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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of CNTO 136 (sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Rheumatoid Arthritis Despite DMARD Therapy

    Summary
    EudraCT number
    2010-022242-24
    Trial protocol
    LT   BG  
    Global end of trial date
    06 Dec 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Dec 2017
    First version publication date
    22 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CR100866
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01604343
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Archimedesweg 29, Leiden, Netherlands, 2333
    Public contact
    Clinical Registry Group, Janssen-Cilag International N.V, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International N.V, ClinicalTrialsEU@its.jnj.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 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to assess the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis (RA) and inhibition of radiographic progression in subjects with moderately to severely active RA who were refractory to disease-modifying antirheumatic drugs (DMARDs).
    Protection of trial subjects
    Safety assessment was evaluated throughout the study based on reported adverse events (AEs), clinical laboratory tests, vital sign measurements, physical examinations, and concomitant medication review.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Jul 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Chile: 68
    Country: Number of subjects enrolled
    Colombia: 41
    Country: Number of subjects enrolled
    Croatia: 10
    Country: Number of subjects enrolled
    Japan: 168
    Country: Number of subjects enrolled
    Korea, Republic of: 68
    Country: Number of subjects enrolled
    Lithuania: 98
    Country: Number of subjects enrolled
    Mexico: 115
    Country: Number of subjects enrolled
    Malaysia: 7
    Country: Number of subjects enrolled
    Poland: 169
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    Russian Federation: 201
    Country: Number of subjects enrolled
    Serbia: 144
    Country: Number of subjects enrolled
    Taiwan: 24
    Country: Number of subjects enrolled
    Ukraine: 152
    Country: Number of subjects enrolled
    United States: 261
    Country: Number of subjects enrolled
    South Africa: 100
    Worldwide total number of subjects
    1670
    EEA total number of subjects
    310
    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)
    1422
    From 65 to 84 years
    248
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 2746 subjects were screened of which 1670 subjects were randomized and received at least one administration of study treatment.

    Period 1
    Period 1 title
    Prior to W52 administration(through W52)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo subcutaneously (SC) every 2 weeks (q2w) from Week 0 up to Week 50. Subjects who met early escape (EE) criteria at Week 18, or late escape (LE) at Week 40, or crossover (CO) at Week 52 were re-randomized to receive sirukumab 50 or 100 mg through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received placebo subcutaneously (SC) every 2 weeks (q2w) from Week 0 up to Week 50.

    Arm title
    Sirukumab 50 mg q4w
    Arm description
    All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 Weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through Week 104.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks.

    Arm title
    Sirukumab 100 mg q2w
    Arm description
    All subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.

    Number of subjects in period 1
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Started
    556
    557
    557
    Completed
    247
    481
    470
    Not completed
    309
    76
    87
         Other
    15
    10
    6
         Physician decision
    4
    1
    2
         Lack of efficacy
    24
    5
    14
         Pregnancy
    1
    1
    -
         Adverse event, serious fatal
    5
    3
    5
         Adverse event, non-fatal
    25
    40
    41
         Consent withdrawn by subject
    19
    12
    16
         Re-randomized at Week 18/40
    211
    -
    -
         Lost to follow-up
    5
    4
    3
    Period 2
    Period 2 title
    Week 52 to Week 104
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Placebo to 50 mg q4w due to EE/LE/CO
    Arm description
    All subjects who were assigned to placebo group and who met EE at Week 18 or LE at Week 40 or CO at Week 52 were re- randomized to receive subcutaneous (SC) sirukumab 50 mg dose regimen q4w up to Week 104.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects who were assigned to placebo group and who met early escape (EE) at Week 18 or LE at Week 40 or CO at Week 52 were re-randomized to receive subcutaneous (SC) sirukumab 50 mg dose regimen q4w up to Week 104.

    Arm title
    Sirukumab 50 mg q4w
    Arm description
    All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through week 104.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks.

    Arm title
    Placebo to 100 mg q2w due to EE/LE/CO
    Arm description
    All subjects who were assigned to placebo group and who met EE at Week 18 or LE at Week 40 or CO at Week 52 were re-randomized to receive subcutaneous (SC) sirukumab 100 mg dose regimen q2w up to Week 104.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects who were assigned to placebo group and who met EE at Week 18 or LE at Week 40 or CO at Week 52 were re-randomized to receive subcutaneous (SC) sirukumab 100 mg dose regimen q2w up to Week 104.

    Arm title
    Sirukumab 100 mg q2w
    Arm description
    All subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.

    Number of subjects in period 2
    Placebo to 50 mg q4w due to EE/LE/CO Sirukumab 50 mg q4w Placebo to 100 mg q2w due to EE/LE/CO Sirukumab 100 mg q2w
    Started
    243
    481
    241
    470
    Treated
    242
    481
    241
    470
    Completed
    200
    414
    195
    429
    Not completed
    43
    67
    46
    41
         Other
    11
    11
    6
    3
         Physician decision
    1
    -
    -
    2
         Lack of efficacy
    6
    11
    2
    3
         Pregnancy
    -
    1
    2
    1
         Adverse event, serious fatal
    4
    2
    5
    -
         Adverse event, non-fatal
    12
    26
    21
    27
         Consent withdrawn by subject
    7
    12
    8
    4
         Lost to follow-up
    2
    4
    2
    1
    Period 3
    Period 3 title
    Post Treatment Safety Follow Up
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received placebo subcutaneously (SC) every 2 weeks (q2w) from Week 0 up to Week 50.

    Arm title
    Placebo to 50 mg q4w due to EE/LE/CO
    Arm description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo, Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects who were assigned to placebo group and who met early escape (EE) at Week 18 or LE at Week 40 or CO at Week 52 were re-randomized to receive subcutaneous (SC) sirukumab 50 mg dose regimen q4w up to Week 104.

    Arm title
    Sirukumab 50 mg q4w
    Arm description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks.

    Arm title
    Placebo to Sirukumab 100 mg q2w due to EE/LE/CO
    Arm description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo, Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects who were assigned to placebo group and who met EE at Week 18 or LE at Week 40 or CO at Week 52 were re-randomized to receive subcutaneous (SC) sirukumab 100 mg dose regimen q2w up to Week 104.

    Arm title
    Sirukumab 100 mg q2w
    Arm description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.

    Number of subjects in period 3
    Placebo Placebo to 50 mg q4w due to EE/LE/CO Sirukumab 50 mg q4w Placebo to Sirukumab 100 mg q2w due to EE/LE/CO Sirukumab 100 mg q2w
    Started
    109
    27
    105
    36
    114
    Safety Population
    109
    26
    105
    36
    114
    Completed
    79
    20
    72
    26
    85
    Not completed
    30
    7
    33
    10
    29
         Other
    15
    2
    20
    6
    14
         Consent withdrawn by subject
    12
    4
    11
    3
    14
         Lost to follow-up
    3
    1
    2
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo subcutaneously (SC) every 2 weeks (q2w) from Week 0 up to Week 50. Subjects who met early escape (EE) criteria at Week 18, or late escape (LE) at Week 40, or crossover (CO) at Week 52 were re-randomized to receive sirukumab 50 or 100 mg through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    Sirukumab 50 mg q4w
    Reporting group description
    All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 Weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through Week 104.

    Reporting group title
    Sirukumab 100 mg q2w
    Reporting group description
    All subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w Total
    Number of subjects
    556 557 557 1670
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    466 478 478 1422
        From 65 to 84 years
    90 79 79 248
        85 years and over
    0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    52.9 ± 11.85 52.9 ± 11.8 53 ± 11.31 -
    Title for Gender
    Units: subjects
        Female
    436 447 452 1335
        Male
    120 110 105 335

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo subcutaneously (SC) every 2 weeks (q2w) from Week 0 up to Week 50. Subjects who met early escape (EE) criteria at Week 18, or late escape (LE) at Week 40, or crossover (CO) at Week 52 were re-randomized to receive sirukumab 50 or 100 mg through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    Sirukumab 50 mg q4w
    Reporting group description
    All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 Weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through Week 104.

