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    Clinical Trial Results:
    Phase 3b/4 Randomized Safety Endpoint Study of 2 Doses of Tofacitinib in Comparison to a Tumor Necrosis Factor (TNF) Inhibitor in Subjects with Rheumatoid Arthritis

    Summary
    EudraCT number
    		 2013-003177-99
    Trial protocol
    		 CZ   SE   FI   NL   SK   GB   ES   AT  
    Global end of trial date
    22 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Aug 2021
    First version publication date
    06 Aug 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A3921133
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02092467
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    13 May 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of tofacitinib at two doses versus tumor necrosis factor inhibitor (TNFi).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 All subjects were enrolled taking background methotrexate.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Mar 2014
    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: 253
    Country: Number of subjects enrolled
    Australia: 53
    Country: Number of subjects enrolled
    Brazil: 251
    Country: Number of subjects enrolled
    Bulgaria: 81
    Country: Number of subjects enrolled
    Canada: 67
    Country: Number of subjects enrolled
    Chile: 96
    Country: Number of subjects enrolled
    China: 2
    Country: Number of subjects enrolled
    Colombia: 107
    Country: Number of subjects enrolled
    Czechia: 262
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    Hong Kong: 25
    Country: Number of subjects enrolled
    Israel: 157
    Country: Number of subjects enrolled
    Jordan: 13
    Country: Number of subjects enrolled
    Lebanon: 4
    Country: Number of subjects enrolled
    Malaysia: 18
    Country: Number of subjects enrolled
    Mexico: 580
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    New Zealand: 23
    Country: Number of subjects enrolled
    Peru: 308
    Country: Number of subjects enrolled
    Poland: 1124
    Country: Number of subjects enrolled
    Puerto Rico: 8
    Country: Number of subjects enrolled
    Russian Federation: 229
    Country: Number of subjects enrolled
    Slovakia: 64
    Country: Number of subjects enrolled
    South Africa: 412
    Country: Number of subjects enrolled
    Spain: 87
    Country: Number of subjects enrolled
    Taiwan: 69
    Country: Number of subjects enrolled
    Thailand: 82
    Country: Number of subjects enrolled
    Turkey: 44
    Country: Number of subjects enrolled
    United Kingdom: 83
    Country: Number of subjects enrolled
    United States: 2035
    Worldwide total number of subjects
    6559
    EEA total number of subjects
    1640
    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)
    4204
    From 65 to 84 years
    2321
    85 years and over
    34

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study started from 14 March 2014 and completed on 22 July 2020.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tofacitinib 5 mg BID
    Arm description
    		 Subjects received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Subjects were followed up for at least 28 days after last dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tofacitinib
    Investigational medicinal product code
    Other name
    CP-690,550
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tofacitinib 5 mg tablet orally BID.

    Arm title
    		 Tofacitinib 10 mg BID
    Arm description
    		 Subjects received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Subjects were followed up for at least 28 days after last dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tofacitinib
    Investigational medicinal product code
    Other name
    CP-690,550
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tofacitinib 10 mg tablet orally BID.

    Arm title
    		 TNFi
    Arm description
    		 In the United States (US), Puerto Rico and Canada, subjects randomised to TNFi arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, subjects randomised to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Subjects were followed up for at least 28 days after last dose of study drug.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received adalimumab 40 mg SC QOW.

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received adalimumab 50 mg SC once weekly.

    Number of subjects in period 1 [1]
    		Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Started
    1455
    1456
    1451
    Completed
    1053
    998
    1060
    Not completed
    402
    458
    391
         Consent withdrawn by subject
    282
    327
    289
         Death
    49
    66
    38
         Unspecified
    32
    30
    24
         Lost to follow-up
    38
    35
    40
         Global Deterioration of Health Status
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline analysis was performed on safety analysis set which included all subjects who were randomised in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tofacitinib 5 mg BID
    Reporting group description
    		 Subjects received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Subjects were followed up for at least 28 days after last dose of study drug.

    Reporting group title
    Tofacitinib 10 mg BID
    Reporting group description
    		 Subjects received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Subjects were followed up for at least 28 days after last dose of study drug.

    Reporting group title
    TNFi
    Reporting group description
    		 In the United States (US), Puerto Rico and Canada, subjects randomised to TNFi arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, subjects randomised to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Subjects were followed up for at least 28 days after last dose of study drug.

    Reporting group values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi Total
    Number of subjects
    		 1455 1456 1451 4362
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 1042 978 989 3009
        From 65-84 years
    		 412 477 457 1346
        85 years and over
    		 1 1 5 7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.75 ( 6.80 ) 61.40 ( 7.07 ) 61.30 ( 7.47 ) -
    Sex: Female, Male
    Units: subjects
        Female
    		 1169 1124 1117 3410
        Male
    		 286 332 334 952
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 1128 1126 1099 3353
        Black or African American
    		 63 65 83 211
        Asian
    		 65 56 55 176
        Other
    		 199 209 214 622
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 438 482 470 1390
        Not Hispanic or Latino
    		 1017 974 981 2972
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Tofacitinib 5 mg BID
    Reporting group description
    		 Subjects received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Subjects were followed up for at least 28 days after last dose of study drug.

    Reporting group title
    Tofacitinib 10 mg BID
    Reporting group description
    		 Subjects received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Subjects were followed up for at least 28 days after last dose of study drug.

    Reporting group title
    TNFi
    Reporting group description
    		 In the United States (US), Puerto Rico and Canada, subjects randomised to TNFi arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, subjects randomised to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Subjects were followed up for at least 28 days after last dose of study drug.

    Subject analysis set title
    All Tofacitinib
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who received treatment in either tofacitinib 5 mg or tofacitinib 10 mg group BID up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.

    Primary: Incidence Rate of Adjudicated Malignancies Excluding Non-melanoma Skin Cancers (NMSC)

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    End point title
    		 Incidence Rate of Adjudicated Malignancies Excluding Non-melanoma Skin Cancers (NMSC)
    End point description
    Incidence rate (number of subjects with event per 100 subject year [SY]) was defined as the total number of subjects with admissible events divided by the total (for all qualifying subjects) time at risk for the cohort/treatment group of interest. Malignancy excluding NMSC were adjudicated by a steering committee. The risk period (RP) was the last contact date. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a subject died, last contact date was the death date. First events were counted within the RP. If a subject did not have an event or had an event but outside the risk period, the subject was censored at the end of RP. The Safety Analysis Set (SAS) included all subjects who were randomised in the study and received at least one dose of the randomised investigational drug (tofacitinib or TNFi).
    End point type
    Primary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi All Tofacitinib
    Number of subjects analysed
    1455
    1456
    1451
    2911
    Units: subjects with event/100 SY
        number (confidence interval 95%)
    1.13 (0.87 to 1.45)
    1.13 (0.86 to 1.45)
    0.77 (0.55 to 1.04)
    1.13 (0.94 to 1.35)
    Statistical analysis title
    		 Tofacitinib 10 mg BID versus Tofacitinib 5 mg BID
    Statistical analysis description
    Secondary comparison. Non-inferiority was to be claimed between tofacitinib 10 mg BID and tofacitinib 5 mg BID if the upper limit of the 95% CI for HR was < 2.0 (non-inferiority criterion).
    Comparison groups
    Tofacitinib 5 mg BID v Tofacitinib 10 mg BID
    Number of subjects included in analysis
    2911
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.43
    Notes
    [1] - Hazard ratio (95 percent [%] confidence interval [CI]) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
    Statistical analysis title
    		 Tofacitinib 5 mg BID versus TNFi
    Statistical analysis description
    Supportive analysis to the primary comparison between All Tofacitinib vs TNFi.
    Comparison groups
    Tofacitinib 5 mg BID v TNFi
    Number of subjects included in analysis
    2906
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.18
    Notes
    [2] - Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
    Statistical analysis title
    		 Tofacitinib 10 mg BID versus TNFi
    Statistical analysis description
    Supportive analysis to the primary comparison between All Tofacitinib vs TNFi.
    Comparison groups
    TNFi v Tofacitinib 10 mg BID
    Number of subjects included in analysis
    2907
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.19
    Notes
    [3] - Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
    Statistical analysis title
    		 All Tofacitinib versus TNFi
    Statistical analysis description
    Primary comparison. Non-inferiority was to be claimed between All Tofacitinib and TNFi if the upper limit of the 95% CI for HR was < 1.8 (non-inferiority criterion).
    Comparison groups
    TNFi v All Tofacitinib
    Number of subjects included in analysis
    4362
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 2.09
    Notes
    [4] - Hazard ratio (95% CI) was based on a univariate Cox proportional hazard model with treatment [All Tofacitinib (ie, tofacitinib 5 mg BID and tofacitinib 10 mg BID combined) and TNFi] as covariate.

    Primary: Incidence Rate of Adjudicated Major Adverse Cardiovascular Events (MACE)

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    End point title
    		 Incidence Rate of Adjudicated Major Adverse Cardiovascular Events (MACE)
    End point description
    MACE included the cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke of any classification, including reversible focal neurologic defects with imaging evidence of a new cerebral lesion consistent with ischemia or hemorrhage. Incidence rate was defined as the total number of subjects with admissible events divided by the total (for all qualifying subjects) time at risk for the cohort/treatment group of interest. Risk period (RP): minimum of last contact date or last study treatment dose date + 60 days. The last contact date was the maximum of (AE start, AE stop, last study visit, withdrawal, telephone contact date). If a subject died, last contact was the death date. First events were counted within the RP. If a subject did not have an event or had an event but outside the risk period, the subject was censored at the end of RP. SAS included all subjects who were randomised in the study and received at least one dose of the randomised investigational drug.
    End point type
    Primary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi All Tofacitinib
    Number of subjects analysed
    1455
    1456
    1451
    2911
    Units: subjects with event/100 SY
        number (confidence interval 95%)
    0.91 (0.67 to 1.21)
    1.05 (0.78 to 1.38)
    0.73 (0.52 to 1.01)
    0.98 (0.79 to 1.19)
    Statistical analysis title
    		 Tofacitinib 10 mg BID versus Tofacitinib 5 mg BID
    Statistical analysis description
    Secondary Comparison. Non-inferiority was to be claimed between tofacitinib 10 mg BID and tofacitinib 5 mg BID if the upper limit of the 95% CI for HR was <2.0 (non-inferiority criterion).
    Comparison groups
    Tofacitinib 5 mg BID v Tofacitinib 10 mg BID
    Number of subjects included in analysis
    2911
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.71
    Notes
    [5] - Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
    Statistical analysis title
    		 Tofacitinib 5 mg BID versus TNFi
    Statistical analysis description
    Supportive analysis to the primary comparison between All Tofacitinib vs TNFi.
    Comparison groups
    Tofacitinib 5 mg BID v TNFi
    Number of subjects included in analysis
    2906
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.91
    Notes
    [6] - Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
    Statistical analysis title
    		 Tofacitinib 10 mg BID versus TNFi
    Statistical analysis description
    Supportive analysis to the primary comparison between All Tofacitinib vs TNFi.
    Comparison groups
    Tofacitinib 10 mg BID v TNFi
    Number of subjects included in analysis
    2907
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 2.18
    Notes
    [7] - Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
    Statistical analysis title
    		 All Tofacitinib versus TNFi
    Statistical analysis description
    Primary comparison. Non-inferiority was to be claimed between All Tofacitinib and TNFi if the upper limit of the 95% CI for HR was < 1.8 (non-inferiority criterion).
    Comparison groups
    TNFi v All Tofacitinib
    Number of subjects included in analysis
    4362
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.94
    Notes
    [8] - Hazard ratio (95% CI) was based on a univariate Cox proportional hazard model with treatment [All Tofacitinib (ie, tofacitinib 5 mg BID and tofacitinib 10 mg BID combined) and TNFi] as covariate.

