Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   41449   clinical trials with a EudraCT protocol, of which   6808   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase IIIB Multicenter, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Abatacept Administered Subcutaneously and Intravenously in Subjects with Rheumatoid Arthritis, Receiving Background Methotrexate, and Experiencing an Inadequate Response to Methotrexate.

    Summary
    EudraCT number
    2007-005434-37
    Trial protocol
    FR   IE   HU   GB   BE   DE   NL   IT   AT   GR  
    Global end of trial date
    12 Sep 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    18 May 2016
    First version publication date
    18 May 2016
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    IM101-174
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00559585
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bristol Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium,
    Public contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, clinical.trials@bms.com
    Scientific contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, clinical.trials@bms.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
    12 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective for this study is to demonstrate that subcutaneous (SC) injections of abatacept are non-inferior to intravenous (IV) infusions of abatacept in ACR 20 responses after 6 months of treatment in subjects who have active RA, are receiving methotrexate and experiencing an inadequate response to methotrexate. The main objective of the long-term (LT) period was to assess the safety and long-term tolerability of SC injections of abatacept as well as the maintenance of efficacy responses in subjects who completed the initial 6-month short-term (ST) period.
    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 Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Jan 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 122
    Country: Number of subjects enrolled
    Taiwan: 51
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    United States: 468
    Country: Number of subjects enrolled
    Argentina: 290
    Country: Number of subjects enrolled
    Australia: 38
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Brazil: 163
    Country: Number of subjects enrolled
    Canada: 60
    Country: Number of subjects enrolled
    Chile: 79
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    India: 75
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Korea, Republic of: 76
    Country: Number of subjects enrolled
    Mexico: 433
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Peru: 201
    Country: Number of subjects enrolled
    Poland: 200
    Country: Number of subjects enrolled
    Russian Federation: 68
    Worldwide total number of subjects
    2493
    EEA total number of subjects
    360
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    2163
    From 65 to 84 years
    329
    85 years and over
    1

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study was conducted at 222 centers in 24 countries.

    Pre-assignment
    Screening details
    2493 subjects were enrolled in the study: Enrolled for Double blind short term period - 2473; randomised - 1464; randomised and treated - 1457. 20 enrolled in Anti-TNF sub-study: randomized in substudy - 18.

    Period 1
    Period 1 title
    Short Term Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Both subject and investigator were blinded in the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Subcutaneous (SC) Abatacept
    Arm description
    Subjects received weekly injections of 125 mg SC abatacept for 6 months (with a loading dose of IV abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, Subjects also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    BMS-188667
    Other name
    Orencia
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept 125-mg/mL was administered as subcutaneous injection once weekly.

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Abatacept was administered as intravenous infusion on day 1 based on weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

    Investigational medicinal product name
    Abatacept matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Abatacept matching placebo was administered as intravenous infusion on Day 15, Day 29, and every 28 days thereafter through day 141.

    Arm title
    Intravenous (IV) Abatacept
    Arm description
    Subjects received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, Subjects also received subcutaneous injections of placebo (subcutaneous placebo).
    Arm type
    Active comparator

    Investigational medicinal product name
    Abatacept matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept matching placebo was administered as subcutaneous injection on Day 8 and weekly thereafter.

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    BMS-188667
    Other name
    Orencia
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Abatacept was administered as intravenous infusion based on the weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

    Arm title
    Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)
    Arm description
    Subjects who had failed one anti-TNF therapy received abatacept 125 mg subcutaneous injections once weekly for 6 months (with an IV abatacept loading dose on Day 1, based on weight: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg). A double-dummy design was used to protect the blind, thus, subjects also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    BMS-188667
    Other name
    Orencia
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept 125-mg/mL was administered as subcutaneous injection once weekly.

    Investigational medicinal product name
    Abatacept matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Abatacept matching placebo was administered as intravenous infusion on Day 15, Day 29, and every 28 days thereafter through day 141.

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Abatacept was administered as intravenous infusion on day 1 based on weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

    Arm title
    Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Arm description
    Subjects who had failed one anti-TNF therapy received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter for 6 months. A double-dummy design was used to protect the blind, thus, subjects also received SC injections of placebo (SC Placebo).
    Arm type
    Active comparator

    Investigational medicinal product name
    Abatacept matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept matching placebo was administered as subcutaneous injection on Day 8 and weekly thereafter.

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    BMS-188667
    Other name
    Orencia
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Abatacept was administered as intravenous infusion based on the weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