    Reporting group title
    Sirukumab 100 mg q2w
    Reporting group description
    All subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.
    Reporting group title
    Placebo to 50 mg q4w due to EE/LE/CO
    Reporting group description
    All subjects who were assigned to placebo group and who met EE at Week 18 or LE at Week 40 or CO at Week 52 were re- randomized to receive subcutaneous (SC) sirukumab 50 mg dose regimen q4w up to Week 104.

    Reporting group title
    Sirukumab 50 mg q4w
    Reporting group description
    All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through week 104.

    Reporting group title
    Placebo to 100 mg q2w due to EE/LE/CO
    Reporting group description
    All subjects who were assigned to placebo group and who met EE at Week 18 or LE at Week 40 or CO at Week 52 were re-randomized to receive subcutaneous (SC) sirukumab 100 mg dose regimen q2w up to Week 104.

    Reporting group title
    Sirukumab 100 mg q2w
    Reporting group description
    All subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.
    Reporting group title
    Placebo
    Reporting group description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    Placebo to 50 mg q4w due to EE/LE/CO
    Reporting group description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    Sirukumab 50 mg q4w
    Reporting group description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    Placebo to Sirukumab 100 mg q2w due to EE/LE/CO
    Reporting group description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    Sirukumab 100 mg q2w
    Reporting group description
    Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Primary: Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response at Week 16

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    End point title
    Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response at Week 16
    End point description
    ACR 20 response is defined as greater than or equal to (>=) 20 percent (%) improvement in both tender joint count (TJC, 68 joints) and swollen joint count (SJC, 66 joints) and >= 20% improvement in 3 of following 5 assessments: Subject's assessment of pain using visual analog scale (VAS) (0-10 scale, 0=no pain and 10=worst possible pain), Subject's global assessment of disease activity by using VAS (scale ranges from 0 to 10, [0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS (scale ranges from 0 to 10, [0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by Health Assessment Questionnaire-Disability Index (HAQ-DI) (scale ranges from 0-no difficulty, to 3-inability to perform a task in that area), and Serum C-reactive protein (CRP). Full analysis set included all randomized subjects. Subjects were set to non-responders if meeting TF criteria prior to week 16 or having data missing.
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
        number (not applicable)
    26.4
    54.8
    53.5
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    Placebo v Sirukumab 50 mg q4w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    28.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22.8
         upper limit
    33.8
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    Placebo v Sirukumab 100 mg q2w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    27.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.6
         upper limit
    32.6

    Primary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 52

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    End point title
    Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 52
    End point description
    vdH-S score is sum of joint erosion score and joint space narrowing (JSN) score. Joint erosion assessment is scored according to the surface area involved, from 0 to 5, with 0 indicating no erosion and 5 indicating complete collapse of bone whereas the JSN assessment including subluxation, is scored from 0 (normal) to 4 (bony ankylosis or complete luxation). Total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage. Efficacy FAS for radiographic assessment includes all randomized subjects who received at least 1 (partial or complete) dose of study agent and who had non-missing baseline vdH-S score. Subjects were analyzed according to randomized treatments they were assigned to, regardless of the treatment groups they actually received. This score was based on imputed value by EE Rules (set scores after EE to missing for placebo arm) and then missing data rules in all treatment groups (imputed using linear extrapolation method).
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    550
    553
    551
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    3.69 ± 9.245
    0.50 ± 2.961
    0.46 ± 3.258
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    Placebo v Sirukumab 100 mg q2w
    Number of subjects included in analysis
    1101
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    van der waerden ANOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    Placebo v Sirukumab 50 mg q4w
    Number of subjects included in analysis
    1103
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    van der waerden ANOVA
    Confidence interval

    Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24

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    End point title
    Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24
    End point description
    The HAQ-DI score is an evaluation of the functional status for a subject. The 20- question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty. Full analysis set included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. Last Observation at or prior EE was used to replace the data after EE for subjects who met EE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Units on Scale
        arithmetic mean (standard deviation)
    -0.2179 ± 0.53081
    -0.4262 ± 0.57631
    -0.4610 ± 0.56784
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    Placebo v Sirukumab 50 mg q4w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least Square (LS) mean difference
    Point estimate
    -0.226
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    -0.17
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    Placebo v Sirukumab 100 mg q2w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -0.256
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    -0.2

    Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response at Week 24

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    End point title
    Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response at Week 24
    End point description
    ACR 50 response is defined as >= 50% improvement in both TJC (68 joints) and SJC (66 joints) and >= 50% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS (the scale ranges from 0 to 10, [0 =very well to 10 =very poor]), Physician’s global assessment of disease activity using VAS (the scale ranges from 0 to 10, [0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI (the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area), and Serum CRP. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders if meeting EE or TF criteria prior to week 24 or having data missing.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
        number (not applicable)
    12.4
    30.2
    33.2
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    Placebo v Sirukumab 50 mg q4w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    17.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.1
         upper limit
    22.4
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    Placebo v Sirukumab 100 mg q2w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    20.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.1
         upper limit
    25.6

    Secondary: Percentage of Subjects With Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission at Week 24

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    End point title
    Percentage of Subjects With Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission at Week 24
    End point description
    The DAS28 based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. The Disease Activity Index Score 28 (DAS28) C-reactive protein (CRP) remission is defined as a DAS28 (CRP) value of less than 2.6 at a visit. Full analysis set included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to not achieving DAS28 remission if meeting EE or TF criteria prior to week 24 or having data missing.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
        number (not applicable)
    5.6
    26.0
    25.5
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    Placebo v Sirukumab 50 mg q4w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    20.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.4
         upper limit
    24.6
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    Placebo v Sirukumab 100 mg q2w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    19.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    15.8
         upper limit
    24

    Secondary: Percentage of Subjects With Major Clinical Response (MCR) at Week 52

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    End point title
    Percentage of Subjects With Major Clinical Response (MCR) at Week 52
    End point description
    MCR was defined as subject achieving ACR 70 response for 6 continuous months (24 weeks) in study period (i.e., through Week 52). An ACR 70 response is defined as >= 70% improvement in both TJC (68 joints) and SJC (66 joints) and >= 70% improvement in 3 of following 5 assessments Subject’s assessment of pain using VAS, Subject’s global assessment of disease activity by using VAS, Physician’s global assessment of disease activity using VAS, Subject’s assessment of physical function as measured by HAQ-DI and Serum CRP. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders if meeting EE, LE or TF criteria prior to week 52 or having data missing.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
        number (not applicable)
    1.8
    5.4
    9.0
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    Placebo v Sirukumab 50 mg q4w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.4
         upper limit
    508
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    Placebo v Sirukumab 100 mg q2w
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    7.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.6
         upper limit
    9.8

    Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response Through Week 52

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    End point title
    Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response Through Week 52
    End point description
    ACR 20 response is defined as >=20% improvement in both TJC(68 joints) and SJC(66 joints) and >=20% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS 0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS(scale ranges from 0 to 10, [0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS (scale ranges from 0 to 10, [0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI (scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area), and Serum CRP. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 18, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    7.4
    18.3
    15.4
        Week 4
    14.2
    36.3
    33.8
        Week 6
    20.3
    45.8
    46.9
        Week 8
    25.9
    47.2
    51.3
        Week 12
    27.3
    53.1
    53.3
        Week 18
    29.3
    54.4
    56.9
        Week 20
    29.5
    53.7
    52.8
        Week 24
    27.0
    53.7
    56.0
        Week 28
    31.5
    53.1
    57.3
        Week 32
    29.5
    53.3
    56.7
        Week 36
    28.4
    54.0
    58.2
        Week 40
    28.8
    53.3
    53.3
        Week 44
    27.7
    49.2
    54.0
        Week 48
    26.8
    50.1
    54.8
        Week 52
    26.6
    49.9
    54.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response

