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    Clinical Trial Results:
    A Multicenter, Parallel-group Study of Long-term Safety and Efficacy of CNTO 136 (sirukumab) for Rheumatoid Arthritis in Subjects Completing Treatment in Studies CNTO136ARA3002 (SIRROUND-D) and CNTO136ARA3003 (SIRROUND-T)

    Summary
    EudraCT number
    		 2012-001176-10
    Trial protocol
    		 LT   ES   IT   DE   PT   AT   GB   BE   NL   PL   HR   BG  
    Global end of trial date
    01 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 May 2019
    First version publication date
    10 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNTO136ARA3004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01856309
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, 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
    01 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of the study was to evaluate the long-term safety of sirukumab in subjects with rheumatoid arthritis, who were refractory to treatment with modifying antirheumatic drugs or anti-tumor necrosis factor alpha agents.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations were based upon the type, incidence, and severity of treatment-emergent adverse events (TEAEs) and adverse events (AEs) of special interest reported throughout the study, and on changes in vital sign measurements, clinical laboratory test results, physical examinations, 12-lead electrocardiograms (ECGs), and Columbia-Suicide Severity Rating Scale (C-SSRS).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 15
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Chile: 50
    Country: Number of subjects enrolled
    Colombia: 29
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Croatia: 8
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 224
    Country: Number of subjects enrolled
    Korea, Republic of: 48
    Country: Number of subjects enrolled
    Lithuania: 81
    Country: Number of subjects enrolled
    Mexico: 112
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 196
    Country: Number of subjects enrolled
    Puerto Rico: 4
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Russian Federation: 198
    Country: Number of subjects enrolled
    Serbia: 118
    Country: Number of subjects enrolled
    Taiwan: 27
    Country: Number of subjects enrolled
    Ukraine: 101
    Country: Number of subjects enrolled
    United States: 449
    Country: Number of subjects enrolled
    South Africa: 71
    Worldwide total number of subjects
    1820
    EEA total number of subjects
    360
    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)
    1539
    From 65 to 84 years
    281
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects who completed participation in studies CNTO136ARA3002 (NCT01604343) and CNTO136ARA3003 (NCT01606761) and consented to participate in extension study were enrolled in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo to 50 mg q4w Due to EE/LE/CO
    Arm description
    		 Subjects initially randomized to placebo, then at early escape (EE), late escape (LE), or cross over (CO) randomized to sirukumab 50 milligram (mg) every 4 weeks (q4w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen (sirukumab 50 mg q4w) upon entering this long-term extension (LTE) study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sirukumab 50 mg
    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 sirukumab 50 milligram (mg) every 4 weeks (q4w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen (sirukumab 50 mg q4w) upon entering this long-term extension (LTE) study.

    Arm title
    		 Placebo to 100 mg q2w Due to EE/LE/CO
    Arm description
    		 Subjects initially randomized to placebo, then at EE, LE, or CO randomized to sirukumab 100 mg every two weeks (q2w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sirukumab 100 mg
    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 randomized to receive sirukumab 100 mg every two weeks (q2w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive sirukumab 100 mg q2w in this LTE study.

    Arm title
    		 Sirukumab 50 mg q4w
    Arm description
    		 Subjects initially randomized to sirukumab 50 mg q4w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sirukumab 50 mg
    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 initially randomized to sirukumab 50 mg q4w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive sirukumab 100 mg q2w in this LTE study.

    Arm title
    		 Sirukumab 100 mg q2w
    Arm description
    		 Subjects initially randomized to sirukumab 100 mg q2w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sirukumab 100 mg
    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 initially randomized to sirukumab 100 mg q2w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive sirukumab 100 mg q2w in this LTE study.

    Number of subjects in period 1
    		Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Started
    305
    291
    606
    618
    Subject fromStudyARA3002
    197
    187
    405
    412
    Subject fromStudyARA3003
    108
    104
    201
    206
    Treated Subjects
    305
    290
    605
    618
    Completed
    6
    3
    11
    9
    Not completed
    299
    288
    595
    609
         Consent withdrawn by subject
    11
    13
    28
    26
         Physician decision
    6
    1
    6
    8
         Adverse event, non-fatal
    31
    31
    55
    65
         Death
    4
    6
    11
    6
         Pregnancy
    -
    -
    -
    1
         Unspecified
    227
    225
    447
    469
         Lost to follow-up
    6
    2
    4
    8
         Noncompliance With Study Drug
    -
    1
    4
    1
         Lack of efficacy
    14
    9
    40
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo to 50 mg q4w Due to EE/LE/CO
    Reporting group description
    		 Subjects initially randomized to placebo, then at early escape (EE), late escape (LE), or cross over (CO) randomized to sirukumab 50 milligram (mg) every 4 weeks (q4w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen (sirukumab 50 mg q4w) upon entering this long-term extension (LTE) study.

    Reporting group title
    Placebo to 100 mg q2w Due to EE/LE/CO
    Reporting group description
    		 Subjects initially randomized to placebo, then at EE, LE, or CO randomized to sirukumab 100 mg every two weeks (q2w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.

    Reporting group title
    Sirukumab 50 mg q4w
    Reporting group description
    		 Subjects initially randomized to sirukumab 50 mg q4w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.

    Reporting group title
    Sirukumab 100 mg q2w
    Reporting group description
    		 Subjects initially randomized to sirukumab 100 mg q2w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.

    Reporting group values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w Total
    Number of subjects
    		 305 291 606 618 1820
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 246 243 524 526 1539
        From 65 to 84 years
    		 59 48 82 92 281
        85 years and over
    		 0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 54 ( 11.92 ) 53.1 ( 11.75 ) 53.1 ( 11.43 ) 53.4 ( 11.29 ) -
    Title for Gender
    Units: subjects
        Female
    		 241 231 479 503 1454
        Male
    		 64 60 127 115 366
    Region of Enrollment
    Units: Subjects
        Argentina
    		 4 5 4 2 15
        Australia
    		 0 1 1 0 2
        Austria
    		 1 1 0 0 2
        Belgium
    		 0 1 0 0 1
        Bulgaria
    		 0 3 3 3 9
        Canada
    		 2 0 2 3 7
        Chile
    		 11 7 14 18 50
        Colombia
    		 2 6 10 11 29
        Croatia
    		 1 2 3 2 8
        France
    		 0 0 1 0 1
        Germany
    		 2 3 10 5 20
        Italy
    		 1 0 0 1 2
        Japan
    		 36 36 74 78 224
        Lithuania
    		 13 10 26 32 81
        Malaysia
    		 3 0 1 1 5
        Mexico
    		 17 16 39 40 112
        Netherlands
    		 1 2 1 1 5
        Poland
    		 36 31 67 62 196
        Portugal
    		 3 0 3 4 10
        Puerto Rico
    		 1 0 3 0 4
        Romania
    		 2 0 2 4 8
        Russia
    		 34 29 63 72 198
        Serbia
    		 21 23 38 36 118
        South Africa
    		 13 16 22 20 71
        Korea, Republic Of
    		 6 5 14 23 48
        Spain
    		 3 2 5 4 14
        Taiwan, Province Of China
    		 5 6 12 4 27
        Ukraine
    		 16 13 31 41 101
        United Kingdom
    		 0 0 1 2 3
        United States
    		 71 73 156 149 449
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 2 1 3 5 11
        Asian
    		 50 47 102 110 309
        Black or African American
    		 10 15 21 23 69
        White
    		 231 211 433 443 1318
        Other
    		 11 15 40 31 97
        Multiple
    		 0 0 0 1 1
        Not reported
    		 1 2 5 4 12
        Unknown
    		 0 0 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo to 50 mg q4w Due to EE/LE/CO
    Reporting group description
    		 Subjects initially randomized to placebo, then at early escape (EE), late escape (LE), or cross over (CO) randomized to sirukumab 50 milligram (mg) every 4 weeks (q4w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen (sirukumab 50 mg q4w) upon entering this long-term extension (LTE) study.

