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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multicenter, two-part, dose ranging and confirmatory study with an operationally seamless design, evaluating efficacy and safety of SAR153191 on top of methotrexate (MTX) in patients with active rheumatoid arthritis who are inadequate responders to MTX therapy

    Summary
    EudraCT number
    2009-016266-90
    Trial protocol
    ES   CZ   FI   HU   EE   DE   LT   PT   NL   GR   RO   AT   BE  
    Global end of trial date
    08 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    07 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC11072
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01061736
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study name: SARIL-RA-MOBILITY
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This phase II/III study in subjects with active rheumatoid arthritis used an operationally seamless design. Main objectives were: Phase II - 12 week dose-ranging study (part A): to evaluate efficacy and safety of 5 dose regimens of sarilumab (SAR153191/REGN88) on top of methotrexate (MTX); Phase III - 52-week confirmatory study (part B): to confirm the efficacy and safety of the 2 dose regimens selected from part A.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    All subjects were treated with weekly MTX for the duration of the study and received the same weekly dose as they were receiving prior to enrollment. Subjects were required to be stable for at least 6 weeks prior to the screening visit.
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Mar 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 154
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Romania: 45
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    Estonia: 20
    Country: Number of subjects enrolled
    Finland: 14
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 55
    Country: Number of subjects enrolled
    Lithuania: 10
    Country: Number of subjects enrolled
    Argentina: 130
    Country: Number of subjects enrolled
    Australia: 27
    Country: Number of subjects enrolled
    Belarus: 14
    Country: Number of subjects enrolled
    Brazil: 72
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Chile: 133
    Country: Number of subjects enrolled
    Colombia: 78
    Country: Number of subjects enrolled
    India: 24
    Country: Number of subjects enrolled
    Korea, Republic of: 46
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Mexico: 175
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    Philippines: 15
    Country: Number of subjects enrolled
    Russian Federation: 213
    Country: Number of subjects enrolled
    South Africa: 97
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Thailand: 3
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    Ukraine: 67
    Country: Number of subjects enrolled
    United States: 187
    Worldwide total number of subjects
    1675
    EEA total number of subjects
    365
    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)
    1460
    From 65 to 84 years
    215
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 247 centers in 36 countries. Overall, 3715 subjects were screened between March 2010 and July 2012, 2040 of whom were screen failures. Screen failures were mainly due to failure to meet the inclusion criterion for severity of the disease and/or due to meeting the exclusion criterion.

    Pre-assignment
    Screening details
    Randomization was performed centrally with allocation generated by Interactive Voice/Web Response System, stratified by geographical region and prior biological use. 306 subjects were randomized in Part A. 1369 subjects were randomized in part B, 172 before dose selection (cohort 1) and 1197 after dose selection (cohort 2).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor
    Blinding implementation details
    Investigators were blinded with regard to each subject's CRP and IL-6 levels, except at screening and baseline, with the swollen and tender joint counts performed by a separate qualified assessor. Two readers, blinded with regard to treatment assignment, chronologic order of the radiographs, and subject's clinical status, independently reviewed and scored images using the modified Sharp/van der Heijde scoring (SHS) system.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part A: SAR 100 mg QW
    Arm description
    Sarilumab 100 mg weekly (qw) on top of MTX for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Arm title
    Part A: SAR 150 mg QW
    Arm description
    Sarilumab 150 mg qw on top of MTX for 12-weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Arm title
    Part A: SAR 100 mg Q2W
    Arm description
    Sarilumab 100 mg every other week (q2w) alternating with placebo on top of MTX for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Investigational medicinal product name
    Placebo (for sarilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Arm title
    Part A: SAR 150 mg Q2W
    Arm description
    Sarilumab 150 mg q2w alternating with placebo on top of MTX for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Investigational medicinal product name
    Placebo (for sarilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Arm title
    Part A: SAR 200 mg Q2W
    Arm description
    Sarilumab 200 mg q2w alternating with placebo on top of MTX for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Investigational medicinal product name
    Placebo (for sarilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Arm title
    Part A: Placebo QW
    Arm description
    Placebo (for sarilumab) qw on top of MTX for 12 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for sarilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Arm title
    Part B cohort 1: Non-selected doses
    Arm description
    Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w on top of MTX up to dose selection. After dose selection, subjects were not continued but were allowed to participate in the open-label, long-term, extension study RA-EXTEND (LTS11210). These subjects were not included in any analysis.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Investigational medicinal product name
    Placebo (for sarilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Arm title
    Part B: SAR 150 mg Q2W
    Arm description
    Sarilumab 150 mg q2w on top of MTX for a maximum of 52 weeks. Subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Arm title
    Part B: SAR 200 mg Q2W
    Arm description
    Sarilumab 200 mg q2w on top of MTX for a maximum of 52 weeks. Subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Arm title
    Part B: Placebo Q2W
    Arm description
    Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for sarilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single injection in abdomen.

