phase: Laquinimod 0.6 mg
    Arm description
    Participants who completed the placebo-controlled phase on placebo and on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Laquinimod
    Investigational medicinal product code
    TV-5600
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Laquinimod as per the dose and schedule specified in the respective arms.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to laquinimod as per the schedule specified in the respective arms.

    Arm title
    Active Treatment Phase: Laquinimod 1.2 mg
    Arm description
    Participants who completed the placebo-controlled phase on placebo and on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Laquinimod
    Investigational medicinal product code
    TV-5600
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Laquinimod as per the dose and schedule specified in the respective arms.

    Arm title
    Active Treatment Phase: Off Drug
    Arm description
    Participants who were discontinued from treatment with laquinimod 1.2 mg during the placebo-controlled phase due to sponsor decision after 01 January 2016 continued to the active-treatment phase off drug for 24 months.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg Active Treatment Phase: Off Drug
    Started
    891
    504
    215
    Completed
    7
    10
    0
    Not completed
    884
    494
    215
         Adverse event, serious fatal
    2
    -
    -
         Consent withdrawn by subject
    58
    220
    32
         Adverse event, non-fatal
    4
    1
    -
         Pregnancy
    2
    5
    2
         Study terminated by sponsor
    809
    243
    174
         Other than specified
    1
    5
    2
         Lost to follow-up
    5
    11
    1
         Lack of efficacy
    3
    1
    2
         Noncompliance
    -
    4
    2
         Participant withdrew per Sponsor request
    -
    4
    -
    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: All participants who completed Period 1, did not continue to Period 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo-Controlled Phase: Placebo
    Reporting group description
    Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.

    Reporting group title
    Placebo-Controlled Phase: Laquinimod 0.6 mg
    Reporting group description
    Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.

    Reporting group title
    Placebo-Controlled Phase: Laquinimod 1.2 mg
    Reporting group description
    Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.

    Reporting group values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg Total
    Number of subjects
    740 727 732 2199
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    740 727 732 2199
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    35.9 ( 8.95 ) 36.8 ( 9.25 ) 36.1 ( 9.22 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    488 510 475 1473
        Male
    252 217 257 726
    Race
    Units: Subjects
        White
    724 712 717 2153
        Black
    3 3 3 9
        Asian
    3 2 3 8
        Other
    10 8 9 27
        Missing
    0 2 0 2
    Kurtzke’s Expanded Disability Status Scale (EDSS) Score
    EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]).
    Units: Subjects
        Less than or equal to (<=) 4.0
    653 635 644 1932
        Greater than (>) 4.0
    87 90 88 265
        Missing
    0 2 0 2
    Normalized Brain Volume
    This characteristic was analysed for a total of 2187 participants (Placebo [737], Laquinimod 0.6 mg [722], and Laquinimod 1.2 mg [728])
    Units: milliliters (mL)
        arithmetic mean (standard deviation)
    1437.2 ( 93.37 ) 1433.0 ( 92.49 ) 1434.4 ( 93.41 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo-Controlled Phase: Placebo
    Reporting group description
    Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.

    Reporting group title
    Placebo-Controlled Phase: Laquinimod 0.6 mg
    Reporting group description
    Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.

    Reporting group title
    Placebo-Controlled Phase: Laquinimod 1.2 mg
    Reporting group description
    Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
    Reporting group title
    Active Treatment Phase: Laquinimod 0.6 mg
    Reporting group description
    Participants who completed the placebo-controlled phase on placebo and on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months.

    Reporting group title
    Active Treatment Phase: Laquinimod 1.2 mg
    Reporting group description
    Participants who completed the placebo-controlled phase on placebo and on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.

    Reporting group title
    Active Treatment Phase: Off Drug
    Reporting group description
    Participants who were discontinued from treatment with laquinimod 1.2 mg during the placebo-controlled phase due to sponsor decision after 01 January 2016 continued to the active-treatment phase off drug for 24 months.