    Number of subjects in period 1 [1]
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study) Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Started
    736
    721
    8
    10
    Completed
    693
    676
    7
    9
    Not completed
    43
    45
    1
    1
         Subject Withdrew-Recurrent Infection
    -
    1
    -
    -
         Death
    1
    1
    -
    -
         Ongoing Infection Risk
    1
    -
    -
    -
         Missed doses
    -
    1
    -
    -
         Subject no longer meets study criteria
    2
    1
    -
    -
         Lack of efficacy
    6
    1
    1
    1
         Early discontinuation
    -
    1
    -
    -
         Consent withdrawn by subject
    11
    5
    -
    -
         Incomplete breast exam
    -
    1
    -
    -
         Subject gain weight
    1
    -
    -
    -
         Physician decision
    -
    1
    -
    -
         Suspended drug due to surgery
    -
    1
    -
    -
         Poor compliance/noncompliance
    3
    -
    -
    -
         Adverse event, non-fatal
    17
    25
    -
    -
         Administrative reason by sponsor
    1
    -
    -
    -
         Lost to follow-up
    -
    6
    -
    -
    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: 2493 subjects were enrolled in the study: 2473 were enrolled for Double blind short term period; 1464 were randomised; 1457 were randomised and treated. Reasons for enrolled but not randomised were: withdrew consent - 61, lost to follow-up - 7, subject no longer meet study criteria - 918, other reasons - 23. 20 enrolled in Anti-TNF sub-study; 2 not randomised as no longer met criteria; 18 randomized in substudy.
    Period 2
    Period 2 title
    Open Label LT Period Main + Sub-Study
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Subcutaneous (SC) Abatacept
    Arm description
    Subjects could either continue with or switch to 125 mg weekly SC abatacept injections until the SC formulation became commercially available on a country basis or the Sponsor terminated the study. The Anti-TNF Sub-study terminated due to low recruitment and Subjects were permitted to roll into the LT Open Label Period.
    Arm type
    Experimental

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    BMS-188667
    Other name
    Orencia
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept 125-mg/mL was administered as subcutaneous injection once weekly.

    Investigational medicinal product name
    Abatacept matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Abatacept matching placebo was administered as intravenous infusion on Day 15, Day 29, and every 28 days thereafter through day 141.

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Abatacept was administered as intravenous infusion on day 1 based on weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

    Number of subjects in period 2 [2]
    Subcutaneous (SC) Abatacept
    Started
    1373
    Completed
    945
    Not completed
    428
         Death
    20
         No longer met criteria
    1
         non-specified
    71
         Lack of efficacy
    89
         Poor compliance/noncompliance
    8
         Pregnancy
    16
         no end of study status page
    1
         Adverse event, non-fatal
    100
         Administrative reason by sponsor
    9
         Consent withdrawn by subject
    81
         Lost to follow-up
    32
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Out of 1385 subjects who completed the short term double blind period, 1373 entered into long term period.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Subcutaneous (SC) Abatacept
    Reporting group description
    Subjects received weekly injections of 125 mg SC abatacept for 6 months (with a loading dose of IV abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, Subjects also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.

    Reporting group title
    Intravenous (IV) Abatacept
    Reporting group description
    Subjects received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, Subjects also received subcutaneous injections of placebo (subcutaneous placebo).

    Reporting group title
    Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)
    Reporting group description
    Subjects who had failed one anti-TNF therapy received abatacept 125 mg subcutaneous injections once weekly for 6 months (with an IV abatacept loading dose on Day 1, based on weight: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg). A double-dummy design was used to protect the blind, thus, subjects also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment.

    Reporting group title
    Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Reporting group description
    Subjects who had failed one anti-TNF therapy received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter for 6 months. A double-dummy design was used to protect the blind, thus, subjects also received SC injections of placebo (SC Placebo).