    Number of subjects in period 1
    Part A: SAR 100 mg QW Part A: SAR 150 mg QW Part A: SAR 100 mg Q2W Part A: SAR 150 mg Q2W Part A: SAR 200 mg Q2W Part A: Placebo QW Part B cohort 1: Non-selected doses Part B: SAR 150 mg Q2W Part B: SAR 200 mg Q2W Part B: Placebo Q2W
    Started
    50
    50
    51
    51
    52
    52
    84
    430
    427
    428
    Treated
    50
    50
    51
    51
    51
    52
    84
    428
    426
    428
    Completed
    37
    46
    45
    48
    45
    49
    0
    336
    330
    354
    Not completed
    13
    4
    6
    3
    7
    3
    84
    94
    97
    74
         Dose regimen not selected
             -
             -
             -
             -
             -
             -
             79
             -
             -
             -
         Other
             -
             1
             2
             -
             1
             -
             -
             18
             15
             21
         Adverse event
             13
             1
             3
             2
             4
             1
             4
             63
             67
             34
         Lack of efficacy
             -
             2
             1
             1
             1
             2
             1
             9
             9
             10
         Poor compliance to protocol
             -
             -
             -
             -
             -
             -
             -
             2
             5
             9
         Not treated
             -
             -
             -
             -
             1
             -
             -
             2
             1
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: SAR 100 mg QW
    Reporting group description
    Sarilumab 100 mg weekly (qw) on top of MTX for 12 weeks.

    Reporting group title
    Part A: SAR 150 mg QW
    Reporting group description
    Sarilumab 150 mg qw on top of MTX for 12-weeks.

    Reporting group title
    Part A: SAR 100 mg Q2W
    Reporting group description
    Sarilumab 100 mg every other week (q2w) alternating with placebo on top of MTX for 12 weeks.

    Reporting group title
    Part A: SAR 150 mg Q2W
    Reporting group description
    Sarilumab 150 mg q2w alternating with placebo on top of MTX for 12 weeks.

    Reporting group title
    Part A: SAR 200 mg Q2W
    Reporting group description
    Sarilumab 200 mg q2w alternating with placebo on top of MTX for 12 weeks.

    Reporting group title
    Part A: Placebo QW
    Reporting group description
    Placebo (for sarilumab) qw on top of MTX for 12 weeks.

    Reporting group title
    Part B cohort 1: Non-selected doses
    Reporting group description
    Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w on top of MTX up to dose selection. After dose selection, subjects were not continued but were allowed to participate in the open-label, long-term, extension study RA-EXTEND (LTS11210). These subjects were not included in any analysis.

    Reporting group title
    Part B: SAR 150 mg Q2W
    Reporting group description
    Sarilumab 150 mg q2w on top of MTX for a maximum of 52 weeks. Subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.

    Reporting group title
    Part B: SAR 200 mg Q2W
    Reporting group description
    Sarilumab 200 mg q2w on top of MTX for a maximum of 52 weeks. Subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.

    Reporting group title
    Part B: Placebo Q2W
    Reporting group description
    Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.