    Primary: Placebo-Controlled Phase: Time to Confirmed Disease Progression (CDP) Confirmed After At Least 3 Months (Number of Participants with CDP After At Least 3 Months)

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    End point title
    Placebo-Controlled Phase: Time to Confirmed Disease Progression (CDP) Confirmed After At Least 3 Months (Number of Participants with CDP After At Least 3 Months)
    End point description
    Time to CDP was defined as the time to a sustained increase in Kurtzke’s Expanded Disability Status Scale (EDSS) score of at least 1 point if baseline EDSS score was less than or equal to 5.0, or at least 0.5 point if the baseline EDSS score was 5.5, over a period of at least three months. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]). Data is presented as distribution of CDP (number of participants with CDP) sustained for 3 months. Intent-to-treat (ITT) analysis set included all randomized participants.
    End point type
    Primary
    End point timeframe
    Baseline to Month 24
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    740
    727
    732
    Units: participants
    73
    66
    69
    Statistical analysis title
    Laquinimod 0.6 mg vs. Placebo
    Statistical analysis description
    The primary analysis for the comparison between laquinimod 0.6 mg versus placebo was conducted using the baseline adjusted Cox proportional hazards model. Categorical EDSS at baseline (less than or equal to [<=] 4 or greater than [>] 4), country/geographical region (CGR), categorical age at baseline (<=38 or >38), and T2 volume at baseline were included as covariates in the model.
    Comparison groups
    Placebo-Controlled Phase: Placebo v Placebo-Controlled Phase: Laquinimod 0.6 mg
    Number of subjects included in analysis
    1467
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7057 [1]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.937
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.668
         upper limit
    1.313
    Notes
    [1] - Threshold for significance at 0.05 level.

    Secondary: Placebo-Controlled Phase: Percent Change From Baseline in Brain Volume at Month 15

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    End point title
    Placebo-Controlled Phase: Percent Change From Baseline in Brain Volume at Month 15
    End point description
    Brain atrophy was defined by the percent change in brain volume from baseline to Month 15. The modified intent-to-treat 1 (mITT1) analysis set included data from all randomized participants at the Month 15 visit. For participants who prematurely discontinued treatment or completed the placebo-controlled phase before Month 15, the last available measurement was used, provided it was performed at least 9 months following the initiation of study drug. Here, 'Number of participants analyzed' = Participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 15
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    619
    636
    616
    Units: percent change
        arithmetic mean (standard deviation)
    -0.8 ( 1.02 )
    -0.4 ( 1.01 )
    -0.4 ( 1.05 )
    No statistical analyses for this end point

    Secondary: Placebo-Controlled Phase: Time to First Confirmed Relapse (Number of Participants with Confirmed Relapse)

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    End point title
    Placebo-Controlled Phase: Time to First Confirmed Relapse (Number of Participants with Confirmed Relapse)
    End point description
    Relapse was defined as appearance of one or more new neurological abnormalities or reappearance or worsening of one or more previously observed neurological abnormalities, lasting for at least 48 hours (in absence of fever or any infection) and immediately preceded by an improving neurological state of at least 30 days from onset of previous relapse. An event was counted as a relapse only when the participant’s symptoms were accompanied by observed objective neurological changes, consistent with an increase of at least 0.5 in EDSS; or one grade in score of 2 or more of 7 Functional Systems (FS) (excluding changes in bowel or bladder function or cognition); or 2 grades in score of one of the FS as compared to previous evaluation. EDSS assesses disability in 8 FS with an overall score ranging from 0 (normal) to 10 (death due to MS). Data is presented as distribution of relapsing participants (number of participants with confirmed relapse). ITT analysis set: all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    740
    727
    732
    Units: participants
    332
    269
    222
    No statistical analyses for this end point

    Secondary: Placebo-Controlled Phase: Time to CDP Confirmed After At Least 6 Months (Number of Participants with CDP After At Least 6 Months)