    Reporting group values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study) Intravenous (IV) Abatacept (Anti-TNF Sub-Study) Total
    Number of subjects
    736 721 8 10 1475
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.9 ± 13.2 50.1 ± 12.6 43 ± 16.6 47.4 ± 11.9 -
    Gender categorical
    Units: Subjects
        Female
    621 580 8 9 1218
        Male
    115 141 0 1 257
    Weight category
    Units: Subjects
        <60 kg
    186 179 2 2 369
        60-100 kg
    492 489 5 6 992
        >100 kg
    58 53 1 2 114
    Race
    Units: Subjects
        White
    550 537 7 9 1103
        Black/African American
    29 27 1 0 57
        American Indian/Alaska Native
    5 1 0 0 6
        Asian
    64 73 0 1 138
        Native Hawaiian/other Pacific Islander
    0 0 0 0 0
        Other
    88 83 0 0 171
    Region
    Units: Subjects
        North America
    142 128 7 7 284
        South America
    359 349 0 0 708
        Europe
    127 128 1 3 259
        Rest of World
    108 116 0 0 224
    Duration of disease category
    Units: Subjects
        <= 2 years
    240 221 5 4 470
        2 - <= 5 years
    155 150 2 0 307
        5- <= 10 years
    142 164 0 2 308
        > 10 years
    199 186 1 4 390
    Rheumatoid Factor Status
    Rheumatoid factor (RF or RhF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of Immunoglobulin (Ig)G, which is itself an antibody. RF and IgG join to form immune complexes which contribute to the disease process. A positive value for RF was >20 IU/mL; a negative value for RF was ≤ 20 IU/mL.
    Units: Subjects
        Negative
    110 100 4 4 218
        Positive
    614 611 4 6 1235
        Unknown
    12 10 0 0 22
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    72 ± 18 71.8 ± 17.6 72.9 ± 21.5 85.8 ± 18.9 -
    Duration of disease
    Units: year
        arithmetic mean (standard deviation)
    7.6 ± 8.1 7.7 ± 7.8 4.6 ± 7.5 12.4 ± 13.3 -
    Number of Tender Joints
    Units: tender joints
        arithmetic mean (standard deviation)
    30.1 ± 14.1 29.1 ± 13.3 29.4 ± 15.2 24.4 ± 16.3 -
    Number of Swollen Joints
    Units: swollen joints
        arithmetic mean (standard deviation)
    20.4 ± 9.6 19.4 ± 8.6 20.4 ± 11.8 17.7 ± 15.1 -
    Subject Pain Assessment
    The subject self-reported pain assessment is a core component of the ACR scoring system where increasing score indicates increasing level of severity as indicated on a 100 mm Visual Analog Scale (VAS) with 0 mm representing no pain and 100 mm representing the most pain possible. For each post-baseline visit in the DB, time-matched baseline Subject Pain Assessment values were presented and represent the mean baseline value for only that cohort of subjects with assessments available at that visit.
    Units: units on a scale
        arithmetic mean (standard deviation)
    67.8 ± 20.1 66.8 ± 20.5 76 ± 18.2 57.5 ± 23.9 -
    Physical Function (Health Assessment Questionnaire Disability Index [HAQ-DI])
    The disability section of the full HAQ includes 20 questions to assess physical The HAQ-DI includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI overall score ranges from a minimum of 0 to a maximum of 3.0.
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.72 ± 0.68 1.67 ± 0.67 1.97 ± 0.44 1.64 ± 0.62 -
    Subject Global Assessment
    Subjects used a horizontal VAS of 100 mm for overall assessment of rheumatoid arthritis. Scale ranged from 0 (very well) to 100 (very poor). Subjects were instructed to draw a vertical through a horizontal line to indicate state of rheumatoid arthritis. Distance from the "very well" end of the horizontal line to the vertical line drawn by the subject was the global disease assessment score on a scale of 1-10, where 1=controlled or equivocal rheumatoid arthritis activity, 1.1-4=mild activity, 4-8=moderate activity, and 8.1-10=high activity.
    Units: units on a scale
        arithmetic mean (standard deviation)
    66.8 ± 20.4 64.9 ± 20 70.9 ± 23.6 60.7 ± 19.4 -
    Physician Global Assessment
    Physician global rheumatoid arthritis assessment core component of the ACR scoring system where increasing score indicates increasing level of severity as indicated on a 100 mm Visual Analog Scale, with 0 mm representing no pain and 100 mm representing the most pain possible.
    Units: units on a scale
        arithmetic mean (standard deviation)
    64.3 ± 16.5 63.1 ± 16.6 66.5 ± 17.3 55.4 ± 20 -
    High Sensitivity C-Reactive Protein (hsCRP) Level
    Hs-CRP is an acute phase reactant protein that is a clinical marker for Rheumatoid Arthritis (RA). Levels of hs-CRP can be used to determine Disease Activity Score (DAS28).
    Units: mg/dL
        arithmetic mean (standard deviation)
    2.62 ± 2.9 2.71 ± 2.94 2.98 ± 3.14 4.77 ± 5.18 -
    Disease Activity Score (CRP)
    The DAS28 (CRP) is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, CRP levels, and subject assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (>5.1), low disease activity (<3.2) and remission (<2.6). A clinically significant response= decrease in DAS28 score of >1.2 from baseline.
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.23 ± 0.85 6.2 ± 0.84 6.31 ± 0.81 5.76 ± 1.2 -
    Baseline Methotrexate (MTX) Dose
    Units: mg/wk
        arithmetic mean (standard deviation)
    16.3 ± 3.6 16.5 ± 3.8 14.4 ± 3.5 15.3 ± 4.3 -

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Subcutaneous (SC) Abatacept
    Reporting group description
    Subjects received weekly injections of 125 mg SC abatacept for 6 months (with a loading dose of IV abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, Subjects also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.

    Reporting group title
    Intravenous (IV) Abatacept
    Reporting group description
    Subjects received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, Subjects also received subcutaneous injections of placebo (subcutaneous placebo).

    Reporting group title
    Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)
    Reporting group description
    Subjects who had failed one anti-TNF therapy received abatacept 125 mg subcutaneous injections once weekly for 6 months (with an IV abatacept loading dose on Day 1, based on weight: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg). A double-dummy design was used to protect the blind, thus, subjects also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment.

    Reporting group title
    Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Reporting group description
    Subjects who had failed one anti-TNF therapy received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter for 6 months. A double-dummy design was used to protect the blind, thus, subjects also received SC injections of placebo (SC Placebo).
    Reporting group title
    Subcutaneous (SC) Abatacept
    Reporting group description
    Subjects could either continue with or switch to 125 mg weekly SC abatacept injections until the SC formulation became commercially available on a country basis or the Sponsor terminated the study. The Anti-TNF Sub-study terminated due to low recruitment and Subjects were permitted to roll into the LT Open Label Period.