    Reporting group values
    Part A: SAR 100 mg QW Part A: SAR 150 mg QW Part A: SAR 100 mg Q2W Part A: SAR 150 mg Q2W Part A: SAR 200 mg Q2W Part A: Placebo QW Part B cohort 1: Non-selected doses Part B: SAR 150 mg Q2W Part B: SAR 200 mg Q2W Part B: Placebo Q2W Total
    Number of subjects
    50 50 51 51 52 52 84 430 427 428 1675
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.9 ± 12.3 50.9 ± 11.1 53.5 ± 11.8 51.2 ± 12.9 48.7 ± 12.4 55.2 ± 12.5 51.1 ± 11.5 50.3 ± 11.9 50.8 ± 12 51.1 ± 11.2 -
    Gender categorical
    Units: Subjects
        Female
    41 42 38 42 42 38 69 345 359 346 1362
        Male
    9 8 13 9 10 14 15 85 68 82 313
    Recruitment Phase
    Units: Subjects
        Part A
    50 50 51 51 52 52 0 0 0 0 306
        Part B Cohort 1
    0 0 0 0 0 0 84 30 28 30 172
        Part B Cohort 2
    0 0 0 0 0 0 0 400 399 398 1197
    Rescued
    Part B (Cohort 1 selected doses and Cohort 2) subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab. ‘Not applicable’ enumerates subjects from Part A or Part B Cohort 1 treated with doses not selected for Part B Cohort 2, and subjects from Cohort 2 who discontinued before or on Week 16.
    Units: Subjects
        Yes
    0 0 0 0 0 0 0 61 55 168 284
        No
    0 0 0 0 0 0 0 336 341 243 920
        Not applicable
    50 50 51 51 52 52 84 33 31 17 471

    End points

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    End points reporting groups
    Reporting group title
    Part A: SAR 100 mg QW
    Reporting group description
    Sarilumab 100 mg weekly (qw) on top of MTX for 12 weeks.

    Reporting group title
    Part A: SAR 150 mg QW
    Reporting group description
    Sarilumab 150 mg qw on top of MTX for 12-weeks.

    Reporting group title
    Part A: SAR 100 mg Q2W
    Reporting group description
    Sarilumab 100 mg every other week (q2w) alternating with placebo on top of MTX for 12 weeks.

    Reporting group title
    Part A: SAR 150 mg Q2W
    Reporting group description
    Sarilumab 150 mg q2w alternating with placebo on top of MTX for 12 weeks.

    Reporting group title
    Part A: SAR 200 mg Q2W
    Reporting group description
    Sarilumab 200 mg q2w alternating with placebo on top of MTX for 12 weeks.

    Reporting group title
    Part A: Placebo QW
    Reporting group description
    Placebo (for sarilumab) qw on top of MTX for 12 weeks.

    Reporting group title
    Part B cohort 1: Non-selected doses
    Reporting group description
    Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w on top of MTX up to dose selection. After dose selection, subjects were not continued but were allowed to participate in the open-label, long-term, extension study RA-EXTEND (LTS11210). These subjects were not included in any analysis.

    Reporting group title
    Part B: SAR 150 mg Q2W
    Reporting group description
    Sarilumab 150 mg q2w on top of MTX for a maximum of 52 weeks. Subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.

    Reporting group title
    Part B: SAR 200 mg Q2W
    Reporting group description
    Sarilumab 200 mg q2w on top of MTX for a maximum of 52 weeks. Subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.

    Reporting group title
    Part B: Placebo Q2W
    Reporting group description
    Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Subjects with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.

    Subject analysis set title
    Part B cohort 2: SAR 150 mg Q2W
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Part B subjects randomized to Sarilumab 150 mg q2w after dose selection.

    Subject analysis set title
    Part B cohort 2: SAR 200 mg Q2W
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Part B subjects randomized to Sarilumab 200 mg q2w after dose selection.

    Subject analysis set title
    Part B cohort 2: Placebo Q2W
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Part B subjects randomized to placebo q2w after dose selection.