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    End point title
    Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response
    End point description
    ACR 50 response is defined as >=50% improvement in both TJC(68 joints) and SJC(66 joints) and >=50% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS(0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS(scale ranges from 0 to 10,[0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS (scale ranges from 0 to 10, [0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI(scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and Serum CRP. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    1.1
    3.2
    2.0
        Week 4
    2.5
    9.2
    9.9
        Week 6
    4.1
    15.6
    14.0
        Week 8
    7.7
    20.3
    18.9
        Week 12
    10.1
    24.6
    28.0
        Week 16
    10.8
    30.0
    26.2
        Week 18
    11.7
    31.2
    31.2
        Week 20
    13.5
    32.7
    33.4
        Week 28
    15.1
    31.6
    33.0
        Week 32
    14.0
    33.6
    35.0
        Week 36
    12.2
    33.4
    34.5
        Week 40
    13.3
    31.1
    33.4
        Week 44
    14.2
    31.4
    33.9
        Week 48
    14.4
    32.9
    34.8
        Week 52
    13.8
    30.3
    35.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 70 Response Through Week 52

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    End point title
    Percentage of Subjects With an American College of Rheumatology (ACR) 70 Response Through Week 52
    End point description
    ACR 70 response is defined as >=70% improvement in both TJC(68 joints) and SJC(66 joints) and >=70% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS(0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS (scale ranges from 0 to 10,[0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS (scale ranges from 0 to 10,[0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI(scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and Serum CRP. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    0.4
    0.7
    0.4
        Week 4
    0.5
    2.0
    3.1
        Week 6
    1.6
    4.7
    4.5
        Week 8
    1.6
    7.2
    7.2
        Week 12
    3.1
    10.4
    10.6
        Week 16
    4.0
    13.5
    13.5
        Week 18
    4.3
    12.6
    14.7
        Week 20
    4.0
    13.1
    16.0
        Week 24
    3.4
    14.9
    16.3
        Week 28
    5.2
    16.0
    16.5
        Week 32
    4.7
    17.4
    17.2
        Week 36
    4.7
    15.8
    16.2
        Week 40
    5.0
    16.9
    17.6
        Week 44
    5.2
    16.3
    17.1
        Week 48
    6.8
    18.5
    17.8
        Week 52
    5.4
    16.5
    18.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 90 Response Through Week 52

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    End point title
    Percentage of Subjects With an American College of Rheumatology (ACR) 90 Response Through Week 52
    End point description
    ACR 90 response is defined as >=90% improvement in both TJC(68 joints) and SJC(66 joints) and >=90% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS(0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS(scale ranges from 0 to 10, [0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS(scale ranges from 0 to 10,[0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI (scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and Serum CRP. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    0
    0
    0
        Week 4
    0
    0.2
    0.2
        Week 6
    0.2
    0.2
    0.2
        Week 8
    0.2
    1.1
    0.5
        Week 12
    0.5
    2.2
    1.8
        Week 16
    0.9
    2.5
    2.9
        Week 18
    1.1
    2.5
    2.5
        Week 20
    0.5
    3.6
    4.1
        Week 24
    0.5
    3.4
    5.2
        Week 28
    0.4
    4.5
    4.7
        Week 32
    1.1
    4.1
    5.7
        Week 36
    0.9
    4.8
    5.4
        Week 40
    0.7
    5.4
    6.1
        Week 44
    0.5
    5.0
    6.6
        Week 48
    0.7
    4.7
    6.3
        Week 52
    1.3
    4.5
    5.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Response Through Week 52

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    End point title
    Percentage of Subjects With Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Response Through Week 52
    End point description
    DAS28 based on CRP is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The values are 0=best to 10=worst. Good responders: improvement from baseline greater than (>) 1.2 with DAS28 less than or equal to (<=) 3.2; moderate responders: improvement from baseline >1.2 with DAS28 >3.2 to <=5.1 or improvement from baseline >0.6 to <=1.2 with DAS28 <=5.1; non-responders: improvement from baseline <=0.6 or improvement from baseline >0.6 and <=1.2 with DAS28 >5.1. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    18.5
    72.0
    72.4
        Week 4
    28.1
    80.1
    78.3
        Week 6
    36.7
    82.4
    80.3
        Week 8
    38.5
    81.7
    81.3
        Week 12
    43.7
    83.3
    81.3
        Week 16
    42.6
    80.4
    79.5
        Week 18
    41.5
    79.7
    79.4
        Week 20
    41.5
    73.8
    72.5
        Week 24
    37.9
    71.5
    72.2
        Week 28
    41.2
    69.7
    72.2
        Week 32
    41.4
    68.2
    70.6
        Week 36
    39.7
    67.7
    69.8
        Week 40
    39.2
    66.8
    67.9
        Week 44
    37.6
    63.2
    64.6
        Week 48
    36.7
    61.9
    64.6
        Week 52
    35.6
    62.5
    64.3
    No statistical analyses for this end point

    Secondary: Change From Baseline in Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Through Week 52

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    End point title
    Change From Baseline in Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Through Week 52
    End point description
    DAS28 based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The values are 0=best to 10=worst. A negative change from baseline in DAS28 (CRP) (that is, a decrease from baseline) indicates improvement from baseline. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Change at Week 2
    -0.319 ± 0.7677
    -1.316 ± 0.7776
    -1.284 ± 0.7605
        Change at Week 4
    -0.515 ± 0.9287
    -1.638 ± 0.9759
    -1.627 ± 0.9529
        Change at Week 6
    -0.707 ± 1.0599
    -1.886 ± 1.0622
    -1.888 ± 1.0340
        Change at Week 8
    -0.754 ± 1.1013
    -2.016 ± 1.1183
    -2.031 ± 1.1138
        Change at Week 12
    -0.881 ± 1.1727
    -2.187 ± 1.1995
    -2.185 ± 1.1950
        Change at Week 16
    -0.908 ± 1.2834
    -2.264 ± 1.2443
    -2.282 ± 1.2283
        Change at Week 18
    -0.895 ± 1.2986
    -2.286 ± 1.2690
    -2.335 ± 1.2314
        Change at Week 20
    -0.920 ± 1.2973
    -2.367 ± 1.3368
    -2.380 ± 1.3158
        Change at Week 24
    -0.912 ± 1.3180
    -2.356 ± 1.3599
    -2.402 ± 1.3048
        Change at Week 28
    -0.979 ± 1.3752
    -2.417 ± 1.4068
    -2.440 ± 1.3245
        Change at Week 32
    -1.010 ± 1.3904
    -2.451 ± 1.4141
    -2.479 ± 1.3304
        Change at Week 36
    -1.019 ± 1.4020
    -2.461 ± 1.3951
    -2.497 ± 1.3231
        Change at Week 40
    -0.985 ± 1.4054
    -2.462 ± 1.4180
    -2.459 ± 1.3901
        Change at Week 44
    -0.994 ± 1.4117
    -2.442 ± 1.4364
    -2.477 ± 1.4381
        Change at Week 48
    -1.026 ± 1.4755
    -2.482 ± 1.4630
    -2.488 ± 1.3783
        Change at Week 52
    -0.992 ± 1.4431
    -2.491 ± 1.4305
    -2.476 ± 1.4109
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission Through Week 52