    Primary: Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response [1] [2]
    End point description
    The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function and acute phase reactant value (C-reactive protein). The analysis was performed in Per protocol (PP) population, defined as subjects who are compliant with the study criteria.
    End point type
    Primary
    End point timeframe
    Day 169
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure. 
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    693
    678
    Units: Subjects
    527
    514
    No statistical analyses for this end point

    Primary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population

    Close Top of page
    End point title
    Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population [3] [4]
    End point description
    Serum samples from all treated adult subjects with active rheumatoid arthritis who were from the Anti-TNF failure population (Subjects who had failed one anti-TNF therapy) were screened for the presence of drug-specific antibodies using Enzyme Linked Immunoabsorbant Assay (ELISA). The analysis was performed in all randomised subjects in the Anti-TNF Failure Sub-study who received at least 1 dose of study medication. n=Number of subjects with at least 1 assessment available.
    End point type
    Primary
    End point timeframe
    Days 1, 85, and 169 and postvisits on Days 28, 56, and 85
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure. 
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study) Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Number of subjects analysed
    8
    10
    Units: Subjects
        Day 85 Anti-abatacept (n=8,10)
    0
    0
        Day 85 Anti-CTLA4-T (n=8,10)
    0
    0
        Day 169 Anti-abatacept (n=6,9)
    0
    0
        Day 169 Anti-CTLA4-T(n=6,9)
    1
    0
        Overall Treatment Anti-abatacept (n=8,10)
    0
    0
        Overall on Treatment Anti-CTLA4-T(n=8,10)
    1
    0
        28 days post Anti-abatacept (n=1,1)
    0
    0
        28 days post Anti-CTLA4-T (n=1,1)
    0
    0
        56 days post Anti-abatacept (n=0,1)
    0
    0
        56 days post Anti-CTLA4-T (n=0,1)
    0
    0
        85 days post Anti-abatacept (n=0,1)
    0
    0
        85 days post Anti-CTLA4-T (n=0,1)
    0
    0
    No statistical analyses for this end point

    Primary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response

    Close Top of page
    End point title
    Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response [5] [6]
    End point description
    The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function and acute phase reactant value (C-reactive protein). Subjects who had failed one anti-TNF therapy were included in the sub-studyThe analysis was performed in all randomised subjects in the Anti-TNF Failure Sub-study who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Day 169
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure. 
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study) Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Number of subjects analysed
    8
    10
    Units: Subjects
    5
    6
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses [7]
    End point description
    The ACR 50 definition of improvement is a 50% improvement from baseline in the number of tender and swollen joint counts, and a 50% improvement from baseline in 3 of the remaining 5 core set measures: Subject global assessment of pain, Subject global assessment of disease activity, physician global assessment of disease activity, Subject assessment of physical function and acute phase reactant value (C-reactive protein). ACR 70 is defined similarly with 70% improvements from baseline for tender and swollen joint counts and 3 out of 5 core measures. Analysis was performed in Per-Protocol population, defined as subjects who are compliant with the study criteria.
    End point type
    Secondary
    End point timeframe
    Day 169
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    693
    678
    Units: Subjects
        ACR 50
    357
    341
        ACR 70
    183
    170
    No statistical analyses for this end point

    Secondary: Double-blind Period: Mean Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) for Subjects With Assessments

    Close Top of page
    End point title
    Double-blind Period: Mean Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) for Subjects With Assessments [8]
    End point description
    The disability section of the full HAQ-DI includes 20 questions to assess physical functions in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip and common activities. The questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. Higher scores=greater dysfunction. A disability index was calculated by summing the worst scores in each domain and dividing by the number of domains answered. Analysis was performed on all subjects who received at least 1 dose of study medication at any time and had HAD-QI scores available.
    End point type
    Secondary
    End point timeframe
    Day 169
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    729
    711
    Units: Units on a scale
        arithmetic mean (standard deviation)
    1.72 ± 0.68
    1.67 ± 0.67
    No statistical analyses for this end point

    Secondary: Double-blind Period: Adjusted Mean Change From Baseline to Day 169 in HAQ-DI

    Close Top of page
    End point title
    Double-blind Period: Adjusted Mean Change From Baseline to Day 169 in HAQ-DI [9]
    End point description
    The HAQ-DI includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI ranges from 0 to a maximum overall score of 3.0. Analysis was performed on all subjects who received at least 1 dose of study medication at any time and had HAD-QI scores available.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 169
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    729
    711
    Units: Units on a scale
        arithmetic mean (standard error)
    -0.69 ± 0.02
    -0.7 ± 0.02
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects Achieving Clinically Meaningful HAQ-DI Response at Day 169

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects Achieving Clinically Meaningful HAQ-DI Response at Day 169 [10]
    End point description
    The disability section of the full HAQ-DI includes 20 questions to assess physical functions in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip and common activities. The questions are evaluated on a 4-point scale: 0=without any difficulty, 1= with some difficulty, 2= with much difficulty, and 3=unable to do. Higher scores=greater dysfunction. A disability index was calculated by summing the worst scores in each domain and dividing by the number of domains answered. Clinically meaningful HAQ-DI response=an improvement of at least 0.3 units from baseline in HAQ-DI. Analysis was performed in all the subjects who received at least 1 dose of study medication at any time and had HAD-QI scores available.
    End point type
    Secondary
    End point timeframe
    Day 169
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    729
    711
    Units: Subjects
    483
    442
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment- related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment- related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation [11]
    End point description
    AE=any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life- threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Treatment-related SAE=possibly, probably, or certainly related to study drug. All randomised subjects who received at least 1 dose of study medication were analysed.
    End point type
    Secondary
    End point timeframe
    Day 1 to 56 days after last dose in short-term or first dose in the long-term, whichever occurs first.
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Subjects
        Deaths
    2
    5
        SAEs
    31
    35
        Treatment-related SAEs
    5
    12
        SAEs Leading to Discontinuation
    8
    14
        AEs
    493
    470
        Treatment-related AEs
    204
    210
        AEs Leading to Discontinuation
    15
    25
    No statistical analyses for this end point