    Primary: Part A: Percentage of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12

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    End point title
    Part A: Percentage of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 [1]
    End point description
    ACR20 response is defined, based on guidelines set forth by the American College of Rheumatology (ACR), as ≥20 % improvement in tender joint count and swollen joint count as well as ≥20% improvement in at least 3 of 5 following measures: C-Reactive Protein (CRP), subject assessment of pain; subject global assessment of disease activity; physician global assessment of disease activity; and Health Assessment Question-Disability Index (HAQ-DI). Analysis was carried out on Part A Intent-to-treat (ITT) population defined as all randomized subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12 (missing data imputed by Last Observation Carried Forward [LOCF]).
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part A and Part B were analyzed separately.
    End point values
    Part A: SAR 100 mg QW Part A: SAR 150 mg QW Part A: SAR 100 mg Q2W Part A: SAR 150 mg Q2W Part A: SAR 200 mg Q2W Part A: Placebo QW
    Number of subjects analysed
    50
    50
    51
    51
    52
    52
    Units: percentage of subjects
        number (not applicable)
    62
    72
    49
    66.7
    65.4
    46.2
    Statistical analysis title
    Sarilumab 100 mg qw vs Placebo
    Statistical analysis description
    Analysis was performed using two-sided Cochran-Mantel-Haenszel test. Pairwise comparisons of the response rates between each dose of sarilumab and placebo were derived. The multiplicity issues were addressed by using the Hommel-procedure.
    Comparison groups
    Part A: SAR 100 mg QW v Part A: Placebo QW
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1155 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    4.64
    Notes
    [2] - Threshold for significance = 0.05.
    Statistical analysis title
    Sarilumab 150 mg qw vs Placebo
    Comparison groups
    Part A: SAR 150 mg QW v Part A: Placebo QW
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0041 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.53
         upper limit
    9.63
    Notes
    [3] - Threshold for significance = 0.05.
    Statistical analysis title
    Sarilumab 100 mg q2w vs Placebo
    Comparison groups
    Part A: Placebo QW v Part A: SAR 100 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7119 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    2.61
    Notes
    [4] - Threshold for significance = 0.05.
    Statistical analysis title
    Sarilumab 150 mg q2w vs Placebo
    Comparison groups
    Part A: SAR 150 mg Q2W v Part A: Placebo QW
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0363 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    5.35
    Notes
    [5] - Threshold for significance = 0.05.
    Statistical analysis title
    Sarilumab 200 mg q2w vs Placebo
    Comparison groups
    Part A: SAR 200 mg Q2W v Part A: Placebo QW
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0426 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    5.29
    Notes
    [6] - Threshold for significance = 0.05.

    Primary: Part B: Percentage of Subjects Achieving ACR20 Response at Week 24

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    End point title
    Part B: Percentage of Subjects Achieving ACR20 Response at Week 24
    End point description
    ACR20 improvement responses were determined without imputation of missing post-baseline values. In addition data collected after treatment discontinuation or rescue was set to missing. Analysis was carried out on the ITT population, which included all subjects randomized after dose selection (cohort 2).
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    Part B cohort 2: SAR 150 mg Q2W Part B cohort 2: SAR 200 mg Q2W Part B cohort 2: Placebo Q2W
    Number of subjects analysed
    400
    399
    398
    Units: percentage of subjects
        number (not applicable)
    58
    66.4
    33.4
    Statistical analysis title
    Sarilumab 150 mg q2w vs. Placebo
    Statistical analysis description
    Analysis was performed using two-sided Cochran-Mantel-Haenszel test. Pairwise comparisons of the response rates between each dose of sarilumab and placebo was derived. The multiplicity issues for part B were addressed by using a Bonferroni correction for each dose together with a hierarchical testing procedure across the 3 co-primary and the main secondary endpoints.The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level.
    Comparison groups
    Part B cohort 2: SAR 150 mg Q2W v Part B cohort 2: Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.773
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.077
         upper limit
    3.703
    Notes
    [7] - Threshold for significance = 0.025.
    Statistical analysis title
    Sarilumab 200 mg q2w vs Placebo
    Comparison groups
    Part B cohort 2: SAR 200 mg Q2W v Part B cohort 2: Placebo Q2W
    Number of subjects included in analysis
    797
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.975
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.957
         upper limit
    5.344
    Notes
    [8] - Theshold for significance = 0.025.