    Reporting group title
    Placebo to 100 mg q2w Due to EE/LE/CO
    Reporting group description
    		 Subjects initially randomized to placebo, then at EE, LE, or CO randomized to sirukumab 100 mg every two weeks (q2w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.

    Reporting group title
    Sirukumab 50 mg q4w
    Reporting group description
    		 Subjects initially randomized to sirukumab 50 mg q4w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.

    Reporting group title
    Sirukumab 100 mg q2w
    Reporting group description
    		 Subjects initially randomized to sirukumab 100 mg q2w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.

    Subject analysis set title
    Sirukumab 100 mg q2w
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects initially randomized to sirukumab 100 mg q2w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.

    Primary: Percentage of Subjects with Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Subjects with Serious Adverse Events (SAEs) [1] [2]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Population included all subjects who were enrolled in this study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Primary
    End point timeframe
    From baseline of this LTE study up to 4.3 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    21.3
    27.8
    26.4
    23.1
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Major Adverse Cardiovascular Events (MACE)

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    End point title
    		 Percentage of Subjects with Major Adverse Cardiovascular Events (MACE) [3] [4]
    End point description
    MACE was defined as a composite of Myocardial Infarction (MI), stroke, death, hospitalization for unstable angina, and hospitalization for Transient Ischemic Attack (TIA). Adjudication of these events by the Endpoint Adjudication Committee (EAC) was performed in a blinded fashion. Population included all subjects who were enrolled in this study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Primary
    End point timeframe
    From baseline of this LTE study up to 4.3 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    2.0
    0.7
    2.3
    1.1
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Malignancies

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    End point title
    		 Percentage of Subjects with Malignancies [5] [6]
    End point description
    Percentage of subjects with one or more malignancy was reported. Population included all subjects who were enrolled in this study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Primary
    End point timeframe
    From baseline of this LTE study up to 4.3 years
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    1.0
    3.4
    1.5
    1.8
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Serious Infections

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    End point title
    		 Percentage of Subjects with Serious Infections [7] [8]
    End point description
    Percentage of subjects with one or more serious infections was reported. Population included all subjects who were enrolled in this study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Primary
    End point timeframe
    From baseline of this LTE study up to 4.3 years
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    7.9
    12.0
    10.4
    10.7
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Gastrointestinal (GI) Perforations

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    End point title
    		 Percentage of Subjects with Gastrointestinal (GI) Perforations [9] [10]
    End point description
    Percentage of subjects with one or more GI perforations was reported. GI perforation is a hole that develops through the entire wall of the stomach, small intestine, large bowel, or gallbladder. Population included all subjects who were enrolled in this study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Primary
    End point timeframe
    From baseline of this LTE study up to 4.3 years
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    0.7
    1.4
    0.7
    0.5
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Hepatobiliary Abnormalities

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    End point title
    		 Percentage of Subjects with Hepatobiliary Abnormalities [11] [12]
    End point description
    Percentage of subjects with hepatobiliary abnormalities was reported. Population included all subjects who were enrolled in this study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses
    End point type
    Primary
    End point timeframe
    From baseline of this LTE study up to 4.3 years
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    0
    0.3
    0.2
    0.2
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Serious or Moderate/Severe Systemic Hypersensitivity Reactions, or Serum Sickness Adverse Events

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    End point title
    		 Percentage of Subjects with Serious or Moderate/Severe Systemic Hypersensitivity Reactions, or Serum Sickness Adverse Events [13] [14]
    End point description
    Percentage of subject with serious or moderate/severe systemic hypersensitivity reactions, or serum sickness adverse events (AEs) was reported. Population included all subjects who were enrolled in this study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Primary
    End point timeframe
    From baseline of this LTE study up to 4.3 years
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    0.3
    0.7
    0.2
    0.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Toxicity Grade 4 Decrease in Neutrophils

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    End point title
    		 Percentage of Subjects with Toxicity Grade 4 Decrease in Neutrophils [15]
    End point description
    Percentage of subjects with toxicity grade 4 decrease in neutrophils was reported. As per National Cancer Institute’s Common Terminology Criteria for Adverse Events, toxicity grade 4 was defined as decrease in neutrophils less than (<) 500 per Cubic Millimeter (mm^3) or < 0.5 * 10^9 per liter. Population included all subjects who were enrolled in this study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Secondary
    End point timeframe
    From baseline of primary studies through end of this LTE study (Approximately 5.3 years)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    1.3
    0
    0.5
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Toxicity Grade 4 Decrease in Platelets

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    End point title
    		 Percentage of Subjects with Toxicity Grade 4 Decrease in Platelets [16]
    End point description
    Percentage of subjects with toxicity grade 4 decrease in platelets was reported. As per National Cancer Institute’s Common Terminology Criteria for Adverse Events, toxicity grade 4 was defined as decreased in platelets <25000/mm^3 or < 25.0 * 10^9 per liter. Population included all subjects who were enrolled in this study. One subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Secondary
    End point timeframe
    From baseline of primary studies through end of this LTE study (Approximately 5.3 years)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with ALT >= 3*ULN, ALT >= 5*ULN, ALT >= 8*ULN

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    End point title
    		 Percentage of Subjects with ALT >= 3*ULN, ALT >= 5*ULN, ALT >= 8*ULN [17]
    End point description
    Percentage of subjects with Alanine Aminotranserase (ALT) >= 3*Upper Limit of Normal (ULN), ALT >= 5*ULN or ALT >= 8*ULN was reported. Population included all subjects who were enrolled in this study. 1 subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Secondary
    End point timeframe
    From baseline of primary studies through end of this LTE study (Approximately 5.3 years)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
    number (not applicable)
        ALT >= 3 * ULN
    14.1
    14.4
    15.9
    17.1
        ALT >= 5 * ULN
    2.0
    2.4
    2.5
    3.9
        ALT >= 8 * ULN
    0
    0.7
    0.2
    0.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with AST >= 3 * ULN, AST >= 5 * ULN, AST >= 8 * ULN

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    End point title
    		 Percentage of Subjects with AST >= 3 * ULN, AST >= 5 * ULN, AST >= 8 * ULN [18]
    End point description
    Percentage of subjects with Aspartate Aminotransferase (AST) >= 3*ULN, AST >= 5*ULN and AST >= 8*ULN was reported. Population included all subjects who were enrolled in this study. 1 subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Secondary
    End point timeframe
    From baseline of primary studies through end of this LTE study (Approximately 5.3 years)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
    number (not applicable)
        AST >= 3 * ULN
    3.9
    6.2
    4.5
    7.8
        AST >= 5 * ULN
    0.3
    1.7
    0.5
    1.1
        AST >= 8 * ULN
    0
    0
    0.2
    0.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with either ALT >= 3 * ULN, AST >= 3 * ULN, and Total Bilirubin >= 2 * ULN