    Secondary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With SAEs, AEs Leading to Discontinuation or Who Died

    Close Top of page
    End point title
    Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With SAEs, AEs Leading to Discontinuation or Who Died [12]
    End point description
    AE=any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Subjects who had failed one anti-TNF therapy were included in the sub-study. All randomised subjects who received at least 1 dose of study medication were analysed.
    End point type
    Secondary
    End point timeframe
    Day 1 to 56 days after last dose in short-term or first dose in the long-term, whichever occurs first.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study) Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Number of subjects analysed
    8
    10
    Units: Subjects
        Deaths
    0
    0
        SAEs
    0
    0
        AEs Leading to Discontinuation
    0
    0
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects With AEs of Special Interest

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects With AEs of Special Interest [13]
    End point description
    AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs: all infections,serious infections,and opportunistic infections; autoimmune disorders; malignancies; acute infusional AEs (prespecified AEs occurring within 1 hr of start of infusion), peri-infusional AEs (prespecified AEs occurring within 24 hrs of the start of infusion), system injection reactions, and local injection site reactions. All randomised subjects who received at least 1 dose of study medication were analysed.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 56 days post last dose in short- term period or first dose in the long -term period, whichever occurs first.
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Subjects
        Infections
    234
    221
        Malignancies
    3
    5
        Autoimmune Disorders
    7
    6
        Acute Infusional AEs
    20
    16
        Peri-infusional AEs
    59
    59
        Local Injection Site Reactions
    19
    18
        Systemic Injection Reactions
    56
    56
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements [14]
    End point description
    Vital sign measurements were performed for subjects before and after infusion/subcutaneous injection of study medication at each visit and included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator. All randomised subjects who received at least 1 dose of study medication were analysed.
    End point type
    Secondary
    End point timeframe
    Day 1 through end of short-term period (Day 169)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality [15]
    End point description
    ULN=upper limit of normal; LLN=lower limit of normal; BL= baseline. Marked abnormality criteria: Hemoglobin: >3 g/dL decrease from BL; hematocrit: <0.75*BL; erythrocytes: <0.75*BL; platelets: <0.67*LLN/>1.5*ULN, or if BL<LLN, use <0.5*BL and <100,000 mm^3; leukocytes: <0.75*LLN/>1.25*ULN, or if BL<LLN use <0.8*BL or >ULN, or if BL>ULN, use >1.2*BL or <LLN; neutrophils+bands: <1.0*10^3 c/uL; eosinophils: >0.750*10^3 c/uL; basophils: >400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750*10^3 c/uL/>7.50*10^3 c/uL. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjects with assessments available.
    End point type
    Secondary
    End point timeframe
    Day 1 through end of short-term period (Day 169)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Subjects
        Low hemoglobin (LLN=11.5 g/dL); n=729, 713
    2
    5
        Low hematocrit (LLN=34%); n=726, 713
    2
    4
        Low erythrocytes(LLN=3.8 x10*6c/uL);n=729, 713
    2
    3
        Low platelets (LLN=140*10^9 c/L); n=725, 709
    1
    0
        High platelets (ULN=450*10^9 c/L); n=725, 709
    0
    0
        Low leukocytes (LLN= 3.8*10^3 c/uL); n=729, 713
    6
    2
        High eosinophils (ULN= 7*10^3 c/uL); n=730, 712
    22
    16
        High basophils (ULN= 0.2*10^3 c/uL); n=730, 712
    0
    0
        High monocytes (ULN=1*10^3 c/uL); n=730, 712
    0
    1
        Low lymphocytes (LLN= 0.7*10^3 c/uL);n=730,712
    40
    42
        Low neutrophils+bands(LLN=1.8*10^3 c/uL);n=730,713
    0
    0
        High leukocytes (ULN = 10.6*10^3 c/uL);n=729, 713
    25
    18
        High lymphocytes (ULN=4.5*10^3 c/uL); n=730,712
    40
    42
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality [16]
    End point description
    Marked abnormality criteria: Alkaline phosphatase (ALP): >2*ULN, or if BL>ULN, use >3*BL; aspartate aminotransferase (AST): >3*ULN, or if BL>ULN, use >4*BL; alanine aminotransferase (ALT): >3*ULN, or if BL>ULN, use >4*BL; G-glutamyl transferase (GGT): >2* ULN, or if BL>ULN, use >3*BL; bilirubin: >2* ULN, or if BL>ULN, use >4*BL; blood urea nitrogen: >2* BL; creatinine: >1.5*BL. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjects with assessments available.
    End point type
    Secondary
    End point timeframe
    Day 1 through end of short-term period (Day 169)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Subjects
        High ALP (ULN=400 U/L); n=730, 713
    1
    3
        High AST (ULN=44 U/L); n=729, 713
    5
    5
        High ALT (ULN=55 U/L);n=729, 713
    12
    16
        High GGT (ULN=65 U/L); n=730, 713
    8
    14
        High bilirubin (ULN=1.2 mg/dL); n=730, 713
    1
    0
        High blood urea nitrogen (26 mg/dL); n=730, 713
    21
    27
        High creatinine (ULN=1.5 mg/dL); n=730, 713
    19
    30
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality [17]
    End point description
    Marked abnormality criteria: Sodium: <0.95*LLN/>1.05*ULN, or if BL<LLN, use <0.95* BL or >ULN, or if BL>ULN, use>1.05* BL or <LLN; potassium: <0.9* LLN/>1.1*ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN, use>1.1* BL or <LLN; chlorine: <0.9*LLN/>1.1* ULN, or if BL<LLN, use <0.9*BL or >ULN, or if BL>ULN, use>1.1*BL or <LLN; calcium: <0.8* LLN/>1.2* ULN, or if BL<LLN, use <0.75*BL or >ULN, or if BL>ULN, use>1.25* BL or <LLN; phosphorous: <0.75* LLN/>1.25*ULN, or if BL<LLN, use 0.67*BL or >ULN, or if BL>ULN, use>1.33* BL or <LLN. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "N" = number of subjects with assessments available.
    End point type
    Secondary
    End point timeframe
    Day 1 through end of short-term period (Day 169)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Subjects
        Low sodium (LLN=135 mEq/L)
    2
    0
        High sodium (ULN=148 mEq/L)
    0
    0
        Low potassium (LLN=3.5 mEq/L)
    9
    9
        High potassium (ULN=5.5 mEq/L)
    1
    0
        Low chlorine (LLN= 96 mEq/L)
    0
    0
        High chlorine (ULN=109 mEq/L)
    0
    0
        Low calcium (LLN=8.4 mg/dL)
    1
    0
        High calcium (ULN=10.6 mg/dL)
    1
    0
        Low phosphorous (LLN=0.8 mg/dL)
    1
    2
        High phosphorous (ULN=5.6 mg/dL)
    0
    1
    No statistical analyses for this end point