    Primary: Part B: Change From Baseline in Health Assessment Question-Disability Index (HAQ-DI) at Week 16

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    End point title
    Part B: Change From Baseline in Health Assessment Question-Disability Index (HAQ-DI) at Week 16
    End point description
    HAQ-DI is a subject-reported questionnaire that assesses the difficulty of performing daily activities: dress/groom, arise, eat, walk, reach, grip, hygiene and common activities. Overall score range from 0=least difficulty to 3=extreme difficulty. An increase in the score indicates a worsening of physical function while a decrease in the score represents improvement. Analysis was carried out on the Cohort 2 ITT population only and included subjects with available data of HAQ-DI at baseline and Week 16.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    End point values
    Part B cohort 2: SAR 150 mg Q2W Part B cohort 2: SAR 200 mg Q2W Part B cohort 2: Placebo Q2W
    Number of subjects analysed
    362
    365
    378
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.63 ± 0.63
    1.69 ± 0.63
    1.61 ± 0.65
        Week 16
    1.08 ± 0.67
    1.11 ± 0.7
    1.31 ± 0.67
        Change From Baseline at Week 16
    -0.54 ± 0.55
    -0.58 ± 0.63
    -0.3 ± 0.58
    Statistical analysis title
    Sarilumab 150 mg q2w vs Placebo
    Statistical analysis description
    Analysis was performed using a mixed model for repeated measures (MMRM). Differences in LS means between each dose of sarilumab and placebo were derived. Testing was performed according to the hierarchical testing procedure (previous endpoint was statistically significant).
    Comparison groups
    Part B cohort 2: SAR 150 mg Q2W v Part B cohort 2: Placebo Q2W
    Number of subjects included in analysis
    740
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -0.235
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.312
         upper limit
    -0.157
    Notes
    [9] - Threshold for significance = 0.025.
    Statistical analysis title
    Sarilumab 200 mg q2w vs Placebo
    Comparison groups
    Part B cohort 2: SAR 200 mg Q2W v Part B cohort 2: Placebo Q2W
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -0.258
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.336
         upper limit
    -0.181
    Notes
    [10] - Threshold for significance = 0.025.

    Primary: Part B: Change From Baseline in Van der Heijde Modified Total Sharp Score (mTSS) at Week 52

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    End point title
    Part B: Change From Baseline in Van der Heijde Modified Total Sharp Score (mTSS) at Week 52
    End point description
    The Sharp method modified by D. van der Heijde involves separate scores for erosions and joint space narrowing based on radiographs to assess the degree of structural damage. Total score range from 0 (normal) to 448 (worst possible total score). An increase in total score represents progression of structural damage. Analysis was carried out on the Cohort 2 ITT population and included subjects with available data of mTSS at baseline and Week 52.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52 (missing data imputed by the linear extrapolation method).
    End point values
    Part B cohort 2: SAR 150 mg Q2W Part B cohort 2: SAR 200 mg Q2W Part B cohort 2: Placebo Q2W
    Number of subjects analysed
    352
    359
    352
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    54.67 ± 63.42
    46.34 ± 57.43
    48.01 ± 65.23
        Week 52
    55.57 ± 63.73
    46.59 ± 57.63
    50.79 ± 65.82
        Change From Baseline at Week 52
    0.9 ± 4.66
    0.25 ± 4.61
    2.78 ± 7.73
    Statistical analysis title
    Sarilumab 150 mg q2w vs Placebo
    Statistical analysis description
    Analysis was performed using two-sided rank-based ANCOVA model. Testing was performed according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Part B cohort 2: Placebo Q2W v Part B cohort 2: SAR 150 mg Q2W
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [11]
    Method
    Rank ANCOVA
    Confidence interval
    Notes
    [11] - Threshold for significance = 0.025.
    Statistical analysis title
    Sarilumab 200 mg q2w vs Placebo
    Comparison groups
    Part B cohort 2: Placebo Q2W v Part B cohort 2: SAR 200 mg Q2W
    Number of subjects included in analysis
    711
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Rank ANCOVA
    Confidence interval
    Notes
    [12] - Threshold for significance = 0.025.