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    End point title
    Placebo-Controlled Phase: Time to CDP Confirmed After At Least 6 Months (Number of Participants with CDP After At Least 6 Months)
    End point description
    Time to CDP was defined as the time to a sustained increase in Kurtzke’s EDSS score of at least 1 point if baseline EDSS score was less than or equal to 5.0, or at least 0.5 point if the baseline EDSS score was 5.5, over a period of at least 6 months. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to MS). Data is presented as distribution of CDP (number of participants with CDP) sustained for 6 months. ITT analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    740
    727
    732
    Units: participants
        number (not applicable)
    49
    49
    51
    No statistical analyses for this end point

    Secondary: Placebo-Controlled Phase: Time to CDP Confirmed After At Least 9 Months (Number of Participants with Confirmed Relapse After At Least 9 Months)

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    End point title
    Placebo-Controlled Phase: Time to CDP Confirmed After At Least 9 Months (Number of Participants with Confirmed Relapse After At Least 9 Months)
    End point description
    Time to CDP was defined as the time to a sustained increase in Kurtzke’s EDSS score of at least 1 point if baseline EDSS score was less than or equal to 5.0, or at least 0.5 point if the baseline EDSS score was 5.5, over a period of at least 9 months. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to MS). Data is presented as distribution of CDP (number of participants with CDP) sustained for 9 months. ITT analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    740
    727
    732
    Units: participants
    38
    38
    39
    No statistical analyses for this end point

    Other pre-specified: Placebo-Controlled Phase: Number of Participants With Adverse Events (AEs)

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    End point title
    Placebo-Controlled Phase: Number of Participants With Adverse Events (AEs)
    End point description
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. Safety analysis set included all participants who were randomized and received at least one dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Month 24
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    740
    727
    732
    Units: participants
    546
    565
    575
    No statistical analyses for this end point

    Other pre-specified: Active-Treatment Phase: Number of Participants With AEs

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    End point title
    Active-Treatment Phase: Number of Participants With AEs
    End point description
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase
    End point values
    Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    891
    504
    Units: participants
    442
    241
    No statistical analyses for this end point

    Other pre-specified: Placebo-Controlled Phase: Number of Participants With Clinically Significant Vital Signs Abnormalities

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    End point title
    Placebo-Controlled Phase: Number of Participants With Clinically Significant Vital Signs Abnormalities
    End point description
    Clinically significant vital signs abnormalities included: Pulse rate: greater than or equal to (>=) 120 beats per minute (bpm) and increase from baseline of >=30 bpm, <=45 bpm and decrease from baseline of >=30 bpm; Systolic blood pressure: >=180 millimeters of mercury (mmHg) and increase from baseline of >=30 mmHg, <=90 and decrease from baseline of >=30 mmHg; Diastolic blood pressure: >=100 mmHg and increase from baseline of >=20 mmHg, <=50 mmHg and decrease from baseline of >=20 mmHg. Safety analysis set included all participants who were randomized and received at least one dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 24
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    740
    727
    732
    Units: participants
    21
    21
    29
    No statistical analyses for this end point

    Other pre-specified: Active-Treatment Phase: Number of Participants With Clinically Significant Vital Signs Abnormalities

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    End point title
    Active-Treatment Phase: Number of Participants With Clinically Significant Vital Signs Abnormalities
    End point description
    Clinically significant vital signs abnormalities included: Pulse rate: >=120 bpm and increase from baseline of >=30 bpm, <=45 bpm and decrease from baseline of >=30 bpm; Systolic blood pressure: >=180 mmHg and increase from baseline of >=30 mmHg, <=90 and decrease from baseline of >=30 mmHg; Diastolic blood pressure: >=100 mmHg and increase from baseline of >=20 mmHg, <=50 mmHg and decrease from baseline of >=20 mmHg. Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase
    End point values
    Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    891
    504
    Units: participants
    17
    7
    No statistical analyses for this end point

    Other pre-specified: Placebo-Controlled Phase: Number of Participants With Shift From Baseline to Endpoint in Electrocardiogram (ECG) Parameters