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    End point title
    		 Percentage of Subjects with either ALT >= 3 * ULN, AST >= 3 * ULN, and Total Bilirubin >= 2 * ULN [19]
    End point description
    Percentage of subjects with either ALT >= 3*ULN or AST >= 3*ULN and total bilirubin >= 2*ULN was reported. Population included all subjects who were enrolled in this study. 1 subject who mistakenly took sirukumab 100mg, when was originally assigned to sirukumab 50mg, was analyzed under the sirukumab 100mg group for all safety analyses.
    End point type
    Secondary
    End point timeframe
    From baseline of primary studies through end of this LTE study (Approximately 5.3 years)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    619
    Units: Percentage of subjects
        number (not applicable)
    0
    0
    0
    0.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Normal Total Cholesterol Value at Baseline and at Least 1 Abnormal Value Post-Baseline

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    End point title
    		 Percentage of Subjects with Normal Total Cholesterol Value at Baseline and at Least 1 Abnormal Value Post-Baseline [20]
    End point description
    Percentage of subjects with normal total cholesterol value at baseline and at least 1 abnormal value post-baseline was reported. Abnormal total cholesterol value was defined as total cholesterol value more than (>) 200 milligrams per deciliter (mg/dL). Population included all subjects who were enrolled in this study and had total cholesterol baseline value within normal range.
    End point type
    Secondary
    End point timeframe
    From baseline of primary studies through end of this LTE study (Approximately 5.3 years)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    177
    163
    354
    345
    Units: Percentage of subjects
        number (not applicable)
    86.4
    81.6
    82.5
    87.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Normal LDL Value at Baseline and at Least 1 Abnormal Value Post- Baseline

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    End point title
    		 Percentage of Subjects with Normal LDL Value at Baseline and at Least 1 Abnormal Value Post- Baseline [21]
    End point description
    Percentage of subjects with normal LDL value at baseline and at least 1 abnormal value post-baseline was reported. Abnormal LDL value was defined as LDL value > 130 mg/dL. Population included all subjects who were enrolled in this study and had LDL baseline value within normal range.
    End point type
    Secondary
    End point timeframe
    From baseline of primary studies through end of this LTE study (Approximately 5.3 years)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    225
    209
    459
    449
    Units: Percentage of Subjects
        number (not applicable)
    70.2
    67.9
    69.7
    70.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Normal HDL Value at Baseline and at Least 1 Abnormal Value Post-Baseline

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    End point title
    		 Percentage of Subjects with Normal HDL Value at Baseline and at Least 1 Abnormal Value Post-Baseline [22]
    End point description
    Percentage of subjects with normal HDL value at baseline and at least 1 abnormal value post-baseline was reported. Abnormal HDL value was defined as HDL value < 40 mg/dL. Population included all subjects who were enrolled in this study and had HDL baseline value within normal range.
    End point type
    Secondary
    End point timeframe
    From baseline of primary studies through end of this LTE study (Approximately 5.3 years)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    277
    273
    533
    569
    Units: Percentage of Subjects
        number (not applicable)
    16.2
    14.7
    16.1
    16.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Normal Triglyceride Value at Baseline and at Least 1 Abnormal Value Post-Baseline

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    End point title
    		 Percentage of Subjects with Normal Triglyceride Value at Baseline and at Least 1 Abnormal Value Post-Baseline [23]
    End point description
    Percentage of subjects with normal triglyceride value at baseline and at least 1 abnormal value post-baseline was reported. Abnormal triglyceride value was defined as triglyceride value > 250 mg/dL. Population included all subjects who were enrolled in this study and had triglyceride baseline value within normal range.
    End point type
    Secondary
    End point timeframe
    From baseline of primary studies through end of this LTE study (Approximately 5.3 years)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arm only.
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    279
    268
    554
    564
    Units: Percentage of subjects
        number (not applicable)
    32.6
    35.1
    36.1
    34.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Achieved American College of Rheumatology (ACR) 50 Response Through Week 260

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    End point title
    		 Percentage of Subjects who Achieved American College of Rheumatology (ACR) 50 Response Through Week 260
    End point description
    ACR 50 response is >= 50 % improvement in both tender joint count (68) and swollen joint count (66) and >= 50% improvement in 3 of 5 assessments:Participant’s assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst pain),PGA of disease activity by using VAS (0 to 10, [0 =very well to 10=very poor]), Physician’s global assessment of disease activity using VAS(0 to 10,[0=no arthritis activity,10=extremely active arthritis]), Participant’s assessment of physical function measured by HAQ-DI (scale 0=no difficulty,3=inability to perform task in that area), serum C-reactive protein (CRP). Subjects analyzed for efficacy per assigned treatment groups from primary studies, regardless of treatments received. Population included all subjects enrolled in study. For "Placebo to 50mg", "Placebo to 100mg" groups, only efficacy data collected after escape to sirukumab was planned to be reported, with exception of baseline data. 'n':number of subjects analyzed at specified time point.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    605
    615
    Units: Percentage of subjects
    number (not applicable)
        At week 2 (n = 0, 0 ,604, 615)
    99999
    99999
    2.5
    2.4
        At week 4 (n = 0, 0, 603, 614)
    99999
    99999
    9.1
    9.7
        At week 6 (n = 0, 0, 511, 527)
    99999
    99999
    16.2
    14.6
        At week 8 (n = 0, 0, 603, 611)
    99999
    99999
    21.4
    20.0
        At week 12 (n = 0, 0, 600, 614)
    99999
    99999
    27.7
    29.6
        At week 16 (n = 0, 0, 603, 614)
    99999
    99999
    31.8
    29.2
        At week 18 (n = 0, 0, 602, 612)
    99999
    99999
    33.7
    32.0
        At week 20 (n = 111, 106, 602, 611)
    4.5
    3.8
    36.9
    38.1
        At week 24 (n = 112, 106, 606, 615)
    17.9
    10.4
    35.1
    37.9
        At week 28 (n = 180, 173, 600, 612)
    24.4
    23.1
    40.0
    39.2
        At week 32 (n = 180, 169, 602, 614)
    29.2
    33.9
    42.3
    42.2
        At week 36 (n = 178, 174, 601, 612)
    29.2
    33.9
    42.3
    43.0
        At week 40 (n = 175, 173, 595, 612)
    38.3
    34.7
    42.0
    42.2
        At week 44 (n = 187, 179, 598, 609)
    40.1
    33.5
    43.3
    44.3
        At week 48 (n = 187, 179, 601, 608)
    43.3
    27.9
    44.6
    44.1
        At week 52 (n = 191, 182, 605, 617)
    41.9
    34.1
    43.0
    44.9
        At week 76 (n = 196, 185, 401, 410)
    56.6
    49.7
    52.4
    56.1
        At week 80 (n = 90, 87, 178, 187)
    38.9
    26.4
    38.2
    44.9
        At week 104 (n = 283, 267, 571, 575)
    48.8
    46.1
    50.3
    53.0
        At week 128 (n = 76, 73, 157, 157)
    35.5
    43.8
    42.7
    46.5
        At week 132 (n = 174, 165, 356, 369)
    51.1
    46.7
    50.0
    53.4
        At week 156 (n = 242, 227, 499, 506)
    48.3
    56.4
    50.3
    52.6
        At week 180 (n= 184, 175, 381, 390)
    52.3
    54.9
    54.6
    56.4
        At week 208 (n = 110, 93, 199, 213)
    50.9
    50.5
    50.8
    59.6
        At week 232 (n = 33, 28, 66, 70)
    48.5
    57.1
    51.5
    57.1
        At week 260 (n = 3, 2, 10, 4)
    66.7
    50.0
    60.0
    25.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Boolean-Based American College of Rheumatology (ACR) or European League Against Rheumatism (EULAR) Remission Through Week 260