    Secondary: Part B: Percentage of Subjects Achieving a Major Clinical Response at Week 52

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    End point title
    Part B: Percentage of Subjects Achieving a Major Clinical Response at Week 52
    End point description
    Major clinical response was defined as an ACR70 response maintained for at least 24 consecutive weeks. ACR70 response uses the same criteria as for ACR20 but requires 70% improvement. Analysis was carried out on Part B Cohort 2 ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Part B cohort 2: SAR 150 mg Q2W Part B cohort 2: SAR 200 mg Q2W Part B cohort 2: Placebo Q2W
    Number of subjects analysed
    400
    399
    398
    Units: percentage of subjects
        number (not applicable)
    12.8
    14.8
    3
    Statistical analysis title
    Sarilumab 150 mg q2w Placebo
    Statistical analysis description
    Analysis was performed using two-sided Cochran-Mantel-Haenszel test. Pairwise comparisons of the response rates between each dose of sarilumab and placebo were derived. Testing was performed according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Part B cohort 2: SAR 150 mg Q2W v Part B cohort 2: Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.661
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.451
         upper limit
    8.863
    Notes
    [13] - Threshold for significance = 0.025.
    Statistical analysis title
    Sarilumab 200 mg q2w vs Placebo
    Comparison groups
    Part B cohort 2: SAR 200 mg Q2W v Part B cohort 2: Placebo Q2W
    Number of subjects included in analysis
    797
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    5.565
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.946
         upper limit
    10.515
    Notes
    [14] - Threshold for significance = 0.025.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to study completion regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths are treatment-emergent that is AEs that developed/worsened and deaths that occurred during the ‘treatment-emergent period’ (from the first IMP injection up to the end of the study).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Part A: Placebo QW
    Reporting group description
    Part A subjects exposed to placebo in combination with MTX (mean exposure of 12 weeks). Excluded 1 subject who received an erroneous IMP kit with Sarilumab 150 mg q2w. He/she was considered in the 150 mg q2w treatment group for safety analysis.

    Reporting group title
    Part A: SAR 100mg Q2W
    Reporting group description
    Part A subjects exposed to sarilumab 100 mg q2w in combination with MTX (mean exposure of 11 weeks).

    Reporting group title
    Part A: SAR 150mg Q2W
    Reporting group description
    Part A subjects exposed to sarilumab 150 mg q2w in combination with MTX (mean exposure of 12 weeks). Included the subject randomized to placebo qw who received sarilumab 150 mg q2w in error.

    Reporting group title
    Part A: SAR 100mg QW
    Reporting group description
    Part A subjects exposed to sarilumab 100 mg qw in combination with MTX (mean exposure of 10 weeks).

    Reporting group title
    Part A: SAR 200mg Q2W
    Reporting group description
    Part A subjects exposed to sarilumab 200 mg q2w in combination with (mean exposure of 11 weeks).

    Reporting group title
    Part A: SAR 150mg QW
    Reporting group description
    Part A subjects exposed to sarilumab 150 mg qw in combination with MTX (mean exposure of 12 weeks).

    Reporting group title
    Part B: Placebo Q2W until rescue
    Reporting group description
    Part B subjects exposed to placebo Q2W in combination with MTX until open-label rescue treatment with highest dose (mean exposure of 40 weeks). Excluded 1 subject who received an erroneous IMP kit with Sarilumab 200 mg q2w. He/she was considered in the 200 mg q2w treatment group for safety analysis.

    Reporting group title
    Part B: SAR 150mg Q2W until rescue
    Reporting group description
    Part B subjects exposed to sarilumab 150 mg q2w in combination with MTX until open-label rescue treatment with highest dose (mean exposure of 42 weeks). Included 3 subjects randomized to sarilumab 200 mg q2w who received at least one dose of sarilumab 150 mg q2w in error (lowest dose received).

    Reporting group title
    Part B: SAR 200mg Q2W until rescue
    Reporting group description
    Part B subjects exposed to sarilumab 200 mg q2w in combination with MTX until open-label rescue treatment with highest dose (mean exposure of 42 weeks). Excluded the 3 subjects who received sarilumab 150 mg q2w in error and included the subject randomized to placebo q2w who received sarilumab 200 mg q2w in error.

    Reporting group title
    Part B: Rescue SAR 200mg Q2W
    Reporting group description
    Part B subjects rescued with sarilumab 200 mg q2w open-label whatever the initial dose received (mean exposure of 28 weeks from beginning of rescue treatment).