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    End point title
    Placebo-Controlled Phase: Number of Participants With Shift From Baseline to Endpoint in Electrocardiogram (ECG) Parameters
    End point description
    ECG parameters included: PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett's formula (QTcB). Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. Safety analysis set included all participants who were randomized and received at least one dose of study drug. Here, 'Number of participants analysed=participants evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Endpoint (Month 24)
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    734
    723
    724
    Units: participants
        Normal - Normal
    463
    467
    470
        Normal - Abnormal NCS
    139
    124
    126
        Normal - Abnormal CS
    0
    6
    5
        Abnormal NCS - Normal
    32
    27
    28
        Abnormal NCS - Abnormal NCS
    98
    96
    90
        Abnormal NCS - Abnormal CS
    1
    1
    2
        Abnormal CS - Normal
    0
    1
    0
        Abnormal CS - Abnormal NCS
    0
    0
    0
        Abnormal CS - Abnormal CS
    1
    1
    3
    No statistical analyses for this end point

    Other pre-specified: Active Treatment Phase: Number of Participants With Shift From Baseline to Endpoint in ECG Parameters

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    End point title
    Active Treatment Phase: Number of Participants With Shift From Baseline to Endpoint in ECG Parameters
    End point description
    ECG parameters included: PR interval, QRS interval, QTcF and QTcB. Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase and had ECG shift from baseline data available.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase), endpoint (Month 24 of active-treatment phase)
    End point values
    Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    888
    501
    Units: participants
        Normal – Normal
    641
    353
        Normal - Abnormal NCS
    137
    80
        Normal - Abnormal CS
    7
    5
        Abnormal NCS – Normal
    18
    17
        Abnormal NCS - Abnormal NCS
    81
    45
        Abnormal NCS - Abnormal CS
    4
    0
        Abnormal CS – Normal
    0
    0
        Abnormal CS - Abnormal NCS
    0
    0
        Abnormal CS - Abnormal CS
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Placebo-Controlled Phase: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry

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    End point title
    Placebo-Controlled Phase: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry
    End point description
    Potentially clinically significant serum chemistry abnormalities included: Glucose <=3 and >=13.88 millimoles per liter (mmol/L); Alanine aminotransferase (ALT) (in units per liter [U/L]), aspartate aminotransferase (AST) (in U/L), alkaline phosphatase (in U/L), gamma-glutamyltransferase (GGT) (in U/L), creatine phosphokinase (CPK) (in U/L), C-reactive protein (CRP) (in milligrams per liter [mg/L]), pancreatic amylase (in U/L)>=3 * upper limit of normal (ULN); Fibrinogen >=6 grams per liter (gm/L); Sodium <=130 and >=150 mmol/L; Potassium <=3.2 and >=5.5 mmol/L; Calcium <=1.87 and >=2.75 mmol/L; Phosphate <=0.65 and >=1.61 mmol/L. Safety analysis set included all participants who were randomized and received at least one dose of study drug. Here, 'Number of participants analysed'=participants evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Month 24
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    736
    723
    724
    Units: participants
    157
    165
    187
    No statistical analyses for this end point

    Other pre-specified: Active Treatment Phase: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry

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    End point title
    Active Treatment Phase: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry
    End point description
    Potentially clinically significant serum chemistry abnormalities included: Glucose <=3 and >=13.88 mmol/L; ALT (in U/L), AST (in U/L), alkaline phosphatase (in U/L), GGT (in U/L), CPK (in U/L), CRP (in mg/L), pancreatic amylase (in U/L)>=3 * ULN; Fibrinogen >=6 gm/L; Sodium <=130 and >=150 mmol/L; Potassium <=3.2 and >=5.5 mmol/L; Calcium <=1.87 and >=2.75 mmol/L; Phosphate <=0.65 and >=1.61 mmol/L; Blood urea nitrogen (in mmol/L); Total bilirubin >=28 micromols per liter (micromols/L); Creatinine >=117 micromols/L; Albumin <=25 gm/L. Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase
    End point values
    Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    891
    504
    Units: participants
    887
    501
    No statistical analyses for this end point