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    End point title
    		 Percentage of Subjects with Boolean-Based American College of Rheumatology (ACR) or European League Against Rheumatism (EULAR) Remission Through Week 260
    End point description
    Boolean based ACR/EULAR remission is achieved if all of the following 4 criteria at that visit are met: tender joint count (68 joints) <=1; swollen joint count (66 joints) <=1; CRP <=1 milligram per deciliter (mg/dL); and patient's global assessment of disease activity on visual analog scale (VAS) <=1 on a 0 (very well ) to 10 (extremely bad) scale. Higher scores indicates worst health condition. Subjects were analyzed for efficacy according to the assigned treatment groups from the primary studies, regardless of the treatments they actually received. Population included all subjects who were enrolled in this study. For "Placebo to 50mg" and "Placebo to 100mg" groups, only efficacy data collected after escape or CO (after Week 18) to sirukumab was planned to be reported, with exception of baseline data. Here 'n' signifies the number of subjects analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    606
    618
    Units: Percentage of subject
    number (not applicable)
        At week 2 (n = 0, 0, 604, 616)
    99999
    99999
    0.2
    0.2
        At week 4 (n = 0, 0, 603, 616)
    99999
    99999
    0.5
    0.6
        At week 6 (n = 0, 0, 511, 527)
    99999
    99999
    0.8
    1.5
        At week 8 (n = 0, 0, 603, 611)
    99999
    99999
    603
    611
        At week 12 (n = 0, 0, 602, 614)
    99999
    99999
    3.2
    4.9
        At week 16 (n = 0, 0, 603, 614)
    99999
    99999
    3.3
    5.7
        At week 18 (n = 0, 0, 603, 613)
    99999
    99999
    4.3
    5.4
        At week 20 (n = 111, 106, 604, 611)
    99999
    99999
    4.5
    5.9
        At week 24 (n = 112, 106, 604, 611)
    0.9
    0.9
    5.3
    8.1
        At week 28 (n = 180, 174, 602, 613)
    2.8
    2.9
    6.0
    6.2
        At week 32 (n = 180, 170, 601, 613)
    2.2
    4.1
    4.8
    7.7
        At week 36 (n = 178, 174, 603, 611)
    2.8
    4.0
    7.8
    9.7
        At week 40 (n = 177, 173, 596, 613)
    4.0
    6.4
    7.2
    9.0
        At week 44 (n = 187, 180, 598, 610)
    4.3
    6.1
    7.4
    9.7
        At week 48 (n = 187, 180, 598, 610)
    4.3
    7.3
    9.8
    9.0
        At week 52 (n = 190, 181, 604, 618)
    6.8
    6.6
    9.3
    7.1
        At week 76 (n = 196, 183, 402, 411)
    9.7
    7.1
    10.7
    9.2
        At week 80 (n = 91, 87, 180, 189)
    6.6
    8.0
    7.8
    6.3
        At week 104 (n = 283, 270, 573, 578)
    10.6
    11.1
    12.6
    10.2
        At week 128 (n = 76, 74, 158, 157)
    2.6
    8.1
    10.8
    8.9
        At week 132 (n = 177, 168, 360, 373)
    12.4
    11.3
    10.8
    10.2
        At week 156 (n = 244, 229, 503, 508)
    9.4
    8.7
    10.9
    11.8
        At week 180 (n = 187, 177, 386, 395)
    11.8
    10.7
    14.2
    13.9
        At week 208 (n = 111, 95, 201, 219)
    12.6
    13.7
    11.4
    19.2
        At week 232 (n = 34, 28, 66, 66)
    11.8
    17.9
    18.2
    9.1
        At week 260 (n = 4, 3, 11, 5)
    0
    0
    18.2
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Disease Activity Index Score 28 (DAS28) (CRP) Remission Through Week 260

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    End point title
    		 Percentage of Subjects With Disease Activity Index Score 28 (DAS28) (CRP) Remission Through Week 260
    End point description
    DAS28 based on CRP is statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment (PGA) of disease activity. Set of 28 joint count is based on evaluation of shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both upper right extremity and upper left extremity also knee joints of lower right and lower left extremities. Values are 0=best to 10=worst. DAS28 (CRP) remission is DAS28 (CRP) value of less than (<) 2.6 at any study visit. Subjects analyzed for efficacy as per assigned treatment groups from primary studies, regardless of treatments received. Population included all subjects enrolled in study. For "Placebo to 50mg" and "Placebo to 100mg" groups, only efficacy data collected after escape or CO (after Week 18) to sirukumab was planned to be reported, with exception of baseline data. 'n': number of subjects analyzed at specified time point.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    606
    618
    Units: Percentage of subjects
    number (not applicable)
        At week 2 (n = 0, 0, 601, 609)
    99999
    99999
    2.7
    2.6
        At week 4 (n = 0, 0, 599, 611)
    99999
    99999
    7.5
    9.0
        At week 6 (n = 0, 0, 502, 524)
    99999
    99999
    10.2
    13.4
        At week 8 (n = 0, 0, 601, 608)
    99999
    99999
    15.0
    18.8
        At week 12 (n = 0, 0, 598, 614)
    99999
    99999
    20.4
    23.5
        At week 16 (n = 0, 0, 602, 612)
    99999
    99999
    23.8
    24.0
        At week 18 (n = 0, 0, 589, 606)
    99999
    99999
    25.6
    25.4
        At week 20 (n = 110, 106, 600, 605)
    1.8
    0
    29.8
    30.1
        At week 24 (n = 111, 106, 603, 610)
    7.2
    7.5
    30.8
    32.1
        At week 28 (n = 180, 173, 595, 608)
    17.8
    20.8
    33.8
    32.7
        At week 32 (n = 177, 170, 597, 609)
    24.9
    24.7
    35.3
    36.9
        At week 36 (n = 178, 174, 596, 610)
    21.3
    30.5
    35.1
    35.4
        At week 40 (n = 174, 172, 594, 608)
    29.9
    32.0
    34.5
    34.9
        At week 44 (n = 184, 178, 595, 607)
    34.2
    30.9
    36.0
    35.4
        At week 48 (n = 184, 179, 592, 605)
    33.2
    31.3
    38.7
    38.3
        At week 52 (n = 189, 181, 601, 610)
    30.7
    32.6
    38.8
    37.4
        At week 76 (n = 195, 183, 399, 408)
    44.6
    44.3
    47.6
    45.8
        At week 80 (n = 90, 84, 175, 184)
    38.9
    39.3
    38.3
    38.6
        At week 104 (n = 279, 266, 571, 573)
    44.8
    47.4
    42.6
    46.6
        At week 128 (n = 73, 72, 156, 154)
    43.8
    43.1
    45.5
    43.5
        At week 132 (n = 169, 165, 350, 365)
    41.4
    47.3
    48.0
    49.0
        At week 156 (n = 235, 233, 486, 500)
    43.0
    47.1
    46.5
    49.6
        At week 180 (n = 180, 170, 376, 388)
    48.9
    48.8
    50.5
    53.9
        At week 208 (n = 109, 93, 197, 213)
    55.0
    54.8
    54.3
    60.1
        At week 232 (n = 27, 25, 56, 57)
    59.3
    52.0
    57.1
    59.6
        At week 260 (n = 3, 2, 9, 4)
    66.7
    100.0
    77.8
    25.0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) Score Through Week 260