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    End point title
    Percentage of Subjects with Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission Through Week 52
    End point description
    DAS28 based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. DAS28 (CRP) remission is defined as a DAS28 (CRP) value of less than 2.6 at a visit. Full analysis set included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to not achieving DAS28 remission after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    0.5
    2.5
    2.7
        Week 4
    1.6
    7.9
    9.3
        Week 6
    3.1
    10.2
    12.6
        Week 8
    3.2
    13.6
    17.8
        Week 12
    4.3
    18.3
    19.6
        Week 16
    5.8
    21.2
    21.9
        Week 18
    6.1
    22.8
    23.7
        Week 20
    5.8
    26.4
    25.5
        Week 24
    5.6
    26.0
    25.5
        Week 28
    7.7
    27.5
    27.1
        Week 32
    7.7
    29.6
    28.4
        Week 36
    8.5
    29.1
    28.0
        Week 40
    7.2
    27.8
    27.3
        Week 44
    8.5
    28.2
    27.5
        Week 48
    9.0
    29.6
    30.2
        Week 52
    8.8
    30.0
    29.1
    No statistical analyses for this end point

    Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI) Score Through Week 52

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    End point title
    Change From Baseline in Simplified Disease Activity Index (SDAI) Score Through Week 52
    End point description
    SDAI score is a derived score combining tender joints (28 joints), swollen joints (28 joints), patient's global assessment of disease activity, physician's global assessments of disease activity, and CRP. The total score range is from 0 to 86 with a lower score indicating less disease activity. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Change at Week 2
    -4.5129 ± 9.68032
    -9.1095 ± 9.64598
    -7.9649 ± 9.58765
        Change at Week 4
    -7.3134 ± 11.87959
    -13.3976 ± 12.00410
    -12.2156 ± 11.65262
        Change at Week 6
    -9.5833 ± 13.15531
    -16.1013 ± 12.80166
    -15.4404 ± 12.18642
        Change at Week 8
    -10.0752 ± 13.54599
    -17.6624 ± 12.98109
    -17.1302 ± 12.92830
        Change at Week 12
    -11.5975 ± 14.53181
    -19.6639 ± 13.67016
    -19.0635 ± 13.63444
        Change at Week 16
    -11.3507 ± 15.72864
    -20.3221 ± 14.14177
    -20.0652 ± 13.85171
        Change at Week 18
    -10.6805 ± 16.31549
    -20.1215 ± 14.75683
    -20.4858 ± 13.72370
        Change at Week 20
    -11.0425 ± 16.42770
    -20.8300 ± 15.31245
    -20.8508 ± 14.44400
        Change at Week 24
    -11.1443 ± 16.37909
    -20.7459 ± 15.48312
    -21.0858 ± 14.57962
        Change at Week 28
    -11.7828 ± 17.04652
    -21.3535 ± 15.98762
    -21.5524 ± 14.69362
        Change at Week 32
    -12.0835 ± 17.11297
    -21.8176 ± 16.15549
    -21.8530 ± 14.58393
        Change at Week 36
    -12.2107 ± 17.24703
    -21.9077 ± 15.95251
    -22.1040 ± 14.54871
        Change at Week 40
    -11.9185 ± 17.32206
    -21.7862 ± 16.12260
    -21.6692 ± 15.33635
        Change at Week 44
    -11.8730 ± 17.41934
    -21.4843 ± 16.33985
    -21.5514 ± 15.78476
        Change at Week 48
    -11.9055 ± 17.91398
    -21.7238 ± 16.45520
    -21.7991 ± 15.34514
        Change at Week 52
    -11.7647 ± 17.61074
    -21.9130 ± 16.32611
    -21.7344 ± 15.64620
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) Score Through Week 52

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    End point title
    Change From Baseline in Clinical Disease Activity Index (CDAI) Score Through Week 52
    End point description
    CDAI score is a derived score of 4 components: tender joints (28 joints), swollen joints (28 joints), patient's global assessment of disease activity, and physician's global assessments of disease activity. Total score ranges from 0 to 76 with a lower score indicating less disease activity. A negative change in CDAI score indicates an improvement in disease activity and a positive change in score indicates a worsening of disease activity. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Change at Week 2
    -4.38 ± 9.210
    -6.82 ± 9.350
    -5.65 ± 9.014
        Change at Week 4
    -7.09 ± 11.241
    -11.13 ± 11.699
    -9.88 ± 11.166
        Change at Week 6
    -9.24 ± 12.407
    -13.79 ± 12.416
    -13.10 ± 11.599
        Change at Week 8
    -9.72 ± 12.714
    -15.37 ± 12.593
    -14.79 ± 12.438
        Change at Week 12
    -11.19 ± 13.625
    -17.36 ± 13.223
    -16.74 ± 13.098
        Change at Week 16
    -10.86 ± 14.716
    -18.04 ± 13.651
    -17.75 ± 13.261
        Change at Week 18
    -10.24 ± 15.245
    -17.82 ± 14.291
    -18.17 ± 13.204
        Change at Week 20
    -10.57 ± 15.338
    -18.53 ± 14.809
    -18.57 ± 13.910
        Change at Week 24
    -10.68 ± 15.302
    -18.45 ± 14.936
    -18.80 ± 14.075
        Change at Week 28
    -11.27 ± 15.926
    -19.06 ± 15.395
    -19.27 ± 14.168
        Change at Week 32
    -11.55 ± 15.950
    -19.57 ± 15.549
    -19.56 ± 14.095
        Change at Week 36
    -11.70 ± 16.099
    -19.66 ± 15.455
    -19.80 ± 14.084
        Change at Week 40
    -11.46 ± 16.236
    -19.54 ± 15.640
    -19.3 ± 14.833
        Change at Week 44
    -11.41 ± 16.126
    -19.24 ± 15.888
    -19.26 ± 15.264
        Change at Week 48
    -11.47 ± 16.594
    -19.47 ± 15.951
    -19.50 ± 14.871
        Change at Week 52
    -11.38 ± 16.348
    -19.67 ± 15.834
    -19.44 ± 15.115
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Simplified Disease Activity Index based (SDAI-based) American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

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    End point title
    Percentage of Subjects With Simplified Disease Activity Index based (SDAI-based) American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52
    End point description
    SDAI-based ACR/EULAR remission in subject at visit if SDAI score of <= 3.3. SDAI score is derived by combining 5 disease assessments: tender joint (28 joints), swollen joint (28 joints) counts, PGA of disease activity by using VAS (scale ranges from 0 to 10 [0 = very well to 10 = very poor]), PhGA of disease activity using VAS (scale ranges from 0 to 10 [0=no arthritis to 10=extremely active arthritis]) and CRP. Change from baseline measures change in disease activity, negative change shows improvement and positive change shows worsening. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to not achieving SDAI-based remission after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    0.2
    0
    0
        Week 4
    0.4
    0.2
    1.3
        Week 6
    0.4
    1.6
    2.3
        Week 8
    0.7
    2.9
    2.9
        Week 12
    1.6
    4.8
    5.2
        Week 16
    2.2
    5.4
    6.6
        Week 18
    1.6
    6.3
    6.8
        Week 20
    1.6
    7.5
    7.7
        Week 24
    2.3
    8.1
    9.5
        Week 28
    2.3
    9.0
    8.4
        Week 32
    2.9
    9.7
    10.2
        Week 36
    1.8
    10.1
    10.6
        Week 40
    2.5
    11.5
    11.5
        Week 44
    2.5
    9.7
    11.7
        Week 48
    3.8
    11.3
    10.4
        Week 52
    3.2
    11.5
    10.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Boolean-based American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