    Secondary: Incidence Rate of Non-fatal Stroke

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    End point title
    		 Incidence Rate of Non-fatal Stroke
    End point description
    Non-fatal stroke included reversible focal neurologic defects with imaging evidence of a new cerebral lesion consistent with ischemia or hemorrhage. Incidence rate was defined as the total number of subjects with admissible events divided by the total (for all qualifying subjects) time at risk for the cohort/treatment group of interest. The RP was minimum of last contact date or last study treatment dose date + 60 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a subject died, last contact date was the death date. First events were counted within the RP. If a subject did not have an event or had an event but outside the risk period, the subject was censored at the end of RP. SAS included all subjects who were randomised in the study and received at least one dose of the randomised investigational drug (tofacitinib or TNFi).
    End point type
    Secondary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects with event/100 SY
        number (confidence interval 95%)
    0.27 (0.15 to 0.45)
    0.33 (0.19 to 0.53)
    0.34 (0.20 to 0.54)
    No statistical analyses for this end point

    Secondary: Incidence Rate of Non-fatal Myocardial Infarction

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    End point title
    		 Incidence Rate of Non-fatal Myocardial Infarction
    End point description
    Incidence rate was defined as the total number of subjects with admissible events divided by the total (for all qualifying subjects) time at risk for the cohort/treatment group of interest. The RP was minimum of last contact date or last study treatment dose date + 60 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a subject died, last contact date was the death date. First events were counted within the RP. If a subject did not have an event or had an event but outside the risk period, the subject was censored at the end of RP. SAS included all subjects who were randomised in the study and received at least one dose of the randomised investigational drug (tofacitinib or TNFi).
    End point type
    Secondary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects with event/100 SY
        number (confidence interval 95%)
    0.37 (0.22 to 0.57)
    0.33 (0.19 to 0.53)
    0.16 (0.07 to 0.31)
    No statistical analyses for this end point

    Secondary: Incidence Rate of Adjudicated Opportunistic Infection Events Including Tuberculosis

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    End point title
    		 Incidence Rate of Adjudicated Opportunistic Infection Events Including Tuberculosis
    End point description
    Opportunistic infections (OI) were reviewed and adjudicated by the opportunistic infection review committee (OIRC). Incidence rate was defined as the total number of subjects with admissible events divided by the total (for all qualifying subjects) time at risk for the cohort/treatment group of interest. The RP was the minimum of last contact date or last study treatment dose date + 28 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a subject died, last contact date was the death date. First events were counted within the RP. If a subject did not have an event or had an event but outside the risk period, the subject was censored at the end of RP. SAS included all subjects who were randomised in the study and received at least one dose of the randomised investigational drug (tofacitinib or TNFi).
    End point type
    Secondary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects with event/100 SY
        number (confidence interval 95%)
    0.76 (0.54 to 1.04)
    0.91 (0.66 to 1.22)
    0.42 (0.26 to 0.64)
    No statistical analyses for this end point

    Secondary: Incidence Rate of Adjudicated Hepatic Events

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    End point title
    		 Incidence Rate of Adjudicated Hepatic Events
    End point description
    Hepatic events (adjudicated) included drug-induced liver injury (DILI) - probable, highly likely and definite, DILI – listed separately, DILI – cases meeting classification and severity, subjects with elevations of transaminase levels greater than (>) 1* upper limit of normal (ULN), greater than or equal to (>=) 3*ULN, >=5*ULN (based on laboratory values). Incidence rate was defined as total number of subjects with admissible events divided by total (for all qualifying subjects) time at risk for the cohort/treatment group of interest. RP was minimum of last contact or last study treatment dose date+28 days. Last contact date was maximum of AE start, AE stop, last study visit, withdrawal, telephone contact date. In case of death, last contact was the death date. First events counted within RP. Subject did not have event or had event outside RP were censored at end of RP. SAS included: subjects randomised in study and received at least one dose of the randomised investigational drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects with event/100 SY
        number (confidence interval 95%)
    0.90 (0.66 to 1.20)
    1.51 (1.18 to 1.91)
    0.70 (0.49 to 0.97)
    No statistical analyses for this end point

    Secondary: Incidence Rate of Adjudicated Cardiovascular Events Other Than Major Adverse Cardiovascular Events (MACE)

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    End point title
    		 Incidence Rate of Adjudicated Cardiovascular Events Other Than Major Adverse Cardiovascular Events (MACE)
    End point description
    Cardiovascular events (adjudicated by a Cardiovascular Endpoint Adjudication Committee) included death (coronary and non-coronary), MI, all coronary revascularization, unstable angina, new ischemic heart disease, stroke (fatal and non-fatal), transient ischemic attack, congestive heart failure, peripheral arterial vascular disease–first diagnosis or procedure, deep vein thrombosis, pulmonary embolism, arterial embolism, arterial thrombosis. Incidence rate: total number of subjects with admissible events divided by total (for all qualifying subjects) time at risk for cohort/treatment group of interest. RP: minimum of last contact or last study treatment dose date +28 days. Last contact date was death date or maximum of dates: AE start, AE stop, last study visit, withdrawal, telephone contact. First events counted within RP. Subject without event or event outside RP were censored at end of RP. SAS: all subjects randomised in study and received at least one dose of drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects with event/100 SY
        number (confidence interval 95%)
    1.21 (0.92 to 1.55)
    1.45 (1.13 to 1.83)
    1.05 (0.78 to 1.38)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    AE was any untoward medical occurrence post treatment; event need not necessarily had causal relationship with the treatment or usage. SAE was any untoward medical occurrence at any dose: resulted in death, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in congenital anomaly. TEAE was an event that occurred for first time during effective duration of treatment and not seen prior to start of treatment or event seen prior to the start of treatment but increase in severity during treatment. RP for AEs: minimum of last contact date or last study treatment dose + 28 days. RP for SAEs: last contact date. Last contact date was death date or maximum of dates: AE start, AE stop, last study visit, withdrawal, telephone contact. First events counted within RP. SAS: subjects randomised in the study and received at least one dose of randomised drug.
    End point type
    Secondary
    End point timeframe
    AEs: Baseline up to minimum of last contact date or last study treatment dose date+28 days (maximum up to 72 months); SAEs: Baseline up to minimum of last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects
        AEs
    1333
    1344
    1308
        SAEs
    373
    420
    339
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Abnormal Laboratory Parameters

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    End point title
    		 Number of Subjects With Clinically Significant Abnormal Laboratory Parameters
    End point description
    Clinically significant laboratory abnormalities: Hematology: hemoglobin, hematocrit, erythrocytes less than [<] 0.8* lower limit of normal [LLN]), platelets (<0.5* LLN; >1.75* ULN), leukocytes (<0.6*LLN; >1.5*ULN), lymphocytes, neutrophils (<0.8*LLN; >1.2*ULN), eosinophils, monocytes (>1.2*ULN); urinalysis: glucose, protein, hemoglobin, and leukocyte esterase (>=1); chemistry: bilirubin, indirect bilirubin (>1.5*ULN) aspartate aminotransferase, alanine aminotransferase (>3.0*ULN), creatinine, triglycerides, cholesterol (>1.3*ULN) and HDL cholesterol (<0.8*LLN). RP was minimum of last contact date or last study treatment dose date +28 days. Last contact date was (date of death or maximum of dates: AE start, AE stop, last study visit, withdrawal, telephone contact). Subjects without event or event outside RP were censored at end of RP. Analysis population: all subjects in SAS with abnormal baseline and >=1 observation of given laboratory test within RP.
    End point type
    Secondary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    919
    911
    915
    Units: subjects
    238
    252
    167
    No statistical analyses for this end point

    Secondary: Incidence Rate of Adjudicated All-Cause Deaths

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    End point title
    		 Incidence Rate of Adjudicated All-Cause Deaths
    End point description
    All-cause death was defined as the death due to any cause during the course of study. Incidence rate was defined as the total number of subjects with admissible events divided by the total (for all qualifying subjects) time at risk for the cohort/treatment group of interest. Incidence rate of all-cause deaths (adjudicated by Adjudication Committee) was reported in this endpoint. The RP was the minimum of last contact date or last study treatment dose date + 28 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a subject died, last contact date was the death date. First events were counted within the RP. If a subject did not have an event or had an event but outside the risk period, the subject was censored at the end of RP. SAS included all subjects who were randomised in the study and received at least one dose of the randomised investigational drug (tofacitinib or TNFi).
    End point type
    Secondary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects with event/100 SY
    number (confidence interval 95%)
        Deaths-Total
    0.50 (0.33 to 0.74)
    0.80 (0.57 to 1.09)
    0.34 (0.20 to 0.54)
        Deaths-Infections
    0.08 (0.02 to 0.20)
    0.18 (0.08 to 0.35)
    0.06 (0.01 to 0.17)
        Deaths-Cardiovascular Events
    0.25 (0.13 to 0.43)
    0.41 (0.25 to 0.63)
    0.20 (0.10 to 0.36)
        Deaths-Malignancies
    0.10 (0.03 to 0.23)
    0.00 (0.00 to 0.08)
    0.02 (0.00 to 0.11)
        Deaths-Other Causes
    0.08 (0.02 to 0.20)
    0.21 (0.10 to 0.38)
    0.06 (0.01 to 0.17)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Reasons For Permanent or Temporary Discontinuation of Study Medication