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    End point title
    		 Change From Baseline in Clinical Disease Activity Index (CDAI) Score Through Week 260
    End point description
    The 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. The 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. Subjects were analyzed for efficacy according to the assigned treatment groups from the primary studies, regardless of the treatments they actually received. Population included all subjects who were enrolled in this study. For "Placebo to 50mg" and "Placebo to 100mg" groups, only efficacy data collected after escape or CO (after Week 18) to sirukumab was planned to be reported, with exception of baseline data. Here 'n' signifies the number of subjects analyzed at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0 of primary studies), Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    606
    614
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 2 (n = 0, 0, 602, 614)
    99999 ( 99999 )
    99999 ( 99999 )
    -6.54 ( 9.464 )
    -6.10 ( 9.295 )
        Change at Week 4 (n = 0, 0, 598, 614)
    99999 ( 99999 )
    99999 ( 99999 )
    -11.09 ( 11.257 )
    -10.73 ( 11.469 )
        Change at Week 6 (n = 0, 0, 510, 524)
    99999 ( 99999 )
    99999 ( 99999 )
    -13.79 ( 12.198 )
    -14.05 ( 11.613 )
        Change at Week 8 (n = 0, 0, 602, 611)
    99999 ( 99999 )
    99999 ( 99999 )
    -15.56 ( 12.736 )
    -15.74 ( 12.333 )
        Change at Week 12 (0, 0, 600, 612)
    99999 ( 99999 )
    99999 ( 99999 )
    -17.79 ( 13.955 )
    -17.89 ( 13.636 )
        Change at Week 16 (0, 0, 600, 612)
    99999 ( 99999 )
    99999 ( 99999 )
    -18.50 ( 13.956 )
    -18.65 ( 13.584 )
        Change at Week 18 (n = 0, 0, 599, 613)
    99999 ( 99999 )
    99999 ( 99999 )
    -18.93 ( 14.459 )
    -18.40 ( 13.524 )
        Change at Week 20 (n = 109, 106, 601, 610)
    -7.19 ( 12.051 )
    -7.01 ( 11.666 )
    -20.72 ( 14.077 )
    -19.96 ( 13.678 )
        Change at Week 24 (n = 111, 106, 605, 615)
    -15.08 ( 11.697 )
    -12.78 ( 11.654 )
    -21.20 ( 13.625 )
    -21.06 ( 13.888 )
        Change at Week 28 (n = 179, 172, 600, 612)
    -19.69 ( 13.518 )
    -19.58 ( 12.578 )
    -21.85 ( 14.000 )
    -21.33 ( 13.655 )
        Change at Week 32 (n = 179, 169, 600, 612)
    -20.36 ( 14.238 )
    -20.69 ( 12.754 )
    -22.37 ( 13.935 )
    -22.17 ( 13.462 )
        Change at Week 36 (n = 177, 174, 600, 611)
    -21.49 ( 12.343 )
    -22.53 ( 12.609 )
    -22.64 ( 13.750 )
    -22.79 ( 13.220 )
        Change at Week 40 (n = 176, 173, 593, 609)
    -22.67 ( 13.374 )
    -22.36 ( 13.208 )
    -23.09 ( 13.890 )
    -22.49 ( 14.268 )
        Change at Week 44 (n = 186, 178, 596, 608)
    -22.80 ( 14.390 )
    -22.31 ( 13.062 )
    -23.19 ( 14.214 )
    23.04 ( 13.484 )
        Change at Week 48 (n = 185, 179, 599, 606)
    -23.74 ( 13.685 )
    -22.56 ( 13.229 )
    -23.22 ( 14.281 )
    -23.20 ( 13.008 )
        Change at Week 52 (n = 190, 183, 603, 617)
    -24.09 ( 13.629 )
    -23.17 ( 13.280 )
    -24.50 ( 13.930 )
    -23.61 ( 12.664 )
        Change at Week 76 (n = 196, 185, 402, 410)
    -27.49 ( 12.763 )
    -25.91 ( 13.537 )
    -25.98 ( 14.077 )
    -24.83 ( 12.664 )
        Change at Week 80 (n = 85, 84, 174, 180)
    -23.31 ( 14.840 )
    -22.67 ( 12.546 )
    -23.27 ( 15.372 )
    -23.70 ( 14.755 )
        Change at Week 104 (n = 280, 267, 569, 573)
    -26.85 ( 13.261 )
    -26.08 ( 12.872 )
    -25.75 ( 13.931 )
    -25.60 ( 13.596 )
        Change at Week 128 (n = 74, 74, 154, 156)
    -24.55 ( 13.797 )
    -25.12 ( 12.102 )
    -25.06 ( 15.496 )
    -2614 ( 14.810 )
        Change at Week 132 (n = 172, 165, 347, 366)
    -27.24 ( 12.671 )
    -26.62 ( 13.334 )
    -26.06 ( 13.661 )
    -24.61 ( 13.391 )
        Change at Week 156 (n = 238, 225, 489, 503)
    -26.53 ( 14.998 )
    -26.85 ( 13.999 )
    -25.59 ( 14.641 )
    -25.60 ( 13.196 )
        Change at Week 180 (n = 180, 168, 375, 388)
    -27.21 ( 14.370 )
    -27.07 ( 13.969 )
    -26.95 ( 13.671 )
    -25.88 ( 13.910 )
        Change at Week 208 (n = 109, 92, 197, 211)
    -27.54 ( 12.054 )
    -27.06 ( 15.579 )
    -27.01 ( 12.968 )
    -27.12 ( 13.008 )
        Change at Week 232 (n = 34, 28, 67, 69)
    -26.61 ( 13.420 )
    -26.25 ( 17.509 )
    -26.06 ( 16.858 )
    -27.23 ( 14.636 )
        Change at Week 260 (n = 3, 2, 10, 4)
    -34.70 ( 4.776 )
    -26.60 ( 20.789 )
    -20.73 ( 11.983 )
    -19.03 ( 18.823 )
    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