    Secondary: Double-blind Period: Minimum Observed Serum Concentration of Abatacept

    Close Top of page
    End point title
    Double-blind Period: Minimum Observed Serum Concentration of Abatacept [18]
    End point description
    A sensitive, validated immunoassay method will be used to measure concentrations of abatacept in serum. Subjects who received at least 1 dose of study medication and from whom at least 1 pharmacokinetic (PK) sample was collected and reported (N). Only subjects with adequate PK profiles were included in the summary statistics and statistical analysis (n). PK values were not sampled for IV abatacept group on Day 120, 127, 134. Here, ‘99999’ represents not estimable data for specified categories in respective arms.
    End point type
    Secondary
    End point timeframe
    Days 57, 85, 113, 120, 127, 134, 141, and 169
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: μg/mL
    geometric mean (standard deviation)
        Day 57 (n=25, n=16)
    31.6 ± 21.483
    23.14 ± 14.008
        Day 85 (n=630, n=649)
    28.3 ± 21.692
    20 ± 13.441
        Day 113 (n=44, n=29)
    26.49 ± 16.569
    18.76 ± 16.322
        Day 120 (n=27)
    25.1 ± 14.933
    99999 ± 99999
        Day 127 (n=28)
    29.16 ± 14.78
    99999 ± 99999
        Day 134 (n=27)
    25.1 ± 15.753
    99999 ± 99999
        Day 141 (n=26, n=26)
    25.79 ± 14.264
    18.1 ± 17.717
        Day 169 (n=530, n=521)
    24.91 ± 14.989
    18.1 ± 17.94
    No statistical analyses for this end point

    Secondary: Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept

    Close Top of page
    End point title
    Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept [19]
    End point description
    Serum concentrations of abatacept were analyzed using a validated ELISA. Steady-state trough observed concentration in serum (Cminss) was measured in μg/mL. Samples were obtained on Days 57, 85, 113, 120, 127, 134, 141, and 169. Subjects who had failed one anti-TNF therapy were included in the sub-study. Subjects who received at least 1 dose of study medication and who had adequate PK profiles were analyzed. n= number of subjects available at each specific time point. PK values were not sampled for IV abatacept group on Day 120, 127, 134. Here, ‘99999’ represents not estimable data for specified categories in respective arms.
    End point type
    Secondary
    End point timeframe
    Days 57, 85, 113, 120, 127, 134, 141, and 169 (ST Period)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study) Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Number of subjects analysed
    8
    10
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Day 57 (n=3, 4)
    25.53 ± 16
    15.51 ± 25
        Day 85 (n=6, 9)
    21.51 ± 26
    12.5 ± 48
        Day 113 (n=6, 6)
    23.14 ± 27
    11.1 ± 31
        Day 120 (n=4, 0)
    25.75 ± 17
    99999 ± 99999
        Day 127 (n=3, 0)
    25.42 ± 9
    99999 ± 99999
        Day 134 (n=3, 0)
    25.55 ± 13
    99999 ± 99999
        Day 141 (n=4, 6)
    20.85 ± 24
    8.34 ± 44
        Day 169 (n=5, 7)
    19.66 ± 25
    9 ± 53
    No statistical analyses for this end point

    Secondary: Double-blind Period: Maximum Observed Serum Concentration of Abatacept