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    End point title
    		 Number of Subjects With Reasons For Permanent or Temporary Discontinuation of Study Medication
    End point description
    Number of subjects who permanent or temporary discontinued study medication due to any AE, treatment related AEs, Coronavirus disease 2019 (COVID 19) related AEs, and herpes zoster were reported. The RP was the minimum of last contact date or last study treatment dose date +28 days. The last contact date was maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a subject died, last contact date was the death date. First events were counted within the RP. If a subject did not have an event or had an event but outside the risk period, the subject was censored at the end of RP. SAS included all subjects who were randomised in the study and received at least one dose of the randomised investigational drug (tofacitinib or TNFi).
    End point type
    Secondary
    End point timeframe
    Baseline up to last contact date (maximum up to 72 months)
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects
        Permanent discontinuation: AE
    210
    304
    210
        Temporary discontinuation: AEs
    665
    736
    576
        Permanent discontinuation: treatment related AE
    111
    179
    114
        Temporary discontinuation: treatment related AE
    407
    458
    297
        Permanent discontinuation: COVID-19 Related AEs
    0
    1
    0
        Temporary discontinuation: COVID-19 Related AEs
    0
    1
    1
        Permanent discontinuation: Herpes Zoster
    6
    13
    2
        Temporary discontinuation: Herpes Zoster
    104
    110
    33
    No statistical analyses for this end point

    Secondary: Change From Baseline in Disease Activity Score 28-4 (DAS28-4) C-Reactive Protein (CRP) at Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63

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    End point title
    		 Change From Baseline in Disease Activity Score 28-4 (DAS28-4) C-Reactive Protein (CRP) at Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
    End point description
    DAS28: disease activity in subjects with rheumatoid arthritis based on 28-joint assessment. DAS28-4(CRP): number of painful joints(TJC28) and swollen joints from 28 joints(SJC28), CRP(milligrams per liter[mg/L]) and PtGA on 100 mm VAS(VAS: score range: 0-100 mm [very well-worst], higher scores=worse condition). DAS28-4(CRP) score range:0-9.4, higher score=more disease activity. DAS28-4(CRP)<=3.2=low disease activity;>3.2 to<=5.1=moderate disease activity;>5.1=high disease activity;<2.6=remission.DAS28-4(CRP)=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*ln(CRP (mg/L)+1)+0.014*PtGA in mm+0.96;ln=natural logarithm. Full Analysis Set(FAS):all randomized subjects and received at least 1 dose. Mixed model for repeated measures(MMRM) used without imputation for missing values. Analyses included data while subjects on treatment and visits with N>50 subject in-group.Number of Subjects Analyzed=number of subjects included in MMRM. Number Analysed=subjects evaluable for each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1409
    1391
    1386
    Units: units on a scale
    least squares mean (standard error)
        Change at Month 2 (n=1325,1301,1316 )
    -2.00 ( 0.03 )
    -2.14 ( 0.03 )
    -1.89 ( 0.03 )
        Change at Month 3 (n=1367, 1328, 1317)
    -2.28 ( 0.03 )
    -2.42 ( 0.03 )
    -2.19 ( 0.03 )
        Change at Month 6 (n=1336, 1298, 1294 )
    -2.50 ( 0.03 )
    -2.68 ( 0.03 )
    -2.40 ( 0.03 )
        Change at Month 9 (n=1286, 1246, 1245)
    -2.64 ( 0.03 )
    -2.80 ( 0.03 )
    -2.54 ( 0.03 )
        Change at Month 12 (n=1254, 1204, 1197)
    -2.70 ( 0.03 )
    -2.85 ( 0.03 )
    -2.60 ( 0.03 )
        Change at Month 15 (n=1218, 1171, 1174)
    -2.78 ( 0.03 )
    -2.93 ( 0.03 )
    -2.67 ( 0.03 )
        Change at Month 18 (n=1184, 1121, 1138)
    -2.78 ( 0.03 )
    -2.95 ( 0.03 )
    -2.76 ( 0.03 )
        Change at Month 21 (n=1169, 1076, 1115)
    -2.82 ( 0.03 )
    -2.97 ( 0.03 )
    -2.76 ( 0.03 )
        Change at Month 24 (n=1134, 1051, 1097)
    -2.82 ( 0.03 )
    -2.99 ( 0.03 )
    -2.77 ( 0.03 )
        Change at Month 27 (n=1099, 1015, 1045)
    -2.91 ( 0.03 )
    -3.03 ( 0.03 )
    -2.81 ( 0.03 )
        Change at Month 30 (n=1073, 999, 1039)
    -2.92 ( 0.03 )
    -3.03 ( 0.03 )
    -2.89 ( 0.03 )
        Change at Month 33 (n=1055, 974, 1037 )
    -2.89 ( 0.03 )
    -3.03 ( 0.03 )
    -2.89 ( 0.03 )
        Change at Month 36 (n=1029, 951, 1014)
    -2.91 ( 0.03 )
    -2.98 ( 0.03 )
    -2.88 ( 0.03 )
        Change at Month 39 (n=984, 888, 960)
    -2.96 ( 0.03 )
    -2.97 ( 0.03 )
    -2.91 ( 0.03 )
        Change at Month 42 (n=851, 768, 831)
    -2.95 ( 0.03 )
    -3.05 ( 0.03 )
    -2.93 ( 0.03 )
        Change at Month 45 (n=710, 642,673)
    -2.94 ( 0.04 )
    -2.96 ( 0.04 )
    -2.97 ( 0.04 )
        Change at Month 48 (n=567, 506, 537)
    -2.98 ( 0.04 )
    -2.99 ( 0.04 )
    -2.93 ( 0.04 )
        Change at Month 51 (n=458, 419, 414)
    -3.00 ( 0.04 )
    -2.95 ( 0.04 )
    -2.96 ( 0.04 )
        Change at Month 54 (n= 363, 329, 322)
    -2.99 ( 0.04 )
    -3.01 ( 0.05 )
    -2.99 ( 0.05 )
        Change at Month 57 (n= 263, 240, 247)
    -2.97 ( 0.05 )
    -2.93 ( 0.05 )
    -3.02 ( 0.05 )
        Change at Month 60 (n=182, 182, 166)
    -3.09 ( 0.06 )
    -2.94 ( 0.06 )
    -3.01 ( 0.06 )
        Change at Month 63 (n=106. 108, 96)
    -3.07 ( 0.08 )
    -2.99 ( 0.07 )
    -3.05 ( 0.08 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI) Score at Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63

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    End point title
    		 Change From Baseline in Simplified Disease Activity Index (SDAI) Score at Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
    End point description
    SDAI numerical sum of 5 outcome parameters: TJC and SJC both based on a 28-joint assessment, patient’s global assessment of health (PtGA) and physician’s global assessment of health (PhyGA) assessed on 0 to 100 millimeter(mm) VAS (higher scores=greater affection due to disease activity) and CRP(mg/L). SDAI total score ranges: 0 to 86 higher score=greater disease activity. SDAI <=3.3 = disease remission, >3.4 to 11 = low disease activity >11 to 26 =moderate disease activity, and >26 = high disease activity. SDAI = (28TJC)+(28SJC)+PhyGA/10+PtGA/10+CRP/10. FAS: all randomised subjects and received at least one dose of drug. MMRM used without imputation for missing values. Analyses included data while subjects were receiving study drug. Visits with N>50 subjects in treatment group included in analyses. Number of Subjects Analyzed: number of subjects included in mixed model for repeated measures. Number Analysed signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1378
    1356
    1346
    Units: units on a scale
    least squares mean (standard error)
        Change at Month 2 (n=1272, 1257, 1258)
    -22.95 ( 0.33 )
    -23.84 ( 0.33 )
    -22.24 ( 0.33 )
        Change at Month 3 (n=1321, 1280, 1273)
    -25.73 ( 0.30 )
    -26.81 ( 0.30 )
    -25.26 ( 0.30 )
        Change at Month 6 (n=1288, 1245, 1244)
    -27.63 ( 0.28 )
    -28.93 ( 0.28 )
    -27.21 ( 0.28 )
        Change at Month 9 (n=1244, 1204, 1197)
    -28.81 ( 0.28 )
    -30.07 ( 0.28 )
    -28.29 ( 0.28 )
        Change at Month 12 (n=1215, 1168, 1143)
    -29.56 ( 0.27 )
    -30.46 ( 0.27 )
    -28.71 ( 0.27 )
        Change at Month 15 (n=1172, 1128, 1129)
    -30.20 ( 0.25 )
    -31.15 ( 0.26 )
    -29.30 ( 0.26 )
        Change at Month 18 (n=1149, 1085, 1092)
    -30.14 ( 0.26 )
    -31.29 ( 0.26 )
    -30.18 ( 0.26 )
        Change at Month 21 (n=1138, 1040, 1072)
    -30.42 ( 0.26 )
    -31.46 ( 0.26 )
    -30.36 ( 0.26 )
        Change at Month 24 (n=1092, 1010, 1051)
    -30.51 ( 0.26 )
    -31.56 ( 0.26 )
    -30.33 ( 0.26 )
        Change at month 27 (n=1056, 979, 1002)
    -31.16 ( 0.25 )
    -31.85 ( 0.26 )
    -30.53 ( 0.26 )
        Change at Month 30 (n=1046, 970, 996)
    -31.27 ( 0.25 )
    -32.02 ( 0.25 )
    -31.24 ( 0.25 )
        Change at Month 33 (n=1027, 947, 997)
    -31.06 ( 0.26 )
    -31.91 ( 0.26 )
    -31.20 ( 0.26 )
        Change at Month 36 (n=994, 917, 978)
    -31.26 ( 0.26 )
    -31.52 ( 0.27 )
    -31.09 ( 0.26 )
        Change at Month 39 (n=954, 857, 920)
    -31.77 ( 0.25 )
    -31.51 ( 0.26 )
    -31.36 ( 0.26 )
        Change at Month 42 (n=819, 733, 800)
    -31.62 ( 0.27 )
    -32.09 ( 0.28 )
    -31.24 ( 0.27 )
        Change at Month 45 (n=692, 617, 646)
    -31.27 ( 0.29 )
    -31.67 ( 0.30 )
    -31.85 ( 0.30 )
        Change at Month 48 (n=547, 485, 522)
    -31.87 ( 0.31 )
    -31.59 ( 0.32 )
    -31.68 ( 0.32 )
        Change at Month 51 (n=438, 406, 400)
    -32.15 ( 0.33 )
    -31.52 ( 0.34 )
    -31.72 ( 0.34 )
        Change at Month 54 (n=347, 316, 314)
    -31.91 ( 0.33 )
    -32.33 ( 0.35 )
    -31.95 ( 0.35 )
        Change at Month 57 (n=253, 235, 242)
    -31.58 ( 0.41 )
    -31.61 ( 0.42 )
    -31.98 ( 0.42 )
        Change at Month 60 (n=174, 179, 161)
    -32.84 ( 0.46 )
    -31.57 ( 0.46 )
    -32.23 ( 0.48 )
        Change at Month 63 (n=102, 107, 95)
    -32.27 ( 0.63 )
    -32.12 ( 0.62 )
    -32.27 ( 0.66 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63