    Other pre-specified: Placebo-Controlled Phase: Number of Participants With Potentially Clinically Significant Abnormal Hematology Values

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    End point title
    Placebo-Controlled Phase: Number of Participants With Potentially Clinically Significant Abnormal Hematology Values
    End point description
    Potentially clinically significant hematological abnormalities included: Hemoglobin <=11.5 grams per deciliter (gm/dL) in males and <=10 gm/dL in females; White blood cells (WBCs) count <=2.5 and >=21*10^9 per liter (L); Absolute neutrophil count (ANC) <=1.49*10^9 per L; Platelet count <=100 and >=600*10^9 per L. Safety analysis set included all participants who were randomized and received at least one dose of study drug. Here, 'Number of participants analysed'=participants evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Month 24
    End point values
    Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    735
    723
    723
    Units: participants
    71
    78
    83
    No statistical analyses for this end point

    Other pre-specified: Active Treatment Phase: Number of Participants With Potentially Clinically Significant Abnormal Hematology Values

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    End point title
    Active Treatment Phase: Number of Participants With Potentially Clinically Significant Abnormal Hematology Values
    End point description
    Potentially clinically significant hematological abnormalities included: Hemoglobin <=11.5, >=20 gm/dL in males, and <=10, >=18.5 gm/dL in females; WBCs count <=2.5 and >=21*10^9 per L; ANC <=1.49*10^9 per L; Platelet count <=100 and >=600*10^9 per L. Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase
    End point values
    Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
    Number of subjects analysed
    891
    504
    Units: participants
    886
    499
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected for the procedure and at each follow-up visit at 2 weeks, 6 weeks, 12 weeks, 24 weeks, and 52 weeks post-treatment
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo-Controlled Phase: Laquinimod 0.6 mg
    Reporting group description
    Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.

    Reporting group title
    Placebo-Controlled Phase: Laquinimod 1.2 mg
    Reporting group description
    Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.

    Reporting group title
    Active Treatment Phase: Early Laquinimod 0.6 mg
    Reporting group description
    Participants who completed the placebo-controlled phase on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months.

    Reporting group title
    Placebo-Controlled Phase: Placebo
    Reporting group description
    Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.

    Reporting group title
    Active Treatment Phase: Early Laquinimod 1.2 mg
    Reporting group description
    Participants who completed the placebo-controlled phase on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.

    Reporting group title
    Active Treatment Phase: Off Drug
    Reporting group description
    Participants who were discontinued from treatment with laquinimod 1.2 mg during the placebo-controlled phase due to sponsor decision after 01 January 2016, continued to the active-treatment phase off drug for 24 months.

    Reporting group title
    Active Treatment Phase: From Placebo to Laquinimod 1.2 mg
    Reporting group description
    Participants who completed the placebo-controlled phase on placebo treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.

    Reporting group title
    Active Treatment Phase: From Placebo to Laquinimod 0.6 mg
    Reporting group description
    Participants who completed the placebo-controlled phase on placebo treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months.