    Close Top of page
    End point title
    Double-blind Period: Maximum Observed Serum Concentration of Abatacept [20]
    End point description
    Subjects who received at least 1 dose of study medication and who had adequate PK profiles for analysis were evaluated for this outcome measure. Here, 'Number of Subjects Analysed' signifies the subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    End of infusion on Days 1 and 113 for IV infusion and in the dosing interval of Days 113 to 120 for subcutaneous
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    39
    30
    Units: μg/mL
        geometric mean (standard deviation)
    40.39 ± 30.148
    222.35 ± 71.92
    No statistical analyses for this end point

    Secondary: Anti-TNF Failure Substudy Double Blind Period: Geometric Mean Maximum Observed Serum Concentration of Abatacept

    Close Top of page
    End point title
    Anti-TNF Failure Substudy Double Blind Period: Geometric Mean Maximum Observed Serum Concentration of Abatacept [21]
    End point description
    Serum concentrations of abatacept were analyzed using a validated enzyme-linked immunosorbent assay. Samples were obtained on Days 57, 85, 113, 120, 127, 134, 141, and 169. Cmax was measured in micrograms per milliliter (μg/mL). Subjects who had failed one anti-TNF therapy were included in the sub-study. Subjects in the Sub-study who received at least 1 dose of study medication and who had adequate pharmacokinetic profiles were analysed. Here, 'Number of Subjects Analysed' signifies the subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    End of infusion on Days 1 and 113 for IV infusion and in the dosing interval of Days 113 to 120 for subcutaneous
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study) Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Number of subjects analysed
    5
    5
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    35.84 ± 24
    229.88 ± 26
    No statistical analyses for this end point

    Secondary: Double-blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

    Close Top of page
    End point title
    Double-blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept [22]
    End point description
    A sensitive, validated immunoassay method was used to measure concentrations of abatacept in serum. The analysis was performed in all the subjects who received at least 1 dose of study medication and who had adequate PK profiles for analysis. Here, 'Number of Subjects Analysed' signifies the subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Dosing interval between Days 113 and 141 (TAU=28 days)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    39
    33
    Units: μg*h/mL
        geometric mean (standard deviation)
    5182.37 ± 2854.136
    39587.08 ± 15444.74
    No statistical analyses for this end point

    Secondary: Anti-TNF Failure Sub-study Double Blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

    Close Top of page
    End point title
    Anti-TNF Failure Sub-study Double Blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept [23]
    End point description
    Serum concentrations of abatacept were analyzed using a validated ELISA. AUC(TAU) was measured as μg*h/mL. Samples were obtained on Days 113, 120, 127, 134, 141, and 169. Subjects who had failed one anti-TNF therapy were included in the sub-study. The analysis was performed in all subjects in the sub-study who received at least 1 dose of study medication and who had adequate PK profiles for analysis. Here, 'Number of Subjects Analysed' signifies the subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Dosing Interval between Days 113 and 141 (TAU=28 days)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study) Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
    Number of subjects analysed
    5
    6
    Units: μg*h/mL
        geometric mean (geometric coefficient of variation)
    4384.3 ± 17
    34260.55 ± 35
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunoabsorbant Assay (ELISA)

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunoabsorbant Assay (ELISA) [24]
    End point description
    Serum samples from all treated adult subjects with active rheumatoid arthritis were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept (anti-ABA) or anti-CTLA4 antibody (anti-CTLA4). The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjects with at least 1 assessment available.
    End point type
    Secondary
    End point timeframe
    Days 1, 85, and 169 and post-visits on Days 28, 56, and 85
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Subjects
        Day 85 anti-ABA (n=700, n=682)
    0
    2
        Day 85 anti-CTLA4 (n=705, n=689)
    0
    0
        Day 85 total (n=706, n=689)
    0
    2
        Day 169 anti-ABA (n=671, n=648)
    3
    4
        Day 169 anti-CTLA4 (n=681, n=658)
    2
    4
        Day 169 total (n=681, n=658)
    5
    8
        Overall on-treatment visits anti-ABA (n=707, 691)
    3
    5
        Overall on-treatment visits anti-CTLA4 (n=716,702)
    2
    4
        Overall on-treatment visits total (n=716, 702)
    5
    9
        28 days post last dose anti-ABA (n=18, n=25)
    0
    0
        28 days post last dose anti-CTLA4 (n=20, n=27)
    0
    2
        28 days post last dose total (n=20, n=27)
    0
    2
        56 days post last dose anti-ABA (n=19, n=22)
    0
    0
        56 days post last dose anti-CTLA4 (n=19, n=23)
    1
    1
        56 days post last dose total (n=19, n=23)
    1
    1
        85 days post last dose anti-ABA (n=12, n=15)
    0
    0
        85 days post last dose anti-CTLA4 (n=13, n=15)
    2
    5
        85 days post last dose total (n=13, n=15)
    2
    5
        Overall post visits anti-ABA (n=26, n=29)
    0
    0
        Overall post visits anti-CTLA4 (n=28, n=31)
    3
    7
        Overall post visits total (n=28, n=31)
    3
    7
        Overall anti-ABA (n=714, n=698)
    3
    5
        Overall anti-CTLA4 (n=725, n=710)
    5
    11
        Overall total (n=725, n=710)
    8
    16
    No statistical analyses for this end point