    Serious adverse events
    Part A: Placebo QW Part A: SAR 100mg Q2W Part A: SAR 150mg Q2W Part A: SAR 100mg QW Part A: SAR 200mg Q2W Part A: SAR 150mg QW Part B: Placebo Q2W until rescue Part B: SAR 150mg Q2W until rescue Part B: SAR 200mg Q2W until rescue Part B: Rescue SAR 200mg Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 51 (5.88%)
    0 / 52 (0.00%)
    3 / 50 (6.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    23 / 427 (5.39%)
    38 / 431 (8.82%)
    48 / 424 (11.32%)
    29 / 284 (10.21%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
    0
    2
    2
    1
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic Thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism Arterial
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    2 / 424 (0.47%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock Haemorrhagic
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Subgaleal Haematoma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Breast Cancer Metastatic
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Ductal Adenocarcinoma Of Pancreas
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 1
    Invasive Lobular Breast Carcinoma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    2 / 427 (0.47%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    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
    0 / 0
    0 / 0
    Metastatic Bronchial Carcinoma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 1
    Neoplasm Of Appendix
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Immediate Post-Injection Reaction
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Impaired Healing
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed Suicide
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    2 / 424 (0.47%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur Fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Rupture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Procedural Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Skin Wound
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Wound Haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Unstable
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cardiovascular Insufficiency
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Sick Sinus Syndrome
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    Bronchial Secretion Retention
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    2 / 431 (0.46%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron Deficiency Anaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    3 / 431 (0.70%)
    4 / 424 (0.94%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic Vein Thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    Nervous system disorders
    Brain Oedema
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    Cauda Equina Syndrome
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Embolic Cerebral Infarction
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Myelitis Transverse
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Viith Nerve Paralysis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Retinal Vascular Thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Abdominal Wall Haematoma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Alcoholic Pancreatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Duodenal Ulcer
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Duodenal Ulcer Perforation
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Gastric Haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus Ureteric
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    1 / 431 (0.23%)
    2 / 424 (0.47%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cholecystitis Chronic
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hepatitis Toxic
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous Lupus Erythematosus
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Lumbar Spinal Stenosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    3 / 427 (0.70%)
    1 / 431 (0.23%)
    2 / 424 (0.47%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    2 / 427 (0.47%)
    0 / 431 (0.00%)
    2 / 424 (0.47%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    Abscess Oral
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    2 / 427 (0.47%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    0 / 0
    Arthritis Bacterial
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    2 / 427 (0.47%)
    0 / 431 (0.00%)
    2 / 424 (0.47%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis Fungal
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Bursitis Infective Staphylococcal
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    3 / 427 (0.70%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    3 / 424 (0.71%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Incision Site Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Infected Skin Ulcer
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Necrotising Fasciitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    0 / 0
    Otitis Media Acute
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Otitis Media Chronic
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pelvic Abscess
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    1 / 431 (0.23%)
    2 / 424 (0.47%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Streptococcal
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Pyelonephritis Chronic
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    1 / 424 (0.24%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Subacute Endocarditis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Subcutaneous Abscess
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Tinea Cruris
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    1 / 431 (0.23%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 427 (0.23%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 427 (0.00%)
    0 / 431 (0.00%)
    0 / 424 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part A: Placebo QW Part A: SAR 100mg Q2W Part A: SAR 150mg Q2W Part A: SAR 100mg QW Part A: SAR 200mg Q2W Part A: SAR 150mg QW Part B: Placebo Q2W until rescue Part B: SAR 150mg Q2W until rescue Part B: SAR 200mg Q2W until rescue Part B: Rescue SAR 200mg Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 51 (21.57%)
    7 / 51 (13.73%)
    15 / 52 (28.85%)
    16 / 50 (32.00%)
    20 / 51 (39.22%)
    17 / 50 (34.00%)
    144 / 427 (33.72%)
    204 / 431 (47.33%)
    224 / 424 (52.83%)
    110 / 284 (38.73%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    5 / 51 (9.80%)
    1 / 51 (1.96%)
    3 / 52 (5.77%)
    2 / 50 (4.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    25 / 427 (5.85%)
    28 / 431 (6.50%)
    28 / 424 (6.60%)
    7 / 284 (2.46%)
         occurrences all number
    5
    1
    3
    2
    2
    3
    29
    35
    43
    8
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    3 / 52 (5.77%)
    2 / 50 (4.00%)
    2 / 51 (3.92%)
    2 / 50 (4.00%)
    14 / 427 (3.28%)
    36 / 431 (8.35%)
    31 / 424 (7.31%)
    16 / 284 (5.63%)
         occurrences all number
    0
    0
    3
    2
    2
    2
    14
    41
    33
    19
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    6 / 50 (12.00%)
    10 / 51 (19.61%)
    5 / 50 (10.00%)
    1 / 427 (0.23%)
    38 / 431 (8.82%)
    57 / 424 (13.44%)
    29 / 284 (10.21%)
         occurrences all number
    0
    0
    1
    10
    13
    5
    1
    62
    87
    46
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    5 / 427 (1.17%)
    25 / 431 (5.80%)
    28 / 424 (6.60%)
    15 / 284 (5.28%)
         occurrences all number
    0
    1
    0
    4
    5
    1
    5
    99
    82
    38
    Musculoskeletal and connective tissue disorders
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    16 / 427 (3.75%)
    4 / 431 (0.93%)
    13 / 424 (3.07%)
    5 / 284 (1.76%)
         occurrences all number
    1
    1
    0
    0
    0
    3
    17
    5
    15
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    16 / 427 (3.75%)
    14 / 431 (3.25%)
    22 / 424 (5.19%)
    13 / 284 (4.58%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    17
    20
    23
    14
    Nasopharyngitis
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 51 (3.92%)
    2 / 52 (3.85%)
    2 / 50 (4.00%)
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    18 / 427 (4.22%)
    25 / 431 (5.80%)
    22 / 424 (5.19%)
    12 / 284 (4.23%)
         occurrences all number
    3
    2
    2
    2
    2
    1
    22
    29
    24
    12
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    1 / 50 (2.00%)
    3 / 51 (5.88%)
    2 / 50 (4.00%)
    24 / 427 (5.62%)
    35 / 431 (8.12%)
    37 / 424 (8.73%)
    11 / 284 (3.87%)
         occurrences all number
    3
    0
    2
    1
    3
    2
    28
    47
    46
    12
    Urinary Tract Infection
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    15 / 427 (3.51%)
    22 / 431 (5.10%)
    23 / 424 (5.42%)
    8 / 284 (2.82%)
         occurrences all number
    1
    1
    1
    3
    1
    0
    16
    24
    28
    10