    Serious adverse events
    Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg Active Treatment Phase: Early Laquinimod 0.6 mg Placebo-Controlled Phase: Placebo Active Treatment Phase: Early Laquinimod 1.2 mg Active Treatment Phase: Off Drug Active Treatment Phase: From Placebo to Laquinimod 1.2 mg Active Treatment Phase: From Placebo to Laquinimod 0.6 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    57 / 727 (7.84%)
    49 / 732 (6.69%)
    24 / 580 (4.14%)
    43 / 740 (5.81%)
    10 / 268 (3.73%)
    5 / 215 (2.33%)
    9 / 236 (3.81%)
    5 / 311 (1.61%)
         number of deaths (all causes)
    1
    1
    2
    2
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of adrenal gland
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    1 / 215 (0.47%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to chest wall
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    1 / 215 (0.47%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papilloma
         subjects affected / exposed
    1 / 727 (0.14%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary gland adenoma
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    5 / 727 (0.69%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    2 / 740 (0.27%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone sarcoma
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    1 / 215 (0.47%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    2 / 740 (0.27%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal growth abnormality
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Unintended pregnancy
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion
         subjects affected / exposed
    0 / 727 (0.00%)
    2 / 732 (0.27%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion missed
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion threatened
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Strangulated hernia
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired hydrocele
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adnexal torsion
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix disorder
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fallopian tube cyst
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Ovarian haemorrhage
         subjects affected / exposed
    1 / 727 (0.14%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polycystic ovaries
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasomotor rhinitis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Affective disorder
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Persecutory delusion
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Personality change due to a general medical condition
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alpha 1 foetoprotein abnormal
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    1 / 215 (0.47%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nuclear magnetic resonance imaging brain abnormal
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 727 (0.00%)
    2 / 732 (0.27%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    Bone contusion
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cartilage injury
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poisoning deliberate
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative adhesion
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 727 (0.28%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 727 (0.14%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic liver injury
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 727 (0.00%)
    4 / 732 (0.55%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    1 / 215 (0.47%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    1 / 1
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    1 / 215 (0.47%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    2 / 580 (0.34%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    1 / 215 (0.47%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 727 (0.28%)
    1 / 732 (0.14%)
    2 / 580 (0.34%)
    7 / 740 (0.95%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    1 / 7
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuromyelitis optica spectrum disorder
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 727 (0.14%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypochromic anaemia
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    2 / 740 (0.27%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 727 (0.14%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coeliac disease
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic necrosis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 727 (0.00%)
    4 / 732 (0.55%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periodontal inflammation
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal adhesions
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune pancreatitis
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 727 (0.00%)
    3 / 732 (0.41%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 727 (0.28%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    2 / 727 (0.28%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    2 / 740 (0.27%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis obstructive
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 727 (0.28%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Ankylosing spondylitis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoroacetabular impingement
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 727 (0.14%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess oral
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    1 / 236 (0.42%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    2 / 740 (0.27%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster oticus
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Ovarian abscess
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 727 (0.28%)
    2 / 732 (0.27%)