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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
    End point description
    SDAI derived by combining 5 disease assessments: tender joint (28), swollen joint (28) counts, PGA of disease activity using VAS (0 to 10 [0 =very well to 10 = very poor]), PGA of disease activity using VAS (0 to 10 [0=no arthritis to 10=extremely active arthritis]) and CRP. 28 joints evaluated for swelling and tenderness are same set of 28 joints used in DAS28 includes shoulder, elbow, wrist, MCP1, MCP2, MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of upper right and left extremities and knee joints of lower right and left extremities. Subjects analyzed for efficacy as per assigned treatment groups from primary studies, regardless of treatments received. Population included subjects enrolled in study. For "Placebo to 50mg" and "Placebo to 100mg" groups, only efficacy data collected after escape or CO (after Week 18) to sirukumab was planned to be reported, with exception of baseline data. 'n': number of subjects analyzed at specified time point.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    606
    618
    Units: Percentage of subjects
    number (not applicable)
        At week 2 (n = 0, 0, 600, 609)
    99999
    99999
    0.2
    0.2
        At week 4 (n = 0, 0, 596, 610)
    99999
    99999
    0.8
    1.1
        At week 6 (n = 0, 0, 502, 522)
    99999
    99999
    1.2
    2.9
        At week 8 (n = 0, 0, 601, 608)
    99999
    99999
    2.8
    3.9
        At week 12 (n = 0, 0, 598, 612)
    99999
    99999
    4.5
    6.4
        At week 16 (n = 0, 0, 600, 611)
    99999
    99999
    5.2
    8.0
        At week 18 (n = 0, 0, 587, 606)
    99999
    99999
    7.5
    7.1
        At week 20 (n = 110, 106, 600, 604)
    0
    0
    8.0
    9.3
        At week 24 (n = 111, 106, 603, 610)
    1.8
    1.9
    9.8
    10.7
        At week 28 (n = 180, 172, 595, 608)
    3.9
    6.4
    10.4
    9.2
        At week 32 (n = 177, 169, 596, 607)
    4.0
    7.1
    9.9
    12.4
        At week 36 (n = 178, 174, 596, 609)
    4.5
    7.5
    11.7
    13.0
        At week 40 (n = 174, 172, 592, 605)
    7.5
    11.0
    13.7
    13.7
        At week 44 (n = 184, 176, 595, 605)
    8.7
    10.2
    11.8
    13.5
        At week 48 (n = 183, 179, 591, 603)
    8.2
    12.3
    14.9
    12.8
        At week 52 (n = 189, 179, 1591, 603)
    9.05
    8.8
    15.0
    12.5
        At week 76 (n = 195, 183, 399, 408)
    16.9
    13.7
    16.8
    14.2
        At week 80 (n = 86, 83, 174, 180)
    9.3
    10.8
    12.6
    11.1
        At week 104 (n = 2789, 264, 568, 571)
    14.3
    18.2
    17.8
    19.8
        At week 128 (n = 73, 72, 155, 154)
    8.2
    15.3
    16.1
    13.6
        At week 132 (n = 169, 165, 347, 364)
    18.3
    15.8
    20.5
    19.0
        At week 156 (n = 235, 223, 483, 499)
    17.9
    14.8
    17.8
    19.4
        At week 180 (n = 180, 167, 374, 387)
    18.3
    20.4
    22.5
    24.0
        At week 208 (n = 108, 92, 196, 211)
    21.3
    20.7
    22.4
    30.3
        At week 232 (n = 27, 25, 55, 57)
    25.39
    20.2
    27.3
    29.8
        At week 260 (N = 3, 2, 9, 4)
    33.3
    50.0
    55.6
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Through Week 260

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    End point title
    		 Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Through Week 260
    End point description
    HAQ-DI score is an evaluation of functional status for a subject. 20-question instrument assesses degree of difficulty person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, activities of daily living). Responses in each functional area scored from 0(no difficulty), to 3, (inability to perform a task in that area. Overall score was sum of domain scores and divided by number of domains answered. Total score: 0-3, 0 = least difficulty and 3 = extreme difficulty. Subjects were analyzed for efficacy according to assigned treatment groups from the primary studies, regardless of treatments actually received. Population included all subjecs enrolled in this study. For "Placebo to 50mg" and "Placebo to 100mg" groups, only efficacy data collected after the escape or CO (after Week 18) to sirukumab was planned to be reported, with exception of baseline data. 'n':number of subjects analyzed at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0 of primary studies), Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    606
    618
    Units: Units on Scale
    arithmetic mean (standard deviation)
        Change at Week 2 (n = 0, 0, 603, 616)
    99999 ( 99999 )
    99999 ( 99999 )
    -0.1136 ( 0.3455 )
    -0.1230 ( 0.3741 )
        Change at Week 4 (n = 0, 0, 602, 616)
    99999 ( 99999 )
    99999 ( 99999 )
    -0.2307 ( 0.4173 )
    -0.2417 ( 0.4034 )
        Change at Week 6 (n = 0, 0, 511, 526)
    99999 ( 99999 )
    99999 ( 99999 )
    -0.3112 ( 0.4944 )
    -0.3683 ( 0.4823 )
        Change at Week 8 (n = 0, 0, 602, 611)
    99999 ( 99999 )
    99999 ( 99999 )
    -0.3499 ( 0.5077 )
    -0.3914 ( 0.5022 )
        Change at Week 12 (n = 0, 0, 601, 613)
    99999 ( 99999 )
    99999 ( 99999 )
    -0.3866 ( 0.5421 )
    -0.4121 ( 0.5270 )
        Change at Week 16 (n = 0, 0, 606, 614)
    99999 ( 99999 )
    99999 ( 99999 )
    -0.3991 ( 0.5611 )
    -0.4414 ( 0.5430 )
        Change at Week 18 (n = 0, 0, 602, 614)
    99999 ( 99999 )
    99999 ( 99999 )
    -0.4365 ( 0.5476 )
    -0.4621 ( 0.5325 )
        Change at Week 20 (n = 111, 106, 602, 611)
    -0.1363 ( 0.4947 )
    -0.2005 ( 0.4987 )
    -0.4425 ( 0.5826 )
    -0.4920 ( 0.5582 )
        Change at Week 24 (n = 112, 106, 605, 615)
    -0.3192 ( 0.5279 )
    -0.3267 ( 0.4739 )
    -0.4506 ( 0.5665 )
    -0.4876 ( 0.5622 )
        Change at Week 28 (n = 180, 174, 601, 612)
    -0.3722 ( 0.5683 )
    -0.3836 ( 0.4741 )
    -0.4736 ( 0.5696 )
    -0.4912 ( 0.5626 )
        Change at Week 32 (n = 180, 170, 601, 614)
    -0.3847 ( 0.5651 )
    -0.4015 ( 0.5532 )
    -0.4769 ( 0.5880 )
    -0.5307 ( 0.5740 )
        Change at Week 36 (n = 178, 174, 602, 611)
    -0.3862 ( 0.5474 )
    -0.4339 ( 0.5432 )
    -0.4850 ( 0.5764 )
    -0.5176 ( 0.5688 )
        Change at Week 40 (n = 177, 173, 593, 613)
    -0.4138 ( 0.5778 )
    -0.4509 ( 0.4988 )
    -0.4850 ( 0.5894 )
    -0.5039 ( 0.5735 )
        Change at Week 44 (n = 187, 181, 597, 610)
    -0.4231 ( 0.5809 )
    -0.4461 ( 0.5206 )
    -0.4906 ( 0.6088 )
    -0.5297 ( 0.5777 )
        Change at Week 48 (n = 187, 179, 601, 609)
    -0.4392 ( 0.5911 )
    -0.4567 ( 0.5254 )
    -0.4890 ( 0.6242 )
    -0.5470 ( 0.5942 )
        Change at Week 52 (n = 191, 182, 604, 618)
    -0.4228 ( 0.5752 )
    -0.4609 ( 0.5455 )
    -0.4946 ( 0.6021 )
    -0.5374 ( 0.5881 )
        Change at Week 76 (n = 196, 185, 402, 411)
    -0.5816 ( 0.6313 )
    -0.5351 ( 0.5605 )
    -0.5628 ( 0.6089 )
    -0.6128 ( 0.5992 )
        Change at Week 80 (n = 91, 87, 179, 187)
    -0.2074 ( 0.5333 )
    -0.3980 ( 0.5579 )
    -0.3834 ( 0.5685 )
    -0.5579 ( 0.5913 )
        Change at Week 104 (n = 282, 269, 573, 579)
    -0.4778 ( 0.6569 )
    -0.4476 ( 0.5263 )
    -0.3615 ( 0.6227 )
    -0.4506 ( 0.5227 )
        Change at Week 128 (n = 76, 74, 157, 157)
    -0.2664 ( 0.5963 )
    -0.4476 ( 0.5263 )
    -0.3615 ( 0.6227 )
    -0.4506 ( 0.5527 )
        Change at Week 132 (n = 178, 169, 362, 375)
    -0.4831 ( 0.6979 )
    -0.4815 ( 0.6656 )
    -0.5045 ( 0.6542 )
    -0.5310 ( 0.6240 )
        Change at Week 156 (n = 243, 231, 503, 505)
    -0.4614 ( 0.6610 )
    -0.4984 ( 0.6520 )
    -0.4719 ( 0.6604 )
    -0.4998 ( 0.6109 )
        Change at Week 180 (n = 187, 276, 384, 393)
    -0.4505 ( 0.7024 )
    -0.4957 ( 0.5969 )
    -0.5072 ( 0.6492 )
    -0.5258 ( 0.6167 )
        Change at Week 208 (n = 109, 276, 384, 393)
    -0.4622 ( 0.6898 )
    -0.4973 ( 0.6032 )
    -0.5031 ( 0.6701 )
    -0.5588 ( 0.6023 )
        Change at Week 232 (n = 34, 29, 67, 69)
    -0.4191 ( 0.7410 )
    -0.4655 ( 0.6477 )
    -0.5877 ( 0.8312 )
    -0.6069 ( 0.6262 )
        Change at Week 260 (n = 3, 2, 9, 3)
    -0.5417 ( 0.8323 )
    -0.3750 ( 1.0607 )
    -0.2083 ( 0.6702 )
    -0.5000 ( 0.4507 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Through Week 260