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    End point title
    		 Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
    End point description
    CDAI is numerical sum of four outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PhyGA both assessed on 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity). CDAI total score ranges from 0 to 76 with higher score indicating greater disease activity. CDAI <=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity. CDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10. FAS included all subjects randomized in study and received at least one dose of drug. MMRM was used without imputation for missing values. Analyses included the data while subjects were receiving the study drug. Only visits with N > 50 subjects in each treatment group were included in the analyses. Number of Subjects Analyzed: number of subjects included in MMRM. Number Analyzed 'n' signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1378
    1356
    1348
    Units: units on a scale
    least squares mean (standard error)
        Change at Month 2 (n=1272, 1258, 1264)
    -21.99 ( 0.32 )
    -22.84 ( 0.32 )
    -21.30 ( 0.32 )
        Change at Month 3 (n=1325, 1281, 1276)
    -24.76 ( 0.29 )
    -25.77 ( 0.29 )
    -24.29 ( 0.30 )
        Change at Month 6 (n=1292, 1246, 1249)
    -26.59 ( 0.27 )
    -27.82 ( 0.28 )
    -26.21 ( 0.28 )
        Change at Month 9 (n=1245, 1207, 1200)
    -27.78 ( 0.27 )
    -29.03 ( 0.27 )
    -27.30 ( 0.27 )
        Change at Month 12 (n=1217, 1169, 1146)
    -28.52 ( 0.26 )
    -29.38 ( 0.26 )
    -27.73 ( 0.26 )
        Change at Month 15 (n=1177, 1129, 1135)
    -29.17 ( 0.25 )
    -30.06 ( 0.25 )
    -28.38 ( 0.25 )
        Change at Month 18 (n=1152, 1086, 1096)
    -29.12 ( 0.25 )
    -30.21 ( 0.26 )
    -29.15 ( 0.25 )
        Change at Month 21 (n=1141, 1041, 1075)
    -29.45 ( 0.25 )
    -30.49 ( 0.26 )
    -29.40 ( 0.25 )
        Change at Month 24 (n=1093, 1013, 1055)
    -29.54 ( 0.25 )
    -30.49 ( 0.26 )
    -29.39 ( 0.25 )
        Change at Month 27 (n=1058 , 979, 1011)
    -30.16 ( 0.24 )
    -30.82 ( 0.25 )
    -29.54 ( 0.25 )
        Change at Month 30 (n=1049, 970, 1002)
    -30.27 ( 0.24 )
    -30.99 ( 0.25 )
    -30.24 ( 0.25 )
        Change at Month 33 (n=1034, 951, 1000)
    -30.05 ( 0.25 )
    -30.85 ( 0.25 )
    -30.23 ( 0.25 )
        Change at Month 36 (n=999, 920, 982)
    -30.29 ( 0.25 )
    -30.50 ( 0.26 )
    -30.14 ( 0.25 )
        Change at Month 39 (n=958, 858, 923)
    -30.78 ( 0.24 )
    -30.49 ( 0.25 )
    -30.35 ( 0.25 )
        Change at Month 42 (n=820, 736, 801)
    -30.66 ( 0.26 )
    -31.05 ( 0.27 )
    -30.25 ( 0.26 )
        Change at Month 45 (n=694, 618, 650)
    -30.28 ( 0.28 )
    -30.68 ( 0.29 )
    -30.83 ( 0.29 )
        Change at Month 48 (n=547, 487, 522)
    -30.85 ( 0.30 )
    -30.57 ( 0.32 )
    -30.69 ( 0.31 )
        Change at Month 51 (n=440, 407, 401)
    -31.09 ( 0.32 )
    -30.50 ( 0.33 )
    -30.74 ( 0.33 )
        Change at Month 54 (n=347, 317, 314)
    -31.03 ( 0.32 )
    -31.38 ( 0.33 )
    -31.02 ( 0.33 )
        Change at Month 57 (n=254, 236, 242)
    -30.62 ( 0.40 )
    -30.75 ( 0.41 )
    -30.95 ( 0.41 )
        Change at Month 60 (n=175, 179, 161)
    -31.74 ( 0.45 )
    -30.57 ( 0.45 )
    -31.31 ( 0.47 )
        Change at Month 63 (n=102, 107, 95)
    -31.23 ( 0.58 )
    -31.08 ( 0.57 )
    -31.65 ( 0.60 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Observed American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean Remission Criteria

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    End point title
    		 Percentage of Subjects Who Achieved Observed American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean Remission Criteria
    End point description
    ACR-EULAR Boolean-based definition of remission subject must satisfy all of the following: TJC28 <=1, SJC28 <=1, CRP <=10 mg/L, PtGA on a 0-100 mm scale, higher scores indicate greater affection due to disease activity. FAS included all subjects who were randomised in the study and received at least one dose of the randomised investigational drug (tofacitinib or TNFi). Analyses included the data while the subjects were receiving the study drug. Here, Number Analysed ‘n’ signifies number of subjects evaluable for each specified time point. Last observation carried forward (LOCF) was applied for missing components, and then composite binary endpoint was calculated. The percentages were calculated using the numbers of subjects evaluable at each visit as the denominators.
    End point type
    Secondary
    End point timeframe
    Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: percentage of subjects
    number (not applicable)
        Month 2 (n=1356, 1342, 1368)
    3.83
    4.99
    3.22
        Month 3 (n=1432, 1424, 1427)
    5.73
    7.72
    6.10
        Month 6 (n=1417, 1398, 1411)
    9.10
    10.66
    7.80
        Month 9 (n=1392, 1349, 1384)
    10.85
    12.60
    8.96
        Month 12 (n=1372, 1332, 1360)
    11.22
    13.06
    9.12
        Month 15 (n=1353, 1311, 1342)
    12.56
    15.18
    10.28
        Month 18 (n=1322, 1284, 1316)
    12.10
    16.04
    11.78
        Month 21 (n=1302, 1255, 1294)
    12.90
    15.22
    13.45
        Month 24 (n=1287, 1226, 1273)
    13.60
    15.99
    13.35
        Month 27 (n=1269, 1211, 1255)
    13.24
    17.59
    14.82
        Month 30 (n=1248, 1191, 1237)
    13.46
    16.96
    14.31
        Month 33 (n=1232, 1177, 1221)
    13.88
    15.97
    14.82
        Month 36 (n=1206, 1162, 1211)
    14.51
    16.18
    14.53
        Month 39 (n=1183, 1140, 1201)
    13.78
    14.30
    15.15
        Month 42 (n=1163, 1110, 1179)
    14.79
    15.41
    15.01
        Month 45 (n=1021, 970, 1023)
    14.89
    15.46
    15.74
        Month 48 (n=865, 806, 839)
    15.14
    13.90
    17.28
        Month 51 (n=698, 671, 689)
    14.33
    15.50
    16.26
        Month 54 (n=564, 548, 550)
    14.01
    16.42
    16.36
        Month 57 (n=444, 445, 431)
    15.54
    14.16
    15.08
        Month 60 (n=327, 330, 321)
    11.31
    12.73
    15.58
        Month 63 (n=221, 230, 223)
    11.76
    16.96
    15.25
        Month 66 (n=122, 131, 122)
    9.02
    16.79
    13.11
        Month 69 (n=46, 46, 48)
    13.04
    19.57
    14.58
        Month 72 (n=12, 18, 15)
    8.33
    22.22
    13.33
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Simplified Disease Activity Index (SDAI) Less Than or Equal to (<=) 3.3

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    End point title
    		 Percentage of Subjects With Simplified Disease Activity Index (SDAI) Less Than or Equal to (<=) 3.3
    End point description
    SDAI is numerical sum of five outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PhyGA both assessed on a 0 to 100 mm VAS (higher scores = greater affection due to disease activity), and CRP (mg/L). SDAI total score ranges from 0 to 86 with higher score indicating greater disease activity. SDAI <=3.3 indicates disease remission, >3.4 to 11 = low disease activity >11 to 26 = moderate disease activity, and >26 = high disease activity. SDAI = (28TJC) + (28SJC) + PhyGA/10+ PtGA/10 + CRP/10. FAS: all subjects randomised in the study and received at least one dose of randomised investigational drug. Analyses included the data while the subjects receiving the study drug. Here, Number Analysed ‘n’ signifies number of subjects evaluable for each specified time point. LOCF was applied for missing components, and then composite binary endpoint was calculated.
    End point type
    Secondary
    End point timeframe
    Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: percentage of subjects
    number (not applicable)
        Month 2 (n=1320, 1308, 1325)
    4.62
    7.03
    4.15
        Month 3 (n=1425, 1409, 1416)
    9.19
    11.14
    7.84
        Month 6 (n=1414, 1391, 1404)
    12.38
    14.23
    10.40
        Month 9 (n=1390, 1349, 1380)
    15.90
    17.72
    12.75
        Month 12 (n=1372, 1332, 1358)
    15.89
    18.69
    13.92
        Month 15 (n=1353, 1311, 1340)
    18.26
    20.29
    15.90
        Month 18 (n=1322, 1284, 1316)
    18.68
    21.96
    16.79
        Month 21 (n=1302, 1255, 1294)
    20.89
    22.07
    17.93
        Month 24 (n=1287, 1226, 1273)
    20.44
    22.76
    18.93
        Month 27 (n=1269, 1211, 1255)
    21.91
    23.62
    21.12
        Month 30 (n=1248, 1191, 1237)
    21.31
    23.68
    21.91
        Month 33 (n=1232, 1177, 1221)
    21.43
    25.06
    22.19
        Month 36 (n=1206, 1162, 1211)
    22.47
    24.35
    21.80
        Month 39 (n=1183, 1140, 1201)
    22.99
    24.21
    21.48
        Month 42 (n=1163, 1110, 1179)
    24.59
    24.23
    23.41
        Month 45 (n=1021, 970, 1023)
    25.27
    23.20
    23.26
        Month 48 (n=865, 806, 839)
    25.32
    23.20
    24.20
        Month 51 (n=698, 671, 689)
    23.35
    23.85
    24.24
        Month 54 (n=564, 548, 550)
    22.34
    24.09
    24.55
        Month 57 (n=444, 445, 431)
    24.10
    23.82
    24.83
        Month 60 (n=327, 330, 321)
    18.65
    20.30
    25.23
        Month 63 (n=221, 230, 223)
    19.00
    23.48
    23.32
        Month 66 (n=122, 131, 122)
    14.75
    21.37
    20.49
        Month 69 (n=46, 46, 48)
    17.39
    17.39
    22.92
        Month 72 (n=12, 8, 15)
    16.67
    22.22
    13.33
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Disease Activity Index (CDAI) <=2.8 