    1 / 580 (0.17%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    2 / 727 (0.28%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    2 / 740 (0.27%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    1 / 268 (0.37%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder abscess
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 727 (0.14%)
    1 / 732 (0.14%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine infection
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    1 / 740 (0.14%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 727 (0.00%)
    0 / 732 (0.00%)
    1 / 580 (0.17%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    0 / 727 (0.00%)
    1 / 732 (0.14%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 727 (0.14%)
    0 / 732 (0.00%)
    0 / 580 (0.00%)
    0 / 740 (0.00%)
    0 / 268 (0.00%)
    0 / 215 (0.00%)
    0 / 236 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg Active Treatment Phase: Early Laquinimod 0.6 mg Placebo-Controlled Phase: Placebo Active Treatment Phase: Early Laquinimod 1.2 mg Active Treatment Phase: Off Drug Active Treatment Phase: From Placebo to Laquinimod 1.2 mg Active Treatment Phase: From Placebo to Laquinimod 0.6 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    262 / 727 (36.04%)
    286 / 732 (39.07%)
    102 / 580 (17.59%)
    243 / 740 (32.84%)
    46 / 268 (17.16%)
    35 / 215 (16.28%)
    43 / 236 (18.22%)
    43 / 311 (13.83%)
    Investigations
    Amylase increased
         subjects affected / exposed
    17 / 727 (2.34%)
    38 / 732 (5.19%)
    6 / 580 (1.03%)
    18 / 740 (2.43%)
    2 / 268 (0.75%)
    2 / 215 (0.93%)
    5 / 236 (2.12%)
    6 / 311 (1.93%)
         occurrences all number
    20
    43
    7
    19
    2
    2
    8
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    122 / 727 (16.78%)
    131 / 732 (17.90%)
    22 / 580 (3.79%)
    116 / 740 (15.68%)
    8 / 268 (2.99%)
    10 / 215 (4.65%)
    10 / 236 (4.24%)
    14 / 311 (4.50%)
         occurrences all number
    238
    227
    38
    222
    14
    13
    15
    25
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 727 (3.85%)
    43 / 732 (5.87%)
    22 / 580 (3.79%)
    30 / 740 (4.05%)
    13 / 268 (4.85%)
    7 / 215 (3.26%)
    9 / 236 (3.81%)
    9 / 311 (2.89%)
         occurrences all number
    32
    50
    25
    35
    16
    7
    12
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    54 / 727 (7.43%)
    85 / 732 (11.61%)
    12 / 580 (2.07%)
    39 / 740 (5.27%)
    8 / 268 (2.99%)
    9 / 215 (4.19%)
    12 / 236 (5.08%)
    1 / 311 (0.32%)
         occurrences all number
    74
    110
    14
    47
    10
    10
    14
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    63 / 727 (8.67%)
    60 / 732 (8.20%)
    40 / 580 (6.90%)
    63 / 740 (8.51%)
    14 / 268 (5.22%)
    8 / 215 (3.72%)
    11 / 236 (4.66%)
    11 / 311 (3.54%)
         occurrences all number
    90
    86
    52
    91
    20
    13
    13
    13
    Respiratory tract infection viral
         subjects affected / exposed
    32 / 727 (4.40%)
    31 / 732 (4.23%)
    14 / 580 (2.41%)
    39 / 740 (5.27%)
    7 / 268 (2.61%)
    3 / 215 (1.40%)
    5 / 236 (2.12%)
    3 / 311 (0.96%)
         occurrences all number
    54
    37
    19
    56
    9
    3
    6
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jul 2013
    Amendment 1 to the protocol was issued after 200 participants were enrolled in the study. Changes to the protocol were considered to have no negative impact on the safety of participants already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: - Disease duration of at least 6 months but not more than 12 years was updated to disease duration of not more than 15 years. - Clarification regarding disallowed medications following early treatment discontinuation (ETD). - Fibrinogen was added to the battery of safety laboratory tests at all visits.
    08 Jun 2014
    Amendment 2 to the protocol was issued after 1566 participants were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of participants already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: An increase in sample size and change in the timing of blinded sample size reassessment due to faster than expected enrollment. - Implementation of more stringent pregnancy prevention measures. - Updates to the introduction and safety sections based on accumulating data with laquinimod.
    24 Feb 2015
    Amendment 3 to the protocol was issued after 2068 participants were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of participants already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: Change in study design to an event-driven analysis based on Food and Drug Administration (FDA) feedback. - Sample size clarification. - Change in timing of blinded sample size reassessment. - Requirement to perform abdominal computed tomography (CT) as soon as possible when pancreatitis is suspected based on DMC recommendation.
    26 Jan 2016
    Amendment 4 to protocol was issued after 2199 participants were enrolled into study. Changes to protocol were considered to have no negative impact on safety of participants already enrolled into study. As a result of data monitoring committee recommendation to stop all laquinimod treatment groups above 0.6 mg, the following major changes (not all-inclusive) were made to protocol: - Laquinimod 1.2-mg treatment group was discontinued. - All ongoing participants were asked to re-consent to a revised form that included information on cardiovascular risk findings at higher doses of laquinimod (1.2 and 1.5 mg). - All participants assigned to placebo treatment in placebo-controlled phase would start treatment with laquinimod 0.6 mg in active treatment phase. - Stopping rules were added for renal and hepatic impairment. - GFR monitoring (and measurement of weight) was to be performed at all visits to assess renal function. - Extra emphasis was placed on moderate/strong inhibitors of cytochrome P450 3A4 (CYP3A4) being disall