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    End point title
    Percentage of Subjects With Boolean-based American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52
    End point description
    A subject was considered as having achieved the Boolean-based American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) remission at a visit if all of the following 4 criteria were met at that visit: Tender joint count (68 joints) less than or equal to (<=) 1; Swollen joint count (66 joints) <=1; CRP <=1 milligram per deciliter (mg/dL); Patient’s Global Assessment of Disease Activity <=1 on a 0 (very well) to 10 (very poor) VAS. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to not achieving Boolean-based remission after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    0.2
    0.4
    0
        Week 4
    0.2
    0.4
    0.7
        Week 6
    0
    0.9
    0.9
        Week 8
    0.2
    1.3
    1.8
        Week 12
    1.3
    2.9
    3.1
        Week 16
    1.6
    3.2
    4.7
        Week 18
    0.7
    3.6
    4.7
        Week 20
    1.3
    4.3
    5.6
        Week 24
    0.9
    4.3
    7.0
        Week 28
    1.1
    5.2
    6.1
        Week 32
    2.3
    5.0
    6.5
        Week 36
    1.3
    7.0
    7.9
        Week 40
    0.9
    5.9
    7.9
        Week 44
    1.4
    5.7
    7.9
        Week 48
    1.8
    7.0
    7.0
        Week 52
    2.2
    7.0
    5.7
    No statistical analyses for this end point

    Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Through Week 52

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    End point title
    Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Through Week 52
    End point description
    The HAQ-DI score is an evaluation of the functional status for a subject. The 20- question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty. Full analysis set included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. LOCF method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Change at Week 2
    -0.075 ± 0.3809
    -0.139 ± 0.3744
    -0.128 ± 0.3939
        Change at Week 4
    -0.130 ± 0.4444
    -0.244 ± 0.4498
    -0.254 ± 0.4184
        Change at Week 6
    -0.170 ± 0.4657
    -0.318 ± 0.4989
    -0.360 ± 0.4910
        Change at Week 8
    -0.172 ± 0.4824
    -0.362 ± 0.5163
    -0.388 ± 0.5163
        Change at Week 12
    -0.191 ± 0.5055
    -0.387 ± 0.5512
    -0.399 ± 0.5364
        Change at Week 16
    -0.201 ± 0.5439
    -0.409 ± 0.5736
    -0.433 ± 0.5489
        Change at Week 18
    -0.217 ± 0.5266
    -0.431 ± 0.5744
    -0.464 ± 0.5496
        Change at Week 20
    -0.209 ± 0.5275
    -0.429 ± 0.6074
    -0.474 ± 0.5797
        Change at Week 28
    -0.232 ± 0.5515
    -0.438 ± 0.5837
    -0.471 ± 0.5763
        Change at Week 32
    -0.225 ± 0.5462
    -0.441 ± 0.6017
    -0.483 ± 0.5886
        Change at Week 36
    -0.226 ± 0.5585
    -0.444 ± 0.5961
    -0.461 ± 0.5810
        Change at Week 40
    -0.230 ± 0.5586
    -0.447 ± 0.5900
    -0.431 ± 0.5921
        Change at Week 44
    -0.228 ± 0.5601
    -0.442 ± 0.6182
    -0.456 ± 0.5956
        Change at Week 48
    -0.227 ± 0.5727
    -0.447 ± 0.6207
    -0.481 ± 0.6043
        Change at Week 52
    -0.225 ± 0.5693
    -0.453 ± 0.6127
    -0.470 ± 0.5959
    No statistical analyses for this end point

    Secondary: Area Under the Curve (AUC) of Change from Baseline in HAQ-DI Score From Week 0 Through Week 24 and From Week 0 Through Week 52

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    End point title
    Area Under the Curve (AUC) of Change from Baseline in HAQ-DI Score From Week 0 Through Week 24 and From Week 0 Through Week 52
    End point description
    AUC of change from baseline in HAQ-DI score is AUC of change from baseline in HAQ-DI score versus the time. AUC was calculated based on measurement at scheduled visits using trapezoidal rule. Functional status was determined as cumulative measure of HAQ-DI over 1 year by using AUC of change from baseline in HAQ-DI score through week 52. Decreases in AUC of change from baseline in HAQ-DI indicate a greater average improvement in physical function over time. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. LOCF method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Week 0 Through Week 24 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Units on a Scale*Day
    arithmetic mean (standard deviation)
        Week 0 Through Week 24
    -28.85 ± 69.783
    -57.99 ± 76.384
    -61.71 ± 75.189
        Week 0 Through Week 52
    -73.55 ± 170.636
    -145.30 ± 184.630
    -153.03 ± 180.633
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Through Week 52

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    End point title
    Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Through Week 52
    End point description
    HAQ-DI response was defined as change of less than -0.22 from baseline in HAQ-DI score. HAQ-DI score is a 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. LOCF method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    34.4
    40.6
    37.0
        Week 4
    38.1
    49.2
    52.2
        Week 6
    42.4
    56.2
    58.0
        Week 8
    44.1
    56.2
    61.0
        Week 12
    44.6
    60.1
    60.9
        Week 16
    45.5
    60.9
    61.9
        Week 18
    45.9
    62.7
    65.4
        Week 20
    46.2
    61.4
    65.4
        Week 24
    46.9
    63.0
    65.4
        Week 28
    47.8
    64.8
    63.4
        Week 32
    46.9
    62.8
    63.7
        Week 36
    47.3
    63.9
    63.7
        Week 40
    47.3
    63.7
    61.8
        Week 44
    47.3
    62.1
    63.2
        Week 48
    47.3
    61.8
    64.6
        Week 52
    47.1
    63.4
    64.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Score of Less Than or Equal to 0.5

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    End point title
    Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Score of Less Than or Equal to 0.5
    End point description
    HAQ-DI score is an evaluation of the functional status for a subject. The 20- question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. LOCF method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 2
    7.9
    12.2
    11.5
        Week 4
    9.9
    15.6
    16.3
        Week 6
    9.5
    18.3
    21.2
        Week 8
    10.6
    21.7
    21.0
        Week 12
    12.2
    22.8
    23.3
        Week 16
    13.3
    24.6
    26.8
        Week 18
    13.7
    24.6
    25.9
        Week 20
    13.1
    26.0
    27.5
        Week 24
    13.1
    25.9
    27.5
        Week 28
    13.8
    26.2
    28.7
        Week 32
    13.7
    26.0
    28.7
        Week 36
    13.7
    27.5
    27.5
        Week 40
    13.7
    27.3
    26.2
        Week 44
    13.1
    27.8
    27.6
        Week 48
    13.8
    28.2
    30.0
        Week 52
    12.4
    27.5
    29.3
    No statistical analyses for this end point

    Secondary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 24

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    End point title
    Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 24
    End point description
    vdH-S score is sum of joint erosion score and joint space narrowing (JSN) score. Joint erosion assessment is scored according to the surface area involved, from 0 to 5, with 0 indicating no erosion and 5 indicating complete collapse of bone whereas the JSN assessment including subluxation, is scored from 0 (normal) to 4 (bony ankylosis or complete luxation). Total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage. Efficacy FAS for radiographic assessment includes all randomized subjects who received at least 1 (partial or complete) dose of study agent and who had non-missing baseline vdH-S score. Subjects were analyzed according to randomized treatments they were assigned to, regardless of the treatment groups they actually received. This score was based on imputed value by EE Rules (set scores after EE to missing for placebo arm) and then missing data rules (imputed using linear extrapolation method).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    550
    553
    551
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    1.96 ± 5.390
    0.35 ± 2.149
    0.30 ± 2.165
    No statistical analyses for this end point

    Secondary: Change From Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Type of Damage (erosion or JSN) at Week 24 and 52