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    End point title
    		 Percentage of Subjects With Clinical Disease Activity Index (CDAI) <=2.8 
    End point description
    CDAI is numerical sum of four outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PhyGA assessed on a 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity). CDAI total score ranges from 0 to 76 with higher score = greater disease activity. CDAI <=2.8 = disease remission, >2.8 to 10 = low disease activity, >10 to 22 = moderate disease activity, >22 = high disease activity. CDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10. FAS: all subjects randomised in the study and received at least one dose of the randomised investigational drug. Analyses included the data while subjects were receiving the study drug. Here, Number Analysed signifies number of subjects evaluable for each specified time point. LOCF was applied for missing components, and then composite binary endpoint was calculated. The percentages were calculated using the numbers of subjects evaluable at each visit as the denominators.
    End point type
    Secondary
    End point timeframe
    Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: percentage of subjects
    number (not applicable)
        Month 2 (n=1320, 1311, 1330)
    4.70
    7.40
    4.36
        Month 3 (n=1425, 1410, 1417)
    9.26
    11.06
    7.76
        Month 6 (n=1414, 1391, 1405)
    12.87
    14.31
    10.32
        Month 9 (n=1390, 1349, 1381)
    15.76
    18.09
    13.25
        Month 12 (n=1372, 1332, 1359)
    16.33
    18.62
    14.64
        Month 15 (n=1353, 1311, 1341)
    18.03
    21.36
    16.41
        Month 18 (n=1322, 1284, 1316)
    19.82
    22.12
    17.93
        Month 21 (n=1302, 1255, 1294)
    21.35
    22.55
    18.70
        Month 24 (n=1287, 1226, 1273)
    20.44
    22.76
    19.48
        Month 27 (n=1269, 1211, 1255)
    22.77
    23.29
    21.51
        Month 30 (n=1248, 1191, 1237)
    21.88
    24.18
    22.31
        Month 33 (n=1232, 1177, 1221)
    22.24
    25.91
    22.36
        Month 36 (n=1206, 1162, 1211)
    23.22
    25.30
    21.64
        Month 39 (n=1183, 1140, 1201)
    23.92
    24.30
    21.90
        Month 42 (n=1163, 1110, 1179)
    25.02
    24.95
    23.66
        Month 45 (n=1021, 970, 1023)
    25.95
    24.23
    23.85
        Month 48 (n=865, 806, 839)
    25.55
    24.44
    24.31
        Month 51 (n=698, 671, 689)
    24.50
    24.89
    25.11
        Month 54 (n=564, 548, 550)
    23.23
    25.00
    25.45
        Month 57 (n=444, 445, 431)
    24.32
    24.04
    25.75
        Month 60 (n=327, 330, 321)
    19.88
    20.91
    26.48
        Month 63 (n=221, 230, 223)
    20.81
    22.17
    22.87
        Month 66 (n=122, 131, 122)
    13.93
    22.14
    17.21
        Month 69 (n=46, 46, 48)
    19.57
    19.57
    18.75
        Month 72 (n=12, 18, 15)
    16.67
    22.22
    13.33
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Simplified Disease Activity Index (SDAI) <=11

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    End point title
    		 Percentage of Subjects With Simplified Disease Activity Index (SDAI) <=11
    End point description
    SDAI is numerical sum of five outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PGA both assessed on a 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity), and CRP (mg/L). SDAI total score ranges from 0 to 86 with higher score indicating greater disease activity. SDAI <=3.3 = disease remission, >3.4 to 11 = disease activity >11 to 26 = moderate disease activity, and >26 = high disease activity. SDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10 + CRP/10. FAS: all subjects randomised in the study and received at least one dose of the randomised investigational drug. Analyses included the data while the subjects were receiving the study drug. Number Analysed signifies number of subjects evaluable for each specified time point. LOCF was applied for missing components, and then composite binary endpoint was calculated. The percentages were calculated using the numbers of subjects evaluable at each visit as the denominators.
    End point type
    Secondary
    End point timeframe
    Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: percentage of subjects
    number (not applicable)
        Month 2 (n=1320, 1308, 1325)
    30.76
    35.02
    28.08
        Month 3 (n=1425, 1409, 1416)
    41.47
    45.00
    37.99
        Month 6 (n=1414, 1391, 1404)
    50.85
    53.56
    45.80
        Month 9 (n=1390, 1349, 1380)
    56.40
    59.82
    52.90
        Month 12 (n=1372, 1332, 1358)
    57.87
    61.11
    54.93
        Month 15 (n=1353, 1311, 1340)
    61.12
    63.92
    57.39
        Month 18 (n=1322, 1284, 1316)
    62.10
    65.19
    60.41
        Month 21 (n=1302, 1255, 1294)
    62.75
    65.26
    61.21
        Month 24 (n=1287, 1226, 1273)
    63.17
    66.15
    61.59
        Month 27 (n=1269, 1211, 1255)
    65.17
    66.97
    63.67
        Month 30 (n=1248, 1191, 1237)
    67.23
    68.35
    65.64
        Month 33 (n=1232, 1177, 1221)
    65.75
    68.82
    65.36
        Month 36 (n=1206, 1162, 1211)
    67.33
    66.61
    65.48
        Month 39 (n=1183, 1140, 1201)
    69.74
    67.11
    66.03
        Month 42 (n=1163, 1110, 1179)
    68.96
    70.72
    66.41
        Month 45 (n=1021, 970, 1023)
    68.36
    68.97
    67.55
        Month 48 (n=865, 806, 839)
    67.28
    64.76
    67.94
        Month 51 (n=698, 671, 689)
    67.91
    67.51
    67.78
        Month 54 (n=564, 548, 550)
    64.89
    68.61
    68.00
        Month 57 (n=444, 445, 431)
    63.51
    66.29
    68.21
        Month 60 (n=327, 330, 321)
    63.30
    66.67
    64.17
        Month 63 (n=221, 230, 223)
    61.54
    68.26
    64.57
        Month 66 (n=122, 131, 122)
    59.02
    71.76
    59.02
        Month 69 (n=46, 46, 48)
    60.87
    65.22
    68.75
        Month 72 (n=12, 18, 15)
    50.00
    66.67
    60.00
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Disease Activity Index (CDAI) <=10

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    End point title
    		 Percentage of Subjects With Clinical Disease Activity Index (CDAI) <=10
    End point description
    CDAI is numerical sum of four outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PhyGA assessed on a 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity). CDAI total score ranges from 0 to 76 with higher score = greater disease activity. CDAI <=2.8 = disease remission, >2.8 to 10 = low disease activity, >10 to 22 = moderate disease activity, >22 = high disease activity. CDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10. FAS: all subjects randomised in the study and received at least one dose of the randomised investigational drug. Analyses included the data while subjects were receiving the study drug. Here, Number Analysed signifies number of subjects evaluable for each specified time point. LOCF was applied for missing components, and then composite binary endpoint was calculated. The percentages were calculated using the numbers of subjects evaluable at each visit as the denominators.
    End point type
    Secondary
    End point timeframe
    Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: percentage of subjects
    number (not applicable)
        Month 2 (n=1320, 1311, 1330)
    29.47
    34.25
    26.92
        Month 3 (n=1425, 1410, 1417)
    40.07
    43.90
    35.99
        Month 6 (n=1414, 1391, 1405)
    49.36
    51.83
    43.63
        Month 9 (n=1390, 1349, 1381)
    55.40
    58.78
    50.91
        Month 12 (n=1372, 1332, 1359)
    56.56
    59.38
    53.57
        Month 15 (n=1353, 1311, 1341)
    60.31
    62.70
    55.93
        Month 18 (n=1322, 1284, 1316)
    60.51
    64.02
    59.42
        Month 21 (n=1302, 1255, 1294)
    61.37
    64.94
    60.20
        Month 24 (n=1287, 1226, 1273)
    62.78
    65.25
    61.19
        Month 27 (n=1269, 1211, 1255)
    64.93
    66.39
    62.87
        Month 30 (n=1248, 1191, 1237)
    67.15
    67.84
    65.00
        Month 33 (n=1232, 1177, 1221)
    65.50
    67.71
    65.03
        Month 36 (n=1206, 1162, 1211)
    66.67
    65.15
    64.66
        Month 39 (n=1183, 1140, 1201)
    68.64
    66.40
    65.61
        Month 42 (n=1163, 1110, 1179)
    68.44
    69.10
    65.82
        Month 45 (n=1021, 970, 1023)
    67.97
    68.66
    67.16
        Month 48 (n=865, 806, 839)
    66.71
    63.15
    67.58
        Month 51 (n=698, 671, 689)
    67.77
    65.87
    67.63
        Month 54 (n=564, 548, 550)
    64.54
    67.88
    68.00
        Month 57 (n=444, 445, 431)
    62.61
    65.39
    67.98
        Month 60 (n=327, 330, 321)
    63.00
    65.15
    65.42
        Month 63 (n=221, 230, 223)
    62.90
    66.52
    66.37
        Month 66 (n=122, 131, 122)
    57.38
    67.94
    61.48
        Month 69 (n=46, 46, 48)
    58.70
    65.22
    66.67
        Month 72 (n=12, 18, 15)
    50.00
    66.67
    53.33
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Disease Activity Score 28-4 (DAS28-4) C-reactive Protein (CRP) <=3.2

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    End point title
    		 Percentage of Subjects With Disease Activity Score 28-4 (DAS28-4) C-reactive Protein (CRP) <=3.2
    End point description
    DAS28: measure of disease activity in subjects with rheumatoid arthritis based on 28-joint assessment. DAS28-4 (CRP): calculated from number of painful joints (TJC28) and swollen joints out of 28 joints (SJC28), CRP (mg/L) and PtGA on 100 mm VAS (VAS: score range: 0-100 mm [very well-worst], higher scores=worse condition). DAS28-4 (CRP) score range: 0-9.4, higher score=more disease activity. DAS28-4 (CRP) <= 3.2 = low disease activity; > 3.2 to <=5.1 = moderate disease activity; >5.1 = high disease activity, and < 2.6 = remission. DAS28-4 (CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP (mg/L) + 1) + 0.014*PtGA in mm + 0.96. Analysis performed on FAS. Analyses included the data while subjects receiving the drug. Number Analysed signifies number of subjects evaluable for each specified time point. LOCF applied for missing components then composite binary endpoint was calculated. The percentages were calculated using number of subjects evaluable at each visit as denominator.
    End point type
    Secondary
    End point timeframe
    Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: percentage of subjects
    number (not applicable)
        Month 2 (n=1347, 1327, 1354)
    31.55
    35.57
    28.36
        Month 3 (n=1430, 1418, 1420)
    41.68
    46.05
    37.54
        Month 6 (n=1416, 1396, 1406)
    50.28
    54.87
    44.88
        Month 9 (n=1392, 1349, 1381)
    56.11
    59.01
    50.91
        Month 12 (n=1372, 1332, 1359)
    57.73
    60.06
    53.05
        Month 15 (n=1353, 1311, 1341)
    60.38
    63.54
    55.03
        Month 18 (n=1322, 1284, 1316)
    61.72
    63.86
    58.51
        Month 21 (n=1302, 1255, 1294)
    62.29
    63.67
    59.27
        Month 24 (n=1287, 1226, 1273)
    61.93
    64.11
    59.78
        Month 27 (n=1269, 1211, 1255)
    64.22
    67.63
    60.56
        Month 30 (n=1248, 1191, 1237)
    64.66
    65.49
    63.22
        Month 33 (n=1232, 1177, 1221)
    63.80
    66.02
    62.82
        Month 36 (n=1206, 1162, 1211)
    64.43
    64.63
    62.59
        Month 39 (n=1183, 1140, 1201)
    65.85
    65.18
    63.53
        Month 42 (n=1163, 1110, 1179)
    65.43
    67.93
    65.31
        Month 45 (n=1021, 970, 1023)
    64.74
    65.77
    64.52
        Month 48 (n=865, 806, 839)
    64.39
    64.52
    64.36
        Month 51 (n=698, 671, 689)
    65.19
    66.47
    65.46
        Month 54 (n=564, 548, 550)
    64.18
    66.24
    66.55
        Month 57 (n=444, 445, 431)
    63.06
    63.60
    67.29
        Month 60 (n=327, 330, 321)
    62.69
    64.24
    65.11
        Month 63 (n=221, 230, 223)
    60.18
    64.35
    68.61
        Month 66 (n=122, 131, 122)
    55.74
    66.41
    60.66
        Month 69 (n=46, 46, 48)
    58.70
    56.52
    70.83
        Month 72 (n=12, 18, 15)
    50.00
    61.11
    73.33
    No statistical analyses for this end point