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    End point title
    		 Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Through Week 260
    End point description
    HAQ-DI score is an evaluation of functional status for a subject. 20-question instrument assesses degree of difficulty person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, activities of daily living). Responses in each functional area scored from 0(no difficulty), to 3, (inability to perform a task in that area. Overall score was sum of domain scores and divided by number of domains answered. Total score: 0-3, 0 = least difficulty and 3 = extreme difficulty. Subjects were analyzed for efficacy according to assigned treatment groups from the primary studies, regardless of treatments actually received. Population included all subjecs enrolled in this study. For "Placebo to 50mg" and "Placebo to 100mg" groups, only efficacy data collected after the escape or CO (after Week 18) to sirukumab was planned to be reported, with exception of baseline data. 'n':number of subjects analyzed at specified time point.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260
    End point values
    		 Placebo to 50 mg q4w Due to EE/LE/CO Placebo to 100 mg q2w Due to EE/LE/CO Sirukumab 50 mg q4w Sirukumab 100 mg q2w
    Number of subjects analysed
    305
    291
    606
    618
    Units: Percentage of subjects
    number (not applicable)
        At week 2 (n = 0, 0, 603, 616)
    99999
    99999
    36.3
    36.4
        At week 4 (n = 0, 0, 602, 616)
    99999
    99999
    48.3
    51.3
        At week 6 (n = 0, 0, 511, 526)
    99999
    99999
    56.4
    57.6
        At week 8 (n = 0, 0, 602, 611)
    99999
    99999
    58.0
    62.5
        At week 12 (n = 0, 0, 601, 613)
    99999
    99999
    60.4
    62.3
        At week 16 (n = 0, 0, 602, 614)
    99999
    99999
    62.0
    63.2
        At week 18 (n = 0, 0, 602, 614)
    99999
    99999
    63.0
    66.0
        At week 20 (n = 111, 106, 602, 611)
    40.5
    45.3
    64.0
    67.1
        At week 24 (n = 112, 106, 605, 615)
    54.5
    54.7
    64.3
    67.0
        At week 28 (n = 180, 174, 601, 612)
    58.3
    61.5
    66.7
    66.8
        At week 36 (n = 178, 174, 602, 611)
    61.2
    64.9
    67.1
    67.9
        At week 40 (n = 177, 174, 602, 611)
    61.0
    67.1
    65.4
    66.6
        At week 44 (n = 187, 181, 597, 610)
    62.6
    65.2
    65.8
    67.9
        At week 48 (n = 187, 181, 597, 610)
    61.5
    65.9
    65.6
    70.1
        At week 52 (N = 191, 182, 604, 618)
    60.7
    65.9
    65.6
    68.9
        At week 76 (n = 191, 182, 604, 618)
    70.4
    69.2
    68.4
    73.7
        At week 80 (n = 91, 87, 179, 187)
    40.7
    58.6
    58.1
    62.0
        At week 104 (n = 282, 269, 573, 579)
    64.2
    68.4
    66.1
    68.0
        At week 128 (n = 76, 74, 157, 157)
    51.3
    64.9
    54.8
    61.1
        At week 132 (n = 178, 169, 362, 375)
    65.2
    63.3
    66.3
    69.9
        At week 156 (n = 243, 231, 503, 505)
    62.6
    64.5
    65.0
    66.9
        At week 180 (n = 187, 231, 503, 505)
    61.0
    69.3
    66.4
    72.3
        At week 208 (n = 109, 94, 201, 217)
    65.1
    69.1
    71.1
    72.4
        At week 232 (n = 34, 29, 67, 69)
    67.6
    69.0
    65.7
    72.5
        At week 280 (n = 66.7, 50.0, 44.4, 66.7)
    66.7
    50.0
    44.4
    66.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline of this LTE study through up to 4.3 years
    Adverse event reporting additional description
    Population included all subjects enrolled. 1subject mistakenly took sirukumab 100mg, originally assigned to sirukumab 50mg, analyzed in sirukumab 100mg group for safety analyses. Treatment group 'Placebo to 100 mg q2w due to EE/LE/CO, 6 deaths happened in ARA3004 study. 1 additional death reported in this group after subject discontinued study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo to 50 mg q4w due to EE/LE or CO
    Reporting group description
    		 Subjects initially randomized to placebo, then at early escape (EE), late escape (LE), or cross over (CO) randomized to sirukumab 50 milligram (mg) every 4 weeks (q4w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen (sirukumab 50 mg q4w) upon entering this long-term extension (LTE) study.

    Reporting group title
    Sirukumab 50 mg q4w Start
    Reporting group description
    		 Subjects initially randomized to sirukumab 50 mg q4w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.

    Reporting group title
    Placebo to 100 mg q2w due to EE/LE or CO
    Reporting group description
    		 Subjects initially randomized to placebo, then at EE, LE, or CO randomized to sirukumab 100 mg every two weeks (q2w) during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.

    Reporting group title
    Sirukumab 100 mg q2w Start
    Reporting group description
    		 Subjects initially randomized to sirukumab 100 mg q2w during the primary studies CNTO136ARA3002 and CNTO136ARA3003, and then continued to receive the same regimen upon entering this LTE study.