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    End point title
    Change From Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Type of Damage (erosion or JSN) at Week 24 and 52
    End point description
    vdH-S score measures structural damage progression as sum of JE and JSN scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints,scored as per surface area-from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32*5) and MAX JES for F-120 (12*10 [5*2 sides of foot]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30*4), and MAX JSS for F-48(12*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS of 448.Efficacy FAS population for radiographic assessments included here. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Imputed value based on EE Rules (set scores after EE to missing for placebo arm) and then missing data rules in all treatment groups (using linear extrapolation method).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    550
    553
    551
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Erosion Score: Change at Week 24
    1.21 ± 3.348
    0.10 ± 1.306
    0.08 ± 1.321
        JSN Score: Change at Week 24
    0.76 ± 2.540
    0.24 ± 1.404
    0.21 ± 1.537
        Erosion Score: Change at Week 52
    2.23 ± 5.903
    0.12 ± 1.809
    0.08 ± 2.005
        JSN Score: Change at Week 52
    1.46 ± 4.311
    0.38 ± 1.839
    0.38 ± 2.184
    No statistical analyses for this end point

    Secondary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Region Hand or Feet and Type Erosion or JSN at Week 24 and 52

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    End point title
    Change from Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Region Hand or Feet and Type Erosion or JSN at Week 24 and 52
    End point description
    vdH-S score measures structural damage progression as sum of JE and JSN scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints,scored as per surface area-from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32*5) and MAX JES for F-120 (12*10 [5*2 sides of foot]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30*4), and MAX JSS for F-48(12*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS of 448.Efficacy FAS population for radiographic assessments included here. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Imputed value based on EE Rules (set scores after EE to missing for placebo arm) and then missing data rules in all treatment groups (using linear extrapolation method).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    550
    553
    551
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Change in Hand Erosion Score at Week 24
    0.74 ± 2.406
    0.07 ± 0.920
    0.03 ± 0.966
        Change in Hand JSN Score at Week 24
    0.51 ± 1.818
    0.16 ± 1.025
    0.16 ± 1.021
        Change in Foot Erosion Score at Week 24
    0.46 ± 1.459
    0.03 ± 0.682
    0.05 ± 0.754
        Change in Foot JSN Score at Week 24
    0.25 ± 1.207
    0.09 ± 0.722
    0.06 ± 1.152
        Change in Hand Erosion Score at Week 52
    1.43 ± 4.378
    0.09 ± 1.296
    0.03 ± 1.312
        Change in Hand JSN Score at Week 52
    0.98 ± 3.196
    0.25 ± 1.378
    0.28 ± 1.808
        Change in Foot Erosion Score at Week 52
    0.80 ± 2.460
    0.03 ± 0.955
    0.06 ± 1.302
        Change in Foot JSN Score at Week 52
    0.48 ± 2.013
    0.13 ± 0.929
    0.10 ± 1.171
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) Greater Than Smallest Detectable Change (SDC) at Weeks 24 and 52

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    End point title
    Percentage of Subjects With Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) Greater Than Smallest Detectable Change (SDC) at Weeks 24 and 52
    End point description
    vdH-S score measures structural damage progression as sum of JE and JSNS.JE is summary of erosion(E) severity in 32 of hand(H) and 12 of feet(F) joints, scored as per the surface area- 0(no E) to 5(complete(CM) collapse of bone); JSN-summary of severity of 30 of H12 of F joints, scored as per sub-luxation(L) from 0(normal) to 4(bony ankylosis or CML). SDC is smallest change in S to be assessed correctly as per limits of agreement. SDC for change from baseline in vdH-SS is determined as:SDC=1.96*SD/(root 2*root k), here SD=standard deviation of difference between 2 readers; k= number of readers. Efficacy FAS population for radiographic assessments included here. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. This score was based on imputed value by EE Rules (set scores after EE to missing for placebo arm) and then missing data rules in all treatment groups (imputed using linear extrapolation method).
    End point type
    Secondary
    End point timeframe
    Weeks 24 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    550
    553
    551
    Units: Percentage of Subjects
    number (not applicable)
        Week 24
    25.3
    8.3
    7.6
        Week 52
    35.5
    12.1
    12.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With a Change of Less Than or Equal to 0 From Baseline in van der Heijde Modified Sharp (vdH-S) Score at Weeks 24 and 52

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    End point title
    Percentage of Subjects With a Change of Less Than or Equal to 0 From Baseline in van der Heijde Modified Sharp (vdH-S) Score at Weeks 24 and 52
    End point description
    vdH-S score measures structural damage progression as sum of JE and JSN scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints,scored as per surface area-from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32*5) and MAX JES for F-120 (12*10 [5*2 sides of foot]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30*4), and MAX JSS for F-48(12*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS of 448.Efficacy FAS population for radiographic assessments included here. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Imputed value based on EE Rules (set scores after EE to missing for placebo arm) and then missing data rules in all treatment groups (using linear extrapolation method).
    End point type
    Secondary
    End point timeframe
    Week 24 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    550
    553
    551
    Units: Percentage of Subjects
    number (not applicable)
        Week 24
    48.4
    65.8
    68.8
        Week 52
    45.5
    59.0
    62.4
    No statistical analyses for this end point

    Secondary: Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) by Reader at Weeks 24 and 52

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    End point title
    Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) by Reader at Weeks 24 and 52
    End point description
    vdH-S score measures structural damage progression as sum of JE and JSN scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints,scored as per surface area-from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32*5) and MAX JES for F-120 (12*10 [5*2 sides of foot]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30*4), and MAX JSS for F-48(12*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS of 448.Efficacy FAS population for radiographic assessments included here. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Imputed value based on EE Rules (set scores after EE to missing for placebo arm) then missing data rules in all treatment groups (using linear extrapolation method).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    550
    553
    551
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Reader 1 at Week 24 (n= 550, 551, 550)
    2.06 ± 5.616
    0.21 ± 2.495
    0.20 ± 2.773
        Reader 2 at Week 24 (n= 550, 553, 551)
    1.65 ± 5.053
    0.38 ± 1.969
    0.33 ± 1.830
        Reader 1 at Week 52 (n= 447, 459, 467)
    2.99 ± 7.940
    0.54 ± 3.285
    0.29 ± 3.325
        Reader 2 at Week 52 (n= 447, 460, 467)
    2.65 ± 7.331
    0.54 ± 2.660
    0.35 ± 2.184
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum C-reactive protein (CRP) Levels Through Week 52

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    End point title
    Change From Baseline in Serum C-reactive protein (CRP) Levels Through Week 52
    End point description
    Serum CRP is a marker of systemic inflammation. A negative change from baseline in CRP represents improvement. FAS included all randomized subjects. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Milligram per Deciliter
    arithmetic mean (standard deviation)
        Baseline
    2.5148 ± 3.38577
    2.4145 ± 2.62179
    2.3952 ± 2.64241
        Change at Week 2
    -0.1339 ± 2.86946
    -2.2867 ± 2.44604
    -2.3198 ± 2.64772
        Change at Week 4
    -0.2209 ± 2.94279
    -2.2707 ± 2.41525
    -2.3406 ± 2.64584
        Change at Week 6
    -0.3432 ± 2.96865
    -2.3124 ± 2.44604
    -2.3451 ± 2.64678
        Change at Week 8
    -0.3561 ± 3.05281
    -2.2919 ± 2.41368
    -2.3392 ± 2.65864
        Change at Week 12
    -0.4099 ± 3.22085
    -2.3038 ± 2.43828
    -2.3274 ± 2.67383
        Change at Week 16
    -0.4890 ± 3.17554
    -2.2841 ± 2.43707
    -2.3166 ± 2.65115
        Change at Week 18
    -0.4375 ± 3.48359
    -2.3030 ± 2.45255
    -2.3114 ± 2.65919
        Change at Week 20
    -0.4682 ± 3.21483
    -2.2973 ± 2.44855
    -2.2798 ± 2.74939
        Change at Week 24
    -0.4610 ± 3.31445
    -2.2974 ± 2.45343
    -2.2891 ± 2.73480
        Change at Week 28
    -0.5108 ± 3.34288
    -2.2937 ± 2.45419
    -2.2820 ± 2.73435
        Change at Week 32
    -0.5332 ± 3.39542
    -2.2474 ± 2.63824
    -2.2907 ± 2.73375
        Change at Week 36
    -0.5128 ± 3.36374
    -2.2515 ± 2.62647
    -2.3085 ± 2.73396
        Change at Week 40
    -0.4623 ± 3.46179
    -2.2429 ± 2.64450
    -2.3032 ± 2.73402
        Change at Week 44
    -0.4631 ± 4.00446
    -2.2398 ± 2.65898
    -2.2895 ± 2.75035
        Change at Week 48
    -0.4372 ± 4.15311
    -2.2561 ± 2.62491
    -2.2944 ± 2.75776
        Change at Week 52
    -0.3854 ± 3.96633
    -2.2399 ± 2.64267
    -2.2976 ± 2.73878
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Duration of Morning Stiffness Through Week 52