    Secondary: Number of Subjects With an American College of Rheumatology 20 Percent (%) (ACR20) Response

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    End point title
    		 Number of Subjects With an American College of Rheumatology 20 Percent (%) (ACR20) Response
    End point description
    ACR20 response: >=20% improvement in TJC (28) and SJC (28) and >=20% improvement in 3 of 5 remaining ACR-core criteria:1)PGA arthritis,2)PtGA arthritis,3)Subject’s assessment arthritis pain,4)subject’s assessment functional disability by HAQ-DI,and 5)CRP (mg/L) at each visit. PGA: physician's global assessment of arthritis on VAS, 0(very well) to 100mm(worst arthritis), higher scores=worse condition. PtGA:subject’s global assessment of arthritis on VAS, 0(very well) to 100 mm(worst arthritis condition), higher scores=worse condition. Subject’s assessment of arthritis pain: assessed on VAS, 0(no pain) to 100mm(most severe pain), higher score=more pain. HAQ-DI: functional disability evaluation, score:0 (no difficulty) to 3(unable to do), higher score=more disability. Analysis performed on FAS and included data while subjects were receiving drug. Number Analysed 'n'=subjects evaluable for each time point. LOCF applied for missing components then composite binary endpoint calculated.
    End point type
    Secondary
    End point timeframe
    Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects
        Month 2 (n=1335, 1316, 1337)
    832
    867
    812
        Month 3 (n=1418, 1398, 1396)
    979
    992
    923
        Month 6 (n=1402, 1375, 1382)
    999
    1012
    981
        Month 9 (n=1375, 1328, 1356)
    1019
    1004
    987
        Month 12 (n=1362, 1308, 1333)
    1033
    992
    966
        Month 15 (n=1341, 1291, 1315)
    1017
    1003
    969
        Month 18 (n=1309, 1266, 1289)
    981
    974
    937
        Month 21 (n=1289, 1238, 1271)
    955
    953
    949
        Month 24 (n=1275, 1209, 1251)
    956
    922
    922
        Month 27 (n=1255, 1190, 1234)
    961
    917
    913
        Month 30 (n=1237, 1173, 1213)
    932
    899
    931
        Month 33 (n=1220, 1157, 1194)
    935
    888
    922
        Month 36 (n=1193, 1145, 1189)
    907
    881
    887
        Month 39 (n=1172,1122, 1180)
    896
    843
    887
        Month 42 (n=1153, 1091, 1154)
    905
    848
    883
        Month 45 (n=1010, 955, 1006)
    780
    718
    790
        Month 48 (n=854, 795, 821)
    654
    587
    639
        Month 51 (n=691, 659, 675)
    535
    485
    518
        Month 54 (n=559, 536, 538)
    434
    396
    400
        Month 57 (n=441, 436, 421)
    337
    321
    302
        Month 60 (n=323, 323, 314)
    243
    237
    232
        Month 63 (n=217, 221, 220)
    163
    166
    161
        Month 66 (n=119, 130, 122)
    85
    101
    89
        Month 69 (n=46, 46, 48)
    26
    36
    37
        Month 72 (n=11, 18, 15)
    5
    15
    10
    No statistical analyses for this end point

    Secondary: Number of Subjects With an American College of Rheumatology 50% (ACR50) Response

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    End point title
    		 Number of Subjects With an American College of Rheumatology 50% (ACR50) Response
    End point description
    ACR50 response is >=50% improvement in TJC (28) and SJC (28) and >=50% improvement in 3 of 5 remaining ACR-core criteria:1)PGA arthritis,2)PtGA arthritis,3)Subject’s assessment arthritis pain, 4)Subject’s assessment functional disability by HAQ-DI,and 5)CRP (mg/L) at each visit. PGA: physician's global assessment of arthritis on VAS, 0(very well) to100mm(worst arthritis), higher scores=worse condition. PtGA: subject assessed health on VAS, 0(very well) to 100mm(worst arthritis condition), higher scores=worse condition. Subject’s assessment of arthritis pain: assessed on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score=more pain. HAQ-DI: functional disability evaluation, score:0(no difficulty) to 3(unable to do), higher score=more disability. Analysis performed on FAS and included data while subjects receiving study drug. Number Analysed 'n'= subjects evaluable for each specified time point. LOCF applied for missing components then composite binary endpoint calculated.
    End point type
    Secondary
    End point timeframe
    Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects
        Month 2 (n=1337, 1321, 1346)
    402
    452
    336
        Month 3 (n=1422, 1405, 1404)
    528
    561
    460
        Month 6 (n=1408, 1378, 1387)
    605
    614
    533
        Month 9 (n=1381, 1333, 1356)
    620
    651
    577
        Month 12 (n=1362, 1312, 1334)
    631
    654
    577
        Month 15 (n=1340, 1290, 1313)
    652
    668
    582
        Month 18 (n=1312, 1265, 1290)
    633
    643
    609
        Month 21 (n=1290, 1234, 1272)
    607
    623
    608
        Month 24 (n=1276, 1209, 1249)
    622
    616
    592
        Month 27 (n=1258, 1194, 1231)
    620
    602
    596
        Month 30 (n=1236, 1177, 1213)
    599
    609
    610
        Month 33 (n=1220, 1158, 1200)
    585
    611
    594
        Month 36 (n=1195, 1143, 1188)
    603
    566
    592
        Month 39 (n=1170, 1121, 1179)
    595
    588
    561
        Month 42 (n=1151, 1093, 1161)
    592
    578
    587
        Month 45 (n=1011, 955, 1008)
    521
    481
    519
        Month 48 (n=854, 794, 826)
    422
    385
    424
        Month 51 (n=693, 659, 677)
    350
    320
    346
        Month 54 (n=560, 538, 540)
    284
    271
    268
        Month 57 (n=440, 437, 422)
    200
    210
    209
        Month 60 (n=325, 322, 314)
    152
    151
    150
        Month 63 (n=220, 223, 219)
    100
    104
    103
        Month 66 (n=122, 129, 121)
    52
    68
    55
        Month 69 (n=45, 45, 47)
    16
    20
    27
        Month 72 (n=11, 18, 15)
    3
    6
    7
    No statistical analyses for this end point

    Secondary: Number of Subjects With an American College of Rheumatology 70% (ACR70) Response

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    End point title
    		 Number of Subjects With an American College of Rheumatology 70% (ACR70) Response
    End point description
    ACR70 response is >= 70% improvement in TJC (28) and SJC (28) and >=70% improvement in 3 of 5 remaining ACR-core criteria: 1)PGA arthritis, 2)PtGA arthritis, 3) Subject’s assessment arthritis pain, 4)Subject’s assessment of functional disability by HAQ-DI, and 5)CRP (mg/L) at each visit. PGA: physician's global assessment on VAS, 0(very well) to 100 mm(worst arthritis), higher scores=worse condition. PtGA: Subject’s global assessment on VAS, 0(very well) to100mm(worst arthritis condition), higher scores=worse condition. Subject’s assessment of arthritis pain: assessed on VAS, 0 (no pain) to 100 mm (most severe pain), higher score=more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (unable to do), higher score=more disability. Analysis performed on FAS and included data while subjects receiving study drug. Number Analysed 'n'= subjects evaluable for each time point. LOCF applied for missing components then composite binary endpoint calculated.
    End point type
    Secondary
    End point timeframe
    Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1455
    1456
    1451
    Units: subjects
        Month 2 (n=1343, 1326, 1354)
    152
    193
    113
        Month 3 (n=1425, 1414, 1413)
    253
    268
    199
        Month 6 (n=1409, 1388, 1397)
    282
    331
    234
        Month 9 (n=1383, 1336, 1366)
    328
    367
    291
        Month 12 (n=1364, 1312, 1338)
    337
    373
    284
        Month 15 (n=1342, 1294, 1323)
    359
    390
    304
        Month 18 (n=1311, 1269, 1295)
    358
    382
    325
        Month 21 (n=1293, 1238, 1277)
    362
    370
    322
        Month 24 (n=1279, 1211, 1255)
    349
    386
    328
        Month 27 (n=1259, 1192, 1238)
    374
    390
    342
        Month 30 (n=1238, 1177, 1221)
    369
    397
    358
        Month 33 (n=1222, 1160, 1204)
    357
    392
    355
        Month 36 (n=1195, 1145, 1193)
    362
    343
    351
        Month 39 (n=1173, 1125, 1186)
    371
    361
    338
        Month 42 (n=1152, 1098, 1163)
    376
    342
    343
        Month 45 (n=1010, 957, 1006)
    313
    298
    298
        Month 48 (n=855, 794, 826)
    256
    228
    238
        Month 51 (n=691, 657, 677)
    216
    195
    199
        Month 54 (n=559, 538, 538)
    159
    163
    160
        Month 57 (n=441, 438, 421)
    128
    127
    118
        Month 60 (n=326, 321, 315)
    79
    83
    92
        Month 63 (n=220, 223, 219)
    58
    57
    64
        Month 66 (n=122, 130, 122)
    25
    38
    35
        Month 69 (n=46, 45, 48)
    8
    15
    14
        Month 72 (n=11, 18, 15)
    2
    5
    4
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63