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Feb 2010
    This amendment was prepared primarily to clarify the Skin Purified Protein Derivative (PPD) test to be performed at screening according to local regulation and to add a statement on male contraception further to Ethic Committee request.
    01 Jun 2010
    This amendment was prepared primarily to indicate randomization specificities in selected countries and to add sampling time points.
    04 Apr 2011
    This amendment was prepared primarily to support the start of the Phase 3 clinical trial with the new drug product (different cell line, manufacturing process, formulation and presentation of the IMP).
    04 Nov 2011
    This amendment was prepared primarily to indicate the two dose regimens that were selected for phase 3 program based on results of the Part A phase 2 study.
    08 Aug 2012
    This amendment was prepared primarily to add new safety measures to prevent the administration of sarilumab to subjects at risk for thrombocytopenia and/or neutropenia.
    29 Oct 2012
    This amendment was prepared primarily to modify the primary objective and primary endpoints. HAQ-DI and mTSS were converted to primary endpoints.
    08 Oct 2013
    This amendment was prepared primarily to re-order the testing of the primary endpoints reconsidering the role of the HAQ-DI endpoint and also change the timing for this specific endpoint.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to system constraints and legibility issue, part B arms with non-selected doses were grouped in the Subject dispositions section and were not reported in the Adverse events section. In total 4 serious AEs (no death) were reported in these arms.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24297381
    http://www.ncbi.nlm.nih.gov/pubmed/25733246
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