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    End point title
    Change From Baseline in the Duration of Morning Stiffness Through Week 52
    End point description
    Duration of morning stiffness was defined as the time elapsed when subject woke up in the morning and was able to resume normal activities without stiffness in minutes (If none was present = 0; If morning stiffness was continuing at the time of assessment or was unusual compared to the recent past, average of duration of stiffness over the past 3 days was reported; If stiffness persisted the entire day, 1440 minutes was recorded). Negative values for this outcome measure represent improvement, i.e. shortening of duration of morning stiffness. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of treatment they actually received. Here 'N'(number of subject analyzed) signifies subject who were evaluable for this outcome measure. LOCF method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    552
    552
    555
    Units: Minutes
    arithmetic mean (standard deviation)
        Change at Week 2
    -22.5 ± 184.96
    -35.2 ± 212.94
    -24.0 ± 177.41
        Change at Week 4
    -27.2 ± 202.02
    -61.6 ± 213.09
    -45.1 ± 181.13
        Change at Week 6
    -35.3 ± 190.54
    -81.0 ± 207.07
    -70.3 ± 206.41
        Change at Week 8
    -41.7 ± 171.05
    -84.1 ± 232.34
    -79.6 ± 213.42
        Change at Week 12
    -53.2 ± 179.24
    -88.1 ± 220.03
    -89.4 ± 217.48
        Change at Week 16
    -52.2 ± 173.24
    -82.2 ± 241.75
    -84.1 ± 224.72
        Change at Week 18
    -60.2 ± 191.68
    -84.6 ± 239.43
    -88.5 ± 223.95
        Change at Week 20
    -62.0 ± 193.64
    -93.5 ± 234.10
    -90.0 ± 229.08
        Change at Week 24
    -63.7 ± 195.58
    -96.7 ± 228.31
    -95.5 ± 234.19
        Change at Week 28
    -68.3 ± 195.42
    -95.2 ± 230.36
    -98.0 ± 235.03
        Change at Week 32
    -68.9 ± 196.31
    -96.5 ± 230.46
    -96.5 ± 231.25
        Change at Week 36
    -68.8 ± 196.90
    -96.5 ± 228.71
    -95.2 ± 226.37
        Change at Week 40
    -68.7 ± 68.7
    -95.7 ± 243.78
    -95.9 ± 233.28
        Change at Week 44
    -69.9 ± 197.38
    -96.6 ± 232.42
    -97.0 ± 234.63
        Change at Week 48
    -69.6 ± 195.50
    -97.8 ± 238.36
    -97.0 ± 230.66
        Change at Week 52
    -67.3 ± 196.98
    -99.1 ± 233.82
    -97.7 ± 231.53
    No statistical analyses for this end point

    Secondary: Change From Baseline in Physical and Mental Component Summary (MCS) Scores of 36-Item Short Form Health Survey (SF-36) at Weeks 24 and 52

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    End point title
    Change From Baseline in Physical and Mental Component Summary (MCS) Scores of 36-Item Short Form Health Survey (SF-36) at Weeks 24 and 52
    End point description
    SF-36(36 questions),consists of 8 multi-item scales:Limitations(LIM) in physical (PHY) functioning due to health (HEL) problems;LIM in usual role activities due to PHY HEL problems;Bodily pain;General mental HEL(psychological distress/well-being);LIM in usual role activities due to personal/emotional problems;LIM in social functioning due to PHY/mental HEL problems;Vitality;General HEL perception.All 8 scales scored from 0- 100(higher scores(S)=better HEL) Based on scale S,summary S,physical component score (PCS)/MCS will be derived.Scoring is based on algorithm provided by developer.Summary MCS/PCS score is also scaled from 0-100(higher S indicating better HEL).FAS included all randomized subjects.Subjects analyzed according to randomized treatment groups they were assigned to,regardless of treatments they actually received.LOCF method was used to impute missing values.The last observation at/prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        PCS :Change at Week 24
    2.290 ± 6.2790
    5.358 ± 7.3312
    5.850 ± 7.0677
        PCS :Change at Week 52
    2.423 ± 6.8069
    5.661 ± 7.7405
    6.162 ± 7.2277
        MCS :Change at Week 24
    2.892 ± 9.1766
    4.898 ± 9.6508
    4.216 ± 9.4819
        MCS :Change at Week 52
    2.690 ± 9.5698
    5.351 ± 9.6397
    4.767 ± 9.7991
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Greater Than or Equal to 4-Point Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 8, 16, 24, 36 and 52

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    End point title
    Percentage of Subjects With Greater Than or Equal to 4-Point Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 8, 16, 24, 36 and 52
    End point description
    Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) is a questionnaire that assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. The questionnaire consists of 13 questions that assess a subject’s level of fatigue and tiredness over the last 7 days. Each question is graded on a 5-point scale (0 - 4); and accordingly, the total FACIT Fatigue scores can range from 0 to 52, with lower score reflecting more fatigue and higher scores reflecting less fatigue. FAS was defined as all randomized subjects. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Week 8, 16, 24, 36 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Percentage of Subjects
    number (not applicable)
        Week 8
    41.0
    55.8
    54.9
        Week 16
    42.4
    58.0
    58.9
        Week 24
    43.9
    61.4
    59.4
        Week 36
    39.7
    57.8
    56.2
        Week 52
    41.0
    59.1
    60.5
    No statistical analyses for this end point

    Secondary: Change from Baseline in Total Scores of Work Limitations Questionnaire (WLQ) Week 8, 16, 24, 36 and 52

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    End point title
    Change from Baseline in Total Scores of Work Limitations Questionnaire (WLQ) Week 8, 16, 24, 36 and 52
    End point description
    The Work Limitations Questionnaire (WLQ) was used to measure the impairment in work-related productivity, with reference to the previous two weeks. Each work-related question is scored from 0 to 4 and the total score ranges from 0-100, with lower scores signifying fewer limitations at work. FAS was defined as all randomized subjects. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Here 'N'(number of subjects analyzed) signifies subjects who were evaluable for this outcome measure. Last Observation Carried Forward (LOCF) method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8, 16, 24, 36 and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    227
    223
    223
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Week 8
    -0.812 ± 3.6230
    -1.946 ± 3.8040
    -2.202 ± 3.8437
        Week 16
    -0.840 ± 4.6414
    -2.406 ± 4.1403
    -2.600 ± 4.3066
        Week 24
    -1.019 ± 4.5328
    -2.765 ± 4.4381
    -2.884 ± 4.5873
        Week 36
    -0.940 ± 4.7982
    -2.921 ± 4.4205
    -2.952 ± 4.5640
        Week 52
    -0.732 ± 5.0288
    -3.057 ± 4.5290
    -2.936 ± 4.3940
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol Health State Visual Analogue Scale (EQ VAS)