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    End point title
    		 Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
    End point description
    HAQ-DI: degree of difficulty subject experienced during past week in 8 domains of daily living activities: dressing/grooming; arising; eating; walking; reach; grip; hygiene; and other activities. Total of 30 items distributed in 8 domains. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score computed as sum of domain scores and divided by number of domains answered. Total possible score range 0 (least difficulty) and 3 (extreme difficulty), higher scores =more difficulty while performing daily living activities. FAS: all randomised subjects and received at least 1 dose of drug. MMRM used without imputation for missing values. Analyses included data while subjects were receiving drug. Visits with N>50 subjects in group included in analyses. Number of Subjects Analyzed" is number of subjects included in MMRM. Number Analysed= signifies number of subjects evaluable for each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
    End point values
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Number of subjects analysed
    1409
    1390
    1388
    Units: units on a scale
    least squares mean (standard error)
        Change at Month 2 (n=1325, 1301, 1323)
    -0.42 ( 0.02 )
    -0.45 ( 0.02 )
    -0.38 ( 0.02 )
        Change at Month 3 (n=1371, 1329, 1320)
    -0.45 ( 0.02 )
    -0.48 ( 0.02 )
    -0.42 ( 0.02 )
        Change at Month 6 (n=1341, 1297, 1299)
    -0.50 ( 0.02 )
    -0.51 ( 0.02 )
    -0.46 ( 0.02 )
        Change at Month 9 (n=1287, 1247, 1248)
    -0.51 ( 0.02 )
    -0.55 ( 0.02 )
    -0.47 ( 0.02 )
        Change at Month 12 (n=1256, 1205, 1200)
    -0.52 ( 0.02 )
    -0.53 ( 0.02 )
    -0.49 ( 0.02 )
        Change at Month 15 (n=1223, 1171, 1179)
    -0.53 ( 0.02 )
    -0.56 ( 0.02 )
    -0.51 ( 0.02 )
        Change at Month 18 (n=1189, 1122, 1143)
    -0.52 ( 0.02 )
    -0.56 ( 0.02 )
    -0.49 ( 0.02 )
        Change at Month 21 (n=1172, 1076, 1118)
    -0.53 ( 0.02 )
    -0.55 ( 0.02 )
    -0.50 ( 0.02 )
        Change at Month 24 (n=1135, 1052, 1101)
    -0.52 ( 0.02 )
    -0.57 ( 0.02 )
    -0.49 ( 0.02 )
        Change at Month 27 (n=1102, 1015, 1054)
    -0.52 ( 0.02 )
    -0.56 ( 0.02 )
    -0.51 ( 0.02 )
        Change at Month 30 (n=1078, 998, 1045)
    -0.53 ( 0.02 )
    -0.55 ( 0.02 )
    -0.50 ( 0.02 )
        Change at Month 33 (n=1063, 977, 1041)
    -0.51 ( 0.02 )
    -0.56 ( 0.02 )
    -0.52 ( 0.02 )
        Change at Month 36 (n=1034, 953, 1020)
    -0.50 ( 0.02 )
    -0.54 ( 0.02 )
    -0.48 ( 0.02 )
        Change at Month 39 (n=989, 892, 964)
    -0.51 ( 0.02 )
    -0.54 ( 0.02 )
    -0.49 ( 0.02 )
        Change at Month 42 (n=854, 770, 833)
    -0.51 ( 0.02 )
    -0.52 ( 0.02 )
    -0.50 ( 0.02 )
        Change at Month 45 (n=713, 642, 678)
    -0.50 ( 0.02 )
    -0.51 ( 0.02 )
    -0.51 ( 0.02 )
        Change at Month 48 (n=569, 509, 539)
    -0.50 ( 0.02 )
    -0.50 ( 0.02 )
    -0.48 ( 0.02 )
        Change at Month 51 (n=461, 420, 416)
    -0.53 ( 0.02 )
    -0.49 ( 0.02 )
    -0.50 ( 0.02 )
        Change at Month 54 (n=364, 330, 324)
    -0.53 ( 0.02 )
    -0.51 ( 0.02 )
    -0.48 ( 0.02 )
        Change at Month 57 (n=266, 240, 247)
    -0.49 ( 0.02 )
    -0.48 ( 0.02 )
    -0.48 ( 0.02 )
        Change at Month 60 (n=185, 181, 167)
    -0.52 ( 0.03 )
    -0.49 ( 0.03 )
    -0.48 ( 0.03 )
        Change at Month 63 (n=107, 108, 96)
    -0.54 ( 0.03 )
    -0.48 ( 0.03 )
    -0.48 ( 0.04 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to last contact date (maximum up to 72 months)
    Adverse event reporting additional description
    Same event may appear as both AE and SAE. What is presented are distinct events. An event may categorized as serious in 1 subject and non-serious in another, or subject may have experienced both serious and non-serious event. Safety analysis set analyzed for AE. Total 153 deaths: 152 adjudicated and 1 occurred after subject discontinued from study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Tofacitinib 5 mg BID
    Reporting group description
    		 Subjects received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Subjects were followed up for at least 28 days after last dose of study drug.

    Reporting group title
    Tofacitinib 10 mg BID
    Reporting group description
    		 Subjects received tofacitinib 10 mg oral tablets (each tablet of 5 mg*2) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Subjects were followed up for at least 28 days after last dose of study drug.

    Reporting group title
    TNFi
    Reporting group description
    		 In the US, Puerto Rico and Canada, subjects randomised to TNFi arm received adalimumab 40 mg every other week (QOW) by SC injection and in all other countries, subjects randomised to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Subjects were followed up for at least 28 days after last dose of study drug.