    Serious adverse events
    		 Placebo to 50 mg q4w due to EE/LE or CO Sirukumab 50 mg q4w Start Placebo to 100 mg q2w due to EE/LE or CO Sirukumab 100 mg q2w Start
    Total subjects affected by serious adverse events
         subjects affected / exposed
    65 / 305 (21.31%)
    160 / 605 (26.45%)
    81 / 291 (27.84%)
    143 / 619 (23.10%)
         number of deaths (all causes)
    5
    13
    7
    8
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute promyelocytic leukaemia
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign ovarian tumour
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammatory pseudotumour
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoproliferative disorder
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoclonal gammopathy
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelofibrosis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer stage III
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of pharynx
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal cancer
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 305 (0.33%)
    2 / 605 (0.33%)
    1 / 291 (0.34%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 305 (0.00%)
    3 / 605 (0.50%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Penetrating aortic ulcer
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis necrotising
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Implant site haematoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue inflammation
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genital haemorrhage
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic prolapse
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Asthma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    1 / 291 (0.34%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diaphragmatic disorder
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    2 / 291 (0.69%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 305 (0.00%)
    3 / 605 (0.50%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Persistent depressive disorder
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device loosening
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 305 (0.66%)
    2 / 605 (0.33%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 305 (0.66%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 305 (0.33%)
    2 / 605 (0.33%)
    2 / 291 (0.69%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle injury
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Patella fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative thrombosis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin injury
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    2 / 305 (0.66%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    2 / 291 (0.69%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound necrosis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 305 (0.33%)
    3 / 605 (0.50%)
    0 / 291 (0.00%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 305 (0.00%)
    3 / 605 (0.50%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 305 (0.33%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    6 / 619 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral artery embolism
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 305 (0.00%)
    4 / 605 (0.66%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cubital tunnel syndrome
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness postural
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IIIrd nerve paralysis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial mass
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mononeuropathy multiplex
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myxoedema coma
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylitic myelopathy
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    2 / 291 (0.69%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulnar tunnel syndrome
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 305 (0.00%)
    3 / 605 (0.50%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Inner ear disorder
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 305 (0.33%)
    3 / 605 (0.50%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal perforation
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scleritis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    2 / 291 (0.69%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric volvulus
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal angiodysplasia haemorrhagic
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids thrombosed
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    2 / 291 (0.69%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    2 / 291 (0.69%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sphincter of Oddi dysfunction
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous vasculitis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis bullous
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity vasculitis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 305 (0.00%)
    5 / 605 (0.83%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    5 / 619 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urethral
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis interstitial
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IgA nephropathy
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incontinence
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lupus nephritis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 305 (0.00%)
    3 / 605 (0.50%)
    1 / 291 (0.34%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stag horn calculus
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 305 (0.00%)
    3 / 605 (0.50%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 305 (0.66%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    2 / 291 (0.69%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atlantoaxial instability
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    2 / 305 (0.66%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Finger deformity
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    2 / 291 (0.69%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 305 (0.00%)
    3 / 605 (0.50%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mixed connective tissue disease
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 305 (0.66%)
    3 / 605 (0.50%)
    9 / 291 (3.09%)
    9 / 619 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 305 (0.00%)
    6 / 605 (0.99%)
    2 / 291 (0.69%)
    5 / 619 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    2 / 305 (0.66%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 305 (0.33%)
    2 / 605 (0.33%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Beta haemolytic streptococcal infection
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis infective staphylococcal
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 305 (0.98%)
    12 / 605 (1.98%)
    4 / 291 (1.37%)
    10 / 619 (1.62%)
         occurrences causally related to treatment / all
    2 / 3
    7 / 12
    5 / 5
    7 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis infected
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 305 (0.66%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 305 (0.00%)
    4 / 605 (0.66%)
    0 / 291 (0.00%)
    5 / 619 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective tenosynovitis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 305 (0.66%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical device site joint infection
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis pneumococcal
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Necrotising fasciitis
         subjects affected / exposed
    1 / 305 (0.33%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    2 / 305 (0.66%)
    2 / 605 (0.33%)
    1 / 291 (0.34%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 305 (1.31%)
    9 / 605 (1.49%)
    8 / 291 (2.75%)
    19 / 619 (3.07%)
         occurrences causally related to treatment / all
    3 / 4
    5 / 9
    5 / 8
    11 / 22
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyomyositis
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 305 (0.33%)
    3 / 605 (0.50%)
    6 / 291 (2.06%)
    5 / 619 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    3 / 6
    3 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    3 / 291 (1.03%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Staphylococcal abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    1 / 291 (0.34%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal endocarditis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 305 (0.00%)
    2 / 605 (0.33%)
    0 / 291 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    2 / 291 (0.69%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 305 (0.33%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 305 (0.00%)
    1 / 605 (0.17%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperlipidaemia
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 305 (0.33%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoproteinaemia
         subjects affected / exposed
    0 / 305 (0.00%)
    0 / 605 (0.00%)
    0 / 291 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo to 50 mg q4w due to EE/LE or CO Sirukumab 50 mg q4w Start Placebo to 100 mg q2w due to EE/LE or CO Sirukumab 100 mg q2w Start
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    139 / 305 (45.57%)
    268 / 605 (44.30%)
    135 / 291 (46.39%)
    281 / 619 (45.40%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    27 / 305 (8.85%)
    35 / 605 (5.79%)
    29 / 291 (9.97%)
    47 / 619 (7.59%)
         occurrences all number
    30
    50
    39
    65
    Aspartate aminotransferase increased
         subjects affected / exposed
    16 / 305 (5.25%)
    22 / 605 (3.64%)
    18 / 291 (6.19%)
    35 / 619 (5.65%)
         occurrences all number
    17
    32
    22
    50
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 305 (4.59%)
    31 / 605 (5.12%)
    14 / 291 (4.81%)
    31 / 619 (5.01%)
         occurrences all number
    16
    33
    15
    35
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    5 / 305 (1.64%)
    23 / 605 (3.80%)
    14 / 291 (4.81%)
    33 / 619 (5.33%)
         occurrences all number
    8
    30
    17
    46
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    10 / 305 (3.28%)
    16 / 605 (2.64%)
    17 / 291 (5.84%)
    26 / 619 (4.20%)
         occurrences all number
    29
    85
    58
    245
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    35 / 305 (11.48%)
    80 / 605 (13.22%)
    30 / 291 (10.31%)
    65 / 619 (10.50%)
         occurrences all number
    52
    117
    42
    86
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    29 / 305 (9.51%)
    32 / 605 (5.29%)
    20 / 291 (6.87%)
    41 / 619 (6.62%)
         occurrences all number
    30
    42
    24
    60
    Upper respiratory tract infection
         subjects affected / exposed
    30 / 305 (9.84%)
    52 / 605 (8.60%)
    35 / 291 (12.03%)
    62 / 619 (10.02%)
         occurrences all number
    41
    77
    55
    97
    Urinary tract infection
         subjects affected / exposed
    11 / 305 (3.61%)
    24 / 605 (3.97%)
    15 / 291 (5.15%)
    17 / 619 (2.75%)
         occurrences all number
    14
    29
    21
    30
    Viral upper respiratory tract infection
         subjects affected / exposed
    37 / 305 (12.13%)
    73 / 605 (12.07%)
    36 / 291 (12.37%)
    80 / 619 (12.92%)
         occurrences all number
    56
    139
    58
    154

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2013
    The amendment included the following important changes 1) Details on the study design, study design rationale, primary and secondary objectives, duration of blinded/open-label treatment, phases, dose regimen, treatment duration (related to the overall sirukumab exposure for a subject from the start of the primary study to the end of his/her LTE study participation), and description on study assessments were updated for clarity, 2) A summary of the PFS-AI and instructions on training to use the PFS-AI were added, 3) Birth control measures were revised. The rationale for cautious coadministration of sirukumab with CYP3A4 substrate drugs was added.
    01 May 2014
    The amendment included the following important changes 1) Efficacy assessments at Week 180 were added, 2) Statement of PK and immunogenicity analyses to be performed in subjects enrolled from the study CNTO136ARA3002 was updated to reflect the number of subjects (750) instead of the percent (50%) previously specified, 3) Tofacitinib and any other biologic therapy for RA were added as prohibited medications during the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the study’s early termination, the full intended length of observation and amount of safety and efficacy data collected for subjects receiving sirukumab treatment was not achieved.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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