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    End point title
    Change From Baseline in EuroQol Health State Visual Analogue Scale (EQ VAS)
    End point description
    The EuroQol Health State Visual Analogue Scale (EQ VAS) records the respondent’s self-rated health on a vertical line, VAS where the endpoints are labeled as 0= ‘Worst imaginable health state’ and 100= ‘Best imaginable health state’. The EQ VAS can be used as a quantitative measure of health outcome as judged by the individual respondents. FAS included all randomized subjects. Here 'N'(number of subjects analyzed) signifies subjects who were evaluable for this outcome measure. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8, 16, 24, and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    554
    557
    556
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Change at Week 8
    5.61 ± 24.415
    11.64 ± 26.979
    12.24 ± 26.025
        Change at Week 16
    5.83 ± 26.177
    14.09 ± 28.581
    14.36 ± 27.884
        Change at Week 24
    6.71 ± 26.520
    14.86 ± 28.747
    16.41 ± 28.830
        Change at Week 36
    8.30 ± 26.144
    16.80 ± 28.595
    17.14 ± 28.329
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol EQ-5D-3L Descriptive System

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    End point title
    Change From Baseline in EuroQol EQ-5D-3L Descriptive System
    End point description
    The EQ-5D-3L Descriptive System comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. FAS included all randomized subjects. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. LOCF method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8, 16, 24, and 52
    End point values
    Placebo Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    556
    557
    557
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Change at Week 8
    0.1041 ± 0.31794
    0.1734 ± 0.32473
    0.1647 ± 0.30146
        Change at Week 16
    0.1131 ± 0.33788
    0.1831 ± 0.34875
    0.1899 ± 0.31149
        Change at Week 24
    0.1263 ± 0.33539
    0.1885 ± 0.33867
    0.2057 ± 0.32081
        Change at Week 52
    0.1255 ± 0.34312
    0.1950 ± 0.33448
    0.2007 ± 0.32895
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening up to Week 120
    Adverse event reporting additional description
    Safety population included all subjects who received at least 1 partial or complete dose of study agent, analysed in treatment received overtime, regardless randomization.One subject inadvertently received Sirukumab 100 mg instead of Sirukumab 50 mg and therefore reported in Sirukumab 100 mg arm (558) instead of Sirukumab 50 mg (556 subjects).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    W0 to W120-Placebo to Sirukumab 50 mg q4w due to EE/LE or CO
    Reporting group description
    Subjects who received placebo in the placebo controlled period were rerandomized (due to EE at Week 18 or LE at Week 40 or CO at Week 52) to receive subcutaneous (SC) sirukumab 50 mg q4w dose regimen up to Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    Week 0 to Week 120-Placebo
    Reporting group description
    Subjects received matching placebo from week 0 to week 52, every 2 weeks (q2w) until either early escape (EE) at Week 18 or late escape (LE) at Week 40 or crossover (CO) at Week 52 and were rerandomized to subcutaneous (SC) sirukumab 50 mg q4w or sirukumab 100 mg q2w dose regimens up to Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    W0 to W120- Placebo to Sirukumab 100 mg q2w Due to EE/LE or CO
    Reporting group description
    Subjects who received placebo in the placebo controlled period were rerandomized (due to EE at Week 18 or LE at Week 40 or CO at Week 52) to receive subcutaneous (SC) sirukumab 100 mg q2w dose up to Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    W0 to W120-Sirukumab 100 mg q2w
    Reporting group description
    Subjects received 100 mg of sirukumab SC injections at Weeks 0, 2 and q2w throught Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Reporting group title
    W0 to W120- Sirukumab 50 mg q4w
    Reporting group description
    Subjects received 50 mg of sirukumab SC injections at Weeks 0, 4, and q4w through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

    Serious adverse events
    W0 to W120-Placebo to Sirukumab 50 mg q4w due to EE/LE or CO Week 0 to Week 120-Placebo W0 to W120- Placebo to Sirukumab 100 mg q2w Due to EE/LE or CO W0 to W120-Sirukumab 100 mg q2w W0 to W120- Sirukumab 50 mg q4w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 242 (12.40%)
    40 / 556 (7.19%)
    35 / 241 (14.52%)
    97 / 558 (17.38%)
    111 / 556 (19.96%)
         number of deaths (all causes)
    5
    1
    6
    5
    7
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic Aneurysm
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic Dissection
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Axillary Vein Thrombosis
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extremity Necrosis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Hypertension
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Labile Hypertension
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrosis Ischaemic
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian Vein Thrombosis
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Shock
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosed Varicose Vein
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Venous Thrombosis Limb
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute Myeloid Leukaemia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Adrenal Adenoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Basal Cell Carcinoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Benign Neoplasm of Thyroid Gland
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Bladder Cancer
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Bladder Transitional Cell Carcinoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Breast Cancer
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon Cancer Metastatic
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Gastric Cancer
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Stromal Tumour
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma Multiforme
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Intraductal Papilloma of Breast
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    2 / 558 (0.36%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Cancer Metastatic
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to Central Nervous System
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to Bone
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine Carcinoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Oropharyngeal Squamous Cell Carcinoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Ovarian Clear Cell Carcinoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Teratoma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Uterine Cancer
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    2 / 558 (0.36%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Influenza Like Illness
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical Device Site Joint Inflammation
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Serositis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden Cardiac Death
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Suicidal Ideation
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast Mass
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Ovarian Cyst
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal Haemorrhage
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal Injury
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chemical Peritonitis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Contusion
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiphyseal Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial Bones Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Femoral Neck Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 556 (0.18%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    2 / 556 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Hand Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Hip Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Humerus Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Joint Capsule Rupture
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Kidney Rupture
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle Rupture
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Post Procedural Complication
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Complication
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural Haemorrhage
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural Pain
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Radius Fracture
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    5 / 558 (0.90%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Road Traffic Accident
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Tendon Injury
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Tendon Rupture
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    1 / 558 (0.18%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna Fracture
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Dehiscence
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    1 / 241 (0.41%)
    3 / 558 (0.54%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    2 / 241 (0.83%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    2 / 241 (0.83%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest X-Ray Abnormal
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver Function Test Increased
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    1 / 241 (0.41%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    Acute Left Ventricular Failure
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Angina Pectoris
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Atrial Fibrillation
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Bradycardia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    1 / 558 (0.18%)
    3 / 556 (0.54%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Sinus Bradycardia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    2 / 558 (0.36%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    3 / 556 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Dyspnoea
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    4 / 556 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Disorder
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Pneumonitis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Pneumothorax Spontaneous
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Mass
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Pulmonary Embolism
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    2 / 241 (0.83%)
    2 / 558 (0.36%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Necrosis
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory Failure
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    2 / 558 (0.36%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Pancytopenia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    2 / 558 (0.36%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal Tunnel Syndrome
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Cerebral Infarction
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Cerebrovascular Accident
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical Myelopathy
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Cervical Radiculopathy
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Stroke
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Headache
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 556 (0.18%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive Encephalopathy
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Intracranial Aneurysm
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Ischaemic Stroke
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Radiculopathy
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    2 / 556 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyramidal Tract Syndrome
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Reversible Cerebral Vasoconstriction Syndrome
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    2 / 558 (0.36%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal Neuralgia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulnar Nerve Palsy
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    1 / 241 (0.41%)
    0 / 558 (0.00%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar Insufficiency
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Eye disorders
    Amaurosis Fugax
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Scleritis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Ulcerative Keratitis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    2 / 556 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Strangulated Hernia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Colitis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    1 / 558 (0.18%)
    0 / 556 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00%)
    0 / 558 (0.00%)
    1 / 556 (0.18%)
         occurrences causally related to treatment / all
    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
    Diverticular Perforation
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 556 (0.00%)
    0 / 241 (0.00