    Serious adverse events
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Total subjects affected by serious adverse events
         subjects affected / exposed
    373 / 1455 (25.64%)
    420 / 1456 (28.85%)
    339 / 1451 (23.36%)
         number of deaths (all causes)
    49
    66
    38
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal neoplasm
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenoma benign
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anogenital warts
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extranodal marginal zone B-cell lymphoma (MALT type)
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder neoplasm
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal lymphoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heavy chain disease
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoproliferative disorder
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of pleura
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma benign
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian granulosa cell tumour
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian neoplasm
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenoma
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sweat gland tumour
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    2 / 1455 (0.14%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Waldenstrom's macroglobulinaemia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic intramural haematoma
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic occlusion
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 1455 (0.14%)
    7 / 1456 (0.48%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral artery embolism
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 1455 (0.14%)
    2 / 1456 (0.14%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Labile blood pressure
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    3 / 1455 (0.21%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicose ulceration
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    3 / 1455 (0.21%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Accidental death
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adverse drug reaction
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    3 / 1455 (0.21%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device intolerance
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 1455 (0.27%)
    5 / 1456 (0.34%)
    5 / 1451 (0.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 1455 (0.07%)
    3 / 1456 (0.21%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical polyp
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial hypertrophy
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial thickening
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Genital prolapse
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis noninfective
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    4 / 1455 (0.27%)
    4 / 1456 (0.27%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    1 / 8
    1 / 4
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 1455 (0.14%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    6 / 1455 (0.41%)
    7 / 1456 (0.48%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    3 / 9
    0 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 1455 (0.34%)
    5 / 1456 (0.34%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 1455 (0.14%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pickwickian syndrome
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 1455 (0.14%)
    3 / 1456 (0.21%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    5 / 1455 (0.34%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    10 / 1455 (0.69%)
    22 / 1456 (1.51%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    3 / 11
    3 / 25
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    7 / 1455 (0.48%)
    5 / 1456 (0.34%)
    5 / 1451 (0.34%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 5
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid lung
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 1455 (0.00%)
    3 / 1456 (0.21%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    2 / 1455 (0.14%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device loosening
         subjects affected / exposed
    0 / 1455 (0.00%)
    3 / 1456 (0.21%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biopsy endometrium normal
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    2 / 1455 (0.14%)
    5 / 1456 (0.34%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back injury
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central cord syndrome
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complicated fracture
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    5 / 1451 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    4 / 1455 (0.27%)
    3 / 1456 (0.21%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    10 / 1455 (0.69%)
    5 / 1456 (0.34%)
    11 / 1451 (0.76%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 5
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    3 / 1455 (0.21%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Graft complication
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    5 / 1455 (0.34%)
    4 / 1456 (0.27%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    5 / 1455 (0.34%)
    3 / 1456 (0.21%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    3 / 1455 (0.21%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    3 / 1455 (0.21%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    3 / 1456 (0.21%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post laminectomy syndrome
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    3 / 1455 (0.21%)
    1 / 1456 (0.07%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory fume inhalation disorder
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    3 / 1455 (0.21%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin wound
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haematoma
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 1455 (0.07%)
    3 / 1456 (0.21%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transplant dysfunction
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    2 / 1455 (0.14%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound necrosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Corneal dystrophy
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Developmental hip dysplasia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exomphalos
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocele
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    4 / 1455 (0.27%)
    2 / 1456 (0.14%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    3 / 1455 (0.21%)
    3 / 1456 (0.21%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    7 / 1455 (0.48%)
    8 / 1456 (0.55%)
    6 / 1451 (0.41%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 8
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 1455 (0.00%)
    4 / 1456 (0.27%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 1455 (0.14%)
    3 / 1456 (0.21%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 1455 (0.07%)
    6 / 1456 (0.41%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac pseudoaneurysm
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic left ventricular failure
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    8 / 1455 (0.55%)
    3 / 1456 (0.21%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diastolic dysfunction
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    4 / 1455 (0.27%)
    3 / 1456 (0.21%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 1455 (0.00%)
    3 / 1456 (0.21%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basilar artery stenosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical cord compression
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma hepatic
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 1455 (0.00%)
    3 / 1456 (0.21%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 1455 (0.14%)
    4 / 1456 (0.27%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial mass
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral radiculopathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Morton's neuralgia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postictal paralysis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Progressive supranuclear palsy
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Quadriplegia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    3 / 1455 (0.21%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Restless legs syndrome
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reversible ischaemic neurological deficit
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 1455 (0.14%)
    3 / 1456 (0.21%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Senile dementia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal claudication
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylitic myelopathy
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 1455 (0.00%)
    3 / 1456 (0.21%)
    5 / 1451 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thecal sac compression
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 1455 (0.14%)
    8 / 1456 (0.55%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 10
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    9 / 1455 (0.62%)
    4 / 1456 (0.27%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 11
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytopenia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Acute vestibular syndrome
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 1455 (0.21%)
    6 / 1456 (0.41%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinopathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Episcleritis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratoconus
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising retinitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vasculitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal compartment syndrome
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    5 / 1455 (0.34%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    4 / 1455 (0.27%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 1455 (0.27%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    3 / 1455 (0.21%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal erosion
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 1455 (0.14%)
    3 / 1456 (0.21%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic enteritis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jejunal ulcer
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jejunal ulcer perforation
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 1455 (0.21%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obturator hernia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal food impaction
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis haemorrhagic
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer haemorrhage
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer perforation
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    3 / 1455 (0.21%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis mesenteric vessel
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    3 / 1456 (0.21%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    3 / 1455 (0.21%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    4 / 1455 (0.27%)
    5 / 1456 (0.34%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cirrhosis alcoholic
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder rupture
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal failure
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 1455 (0.27%)
    6 / 1456 (0.41%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder diverticulum
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Focal segmental glomerulosclerosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal atrophy
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal disorder
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal haematoma
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid mass
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 1455 (0.48%)
    2 / 1456 (0.14%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    3 / 1455 (0.21%)
    2 / 1456 (0.14%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    4 / 1455 (0.27%)
    4 / 1456 (0.27%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone disorder
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone hypertrophy
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dupuytren's contracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip deformity
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    4 / 1455 (0.27%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint contracture
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint destruction
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint instability
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Knee deformity
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kyphosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle tightness
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    29 / 1455 (1.99%)
    23 / 1456 (1.58%)
    16 / 1451 (1.10%)
         occurrences causally related to treatment / all
    0 / 35
    0 / 26
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    11 / 1455 (0.76%)
    10 / 1456 (0.69%)
    12 / 1451 (0.83%)
         occurrences causally related to treatment / all
    1 / 16
    2 / 13
    2 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal instability
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    3 / 1455 (0.21%)
    4 / 1456 (0.27%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondyloarthropathy
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovial disorder
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic spinal stenosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    3 / 1455 (0.21%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary histoplasmosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    4 / 1455 (0.27%)
    4 / 1456 (0.27%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    2 / 1455 (0.14%)
    4 / 1456 (0.27%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone tuberculosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    10 / 1455 (0.69%)
    9 / 1456 (0.62%)
    7 / 1451 (0.48%)
         occurrences causally related to treatment / all
    4 / 10
    4 / 10
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 1455 (0.07%)
    5 / 1456 (0.34%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carbuncle
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    12 / 1455 (0.82%)
    13 / 1456 (0.89%)
    15 / 1451 (1.03%)
         occurrences causally related to treatment / all
    5 / 14
    10 / 14
    5 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chorioretinitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complicated appendicitis
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 1455 (0.14%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated varicella zoster virus infection
         subjects affected / exposed
    0 / 1455 (0.00%)
    4 / 1456 (0.27%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    7 / 1455 (0.48%)
    6 / 1456 (0.41%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    2 / 7
    4 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis meningococcal
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia pyelonephritis
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    External ear cellulitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye infection
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 1455 (0.27%)
    7 / 1456 (0.48%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes oesophagitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes ophthalmic
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    9 / 1455 (0.62%)
    11 / 1456 (0.76%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    7 / 9
    11 / 11
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Histoplasmosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected bite
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    4 / 1455 (0.27%)
    3 / 1456 (0.21%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 1455 (0.14%)
    3 / 1456 (0.21%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device site joint infection
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nail infection
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroborreliosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurocryptococcosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    2 / 1455 (0.14%)
    3 / 1456 (0.21%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parotid abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis tuberculous
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perihepatic abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal tuberculosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    50 / 1455 (3.44%)
    56 / 1456 (3.85%)
    43 / 1451 (2.96%)
         occurrences causally related to treatment / all
    33 / 60
    41 / 63
    26 / 46
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural pneumonia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    3 / 1455 (0.21%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulpitis dental
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 1455 (0.14%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 1455 (0.14%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyometra
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal tuberculosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salmonella sepsis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 1455 (0.41%)
    6 / 1456 (0.41%)
    5 / 1451 (0.34%)
         occurrences causally related to treatment / all
    5 / 6
    3 / 6
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 1455 (0.27%)
    9 / 1456 (0.62%)
    3 / 1451 (0.21%)
         occurrences causally related to treatment / all
    1 / 4
    3 / 9
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinobronchitis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tick-borne fever
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 1455 (0.27%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    14 / 1455 (0.96%)
    14 / 1456 (0.96%)
    9 / 1451 (0.62%)
         occurrences causally related to treatment / all
    10 / 16
    9 / 14
    5 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 1455 (0.00%)
    3 / 1456 (0.21%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    2 / 1451 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 1455 (0.07%)
    1 / 1456 (0.07%)
    4 / 1451 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 1455 (0.14%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 1455 (0.00%)
    1 / 1456 (0.07%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypochloraemia
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 1455 (0.00%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 1455 (0.07%)
    2 / 1456 (0.14%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 1455 (0.14%)
    4 / 1456 (0.27%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    0 / 1455 (0.00%)
    0 / 1456 (0.00%)
    1 / 1451 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 1455 (0.07%)
    0 / 1456 (0.00%)
    0 / 1451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1108 / 1455 (76.15%)
    1127 / 1456 (77.40%)
    1056 / 1451 (72.78%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    67 / 1455 (4.60%)
    75 / 1456 (5.15%)
    48 / 1451 (3.31%)
         occurrences all number
    85
    100
    65
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    177 / 1455 (12.16%)
    160 / 1456 (10.99%)
    159 / 1451 (10.96%)
         occurrences all number
    218
    197
    202
    Vascular disorders
    Hypertension
         subjects affected / exposed
    129 / 1455 (8.87%)
    152 / 1456 (10.44%)
    127 / 1451 (8.75%)
         occurrences all number
    143
    175
    142
    Nervous system disorders
    Headache
         subjects affected / exposed
    50 / 1455 (3.44%)
    75 / 1456 (5.15%)
    64 / 1451 (4.41%)
         occurrences all number
    56
    91
    79
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    75 / 1455 (5.15%)
    100 / 1456 (6.87%)
    73 / 1451 (5.03%)
         occurrences all number
    90
    131
    81
    Lymphopenia
         subjects affected / exposed
    107 / 1455 (7.35%)
    151 / 1456 (10.37%)
    36 / 1451 (2.48%)
         occurrences all number
    186
    291
    57
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    99 / 1455 (6.80%)
    81 / 1456 (5.56%)
    74 / 1451 (5.10%)
         occurrences all number
    114
    98
    90
    Nausea
         subjects affected / exposed
    67 / 1455 (4.60%)
    96 / 1456 (6.59%)
    61 / 1451 (4.20%)
         occurrences all number
    82
    112
    69
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    77 / 1455 (5.29%)
    70 / 1456 (4.81%)
    72 / 1451 (4.96%)
         occurrences all number
    86
    89
    87
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    111 / 1455 (7.63%)
    90 / 1456 (6.18%)
    124 / 1451 (8.55%)
         occurrences all number
    150
    128
    173
    Back pain
         subjects affected / exposed
    101 / 1455 (6.94%)
    113 / 1456 (7.76%)
    112 / 1451 (7.72%)
         occurrences all number
    120
    132
    124
    Osteoarthritis
         subjects affected / exposed
    84 / 1455 (5.77%)
    71 / 1456 (4.88%)
    77 / 1451 (5.31%)
         occurrences all number
    102
    79
    91
    Rheumatoid arthritis
         subjects affected / exposed
    183 / 1455 (12.58%)
    188 / 1456 (12.91%)
    202 / 1451 (13.92%)
         occurrences all number
    276
    273
    290
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    221 / 1455 (15.19%)
    243 / 1456 (16.69%)
    168 / 1451 (11.58%)
         occurrences all number
    334
    313
    215
    Gastroenteritis
         subjects affected / exposed
    61 / 1455 (4.19%)
    76 / 1456 (5.22%)
    52 / 1451 (3.58%)
         occurrences all number
    78
    89
    56
    Herpes zoster
         subjects affected / exposed
    175 / 1455 (12.03%)
    160 / 1456 (10.99%)
    59 / 1451 (4.07%)
         occurrences all number
    188
    175
    59
    Influenza
         subjects affected / exposed
    92 / 1455 (6.32%)
    95 / 1456 (6.52%)
    71 / 1451 (4.89%)
         occurrences all number
    120
    117
    104
    Latent tuberculosis
         subjects affected / exposed
    89 / 1455 (6.12%)
    72 / 1456 (4.95%)
    94 / 1451 (6.48%)
         occurrences all number
    89
    73
    94
    Nasopharyngitis
         subjects affected / exposed
    168 / 1455 (11.55%)
    172 / 1456 (11.81%)
    164 / 1451 (11.30%)
         occurrences all number
    231
    248
    233
    Pharyngitis
         subjects affected / exposed
    87 / 1455 (5.98%)
    81 / 1456 (5.56%)
    75 / 1451 (5.17%)
         occurrences all number
    103
    107
    96
    Sinusitis
         subjects affected / exposed
    97 / 1455 (6.67%)
    81 / 1456 (5.56%)
    94 / 1451 (6.48%)
         occurrences all number
    134
    132
    133
    Upper respiratory tract infection
         subjects affected / exposed
    319 / 1455 (21.92%)
    318 / 1456 (21.84%)
    264 / 1451 (18.19%)
         occurrences all number
    564
    533
    415
    Urinary tract infection
         subjects affected / exposed
    190 / 1455 (13.06%)
    220 / 1456 (15.11%)
    186 / 1451 (12.82%)
         occurrences all number
    308
    372
    284

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2013
    To reduce the study from 8 years to 5 years, to increased N from 3900 to approximately 4000, to eliminate the double-blind substudy, to change the comparator from all adalimumab to adalimumab in US, Puerto Rico and Canada with etanercept in the rest of world, to reduce joint counts from 66/68 to 28 at every visit, to remove the following Patient Reported Outcomes (PROs): Medical Outcomes Study (MOS) Sleep Scale, Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-fatigue), and Rheumatoid Arthritis (RA) Healthcare Resource Utilization Questionnaires and reduced the frequency of 36-Item Short Form Health Survey (SF-36), EuroQol EQ-5D Health State Profile (EuroQol EQ-5D), and Work Productivity and Activity Impairment Questionnaires, eliminated routine electrocardiograms, except at screening Visit and end of study Visit, to remove laboratory testing not used in safety evaluation of either tofacitinib or TNFi’s, to align monitoring and discontinuation criteria with the US approved labeling.
    20 Nov 2013
    To make typographical corrections and clarifications, to make changes to reporting processes for the primary safety endpoints to limit their inclusion in AE tables reviewed outside the blinded Steering Committee, to add a washout period for rituximab as a prohibited concomitant disease-modifying anti-rheumatic drug (DMARD).
    18 Mar 2019
    To reduce treatment in the tofacitinib 10 mg BID arm to 5 mg BID in response to a recommendation from the Data Safety Monitoring Board for a safety signal, to add requirement for all subjects to provide a consent addendum, which they were required to sign agreeing to continue in the study, deep vein thrombosis, pulmonary emboli, arterial thrombosis and arterial emboli were added to the cardiovascular adjudication charter and were noted as additional events to be adjudicated.

    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.
    None reported
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