    Secondary: Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period

    Close Top of page
    End point title
    Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period [25]
    End point description
    C-reactive protein is an acute phase reactant protein that is a clinical marker for rheumatoid arthritis. Time-matched median percent change from baseline= (time-matched baseline value - Post-baseline value)/time-matched baseline value*100, where the time-matched baseline value represents the median baseline value for only that cohort of subjects with measurements available at that visit. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjects with at least 1 assessment available.
    End point type
    Secondary
    End point timeframe
    Baseline to Days 15, 29, 57, 85, 113, 141, and 169
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Percentage change
    median (inter-quartile range (Q1-Q3))
        Day 15 (n=720, n=703)
    34.16 (-11.11 to 58.8)
    33.74 (-6.24 to 58.41)
        Day 29 (n=727, n=711)
    39.74 (3.83 to 66.99)
    42.52 (0.42 to 68.66)
        Day 57 (n=727, n=711)
    47.88 (6.84 to 73.53)
    51.42 (7.53 to 74.95)
        Day 85 (n=727, n=711)
    52.9 (8.7 to 78.25)
    53.65 (11.05 to 79.42)
        Day 113 (n=727, n=711)
    53.33 (7.09 to 80.29)
    58.12 (11.21 to 81.26)
        Day 141 (n=727, n=711)
    56.12 (5.28 to 83.24)
    58.39 (16.14 to 81.52)
        Day 169 (n=727, n=711)
    57.18 (11.18 to 83.28)
    56.81 (17.92 to 82.7)
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay [26]
    End point description
    An electro-chemiluminescence immunoassay screened sera for drug-specific antibodies, immuno-competition was used to identify specific anti-abatacept reactivity. CTLA4 and Possibly Ig category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; abatacept molecule). Ig and/or Junction (JNCT) category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if baseline value was missing. Trt=treatment. The analysis was performed in all the subjects who received at least 1 dose of abatacept and had at least 1 immunogenicity result reported during the short-term period.
    End point type
    Secondary
    End point timeframe
    Days 85, and 169 and post-visits on Days 28, 56, and 85
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Subjects
        Day 85 CTLA4 + possibly Ig (n=78, n=67)
    0
    0
        Day 85 Ig +/- JNCT (n=78, n=67)
    0
    0
        Day 85 total (n=78, n=67)
    0
    0
        Day 169 CTLA4 + possibly Ig (n=75, n=67)
    0
    1
        Day 169 Ig +/- JNCT (n=75, n=67)
    0
    0
        Day 169 total (n=75, n=67)
    0
    1
        Overall on-TRT CTLA4 + possibly Ig (n=79, 70)
    0
    1
        Overall on-TRT Ig +/- JNCT (n=79, 70)
    0
    0
        Overall on-TRT total (n=79, 70)
    0
    1
        28 days post last dose CTLA4+possibly Ig (n=2,n=2)
    0
    0
        28 days post last dose Ig +/- JNCT (n=2, n=2)
    0
    0
        28 days post last dose Total (n=2, n=2)
    0
    0
        56 days post last dose CTLA4+possibly Ig (n=2,n=2)
    0
    0
        56 days post last dose Ig +/- JNCT (n=2, n=2)
    0
    0
        56 days post last dose total (n=2, n=2)
    0
    0
        85 days post last dose CTLA4+possibly Ig (n=1,n=1)
    0
    0
        85 days post last dose Ig +/- JNCT (n=1, n=1)
    0
    0
        85 days post last dose total (n=1, n=1)
    0
    0
        Overall post visits CTLA4+possibly Ig (n=3, n=2)
    0
    0
        Overall post visits Ig +/- JNCT (n=3, n=2)
    0
    0
        Overall post visits total (n=3, n=2)
    0
    0
        Overall CTLA4+possibly Ig (n=82, n=71)
    0
    1
        Overall Ig +/- JNCT (n=82, n=71)
    0
    0
        Overall total (n=82, n=71)
    0
    1
    No statistical analyses for this end point

    Secondary: Double-blind Period: Number of Subjects Seroconverting by Day 169 According to Status (Negative or Positive) at Baseline

    Close Top of page
    End point title
    Double-blind Period: Number of Subjects Seroconverting by Day 169 According to Status (Negative or Positive) at Baseline [27]
    End point description
    Rheumatoid factor (RF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of Immunoglobulin (Ig)G, which is itself an antibody. RF and IgG join to form immune complexes which contribute to the disease process. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjectsts with at least 1 assessment available.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 169
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    Subcutaneous (SC) Abatacept Intravenous (IV) Abatacept
    Number of subjects analysed
    736
    721
    Units: Subjects
        Baseline RF negative
    106
    93
        Baseline RF negative; Day 169 RF positive
    2
    3
        Baseline RF positive
    586
    582
        Baseline RF positive ; Day 169 RF negative
    33
    40
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Number of Subjects Achieving ACR 20 Response at Days 169, 729, 1261, and 1821

    Close Top of page
    End point title
    Open-Label LT Period: Number of Subjects Achieving ACR 20 Response at Days 169, 729, 1261, and 1821
    End point description
    The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function and acute phase reactant value (C-reactive protein). The analysis was performed in all the subjects who entered the LT period and received at least 1 dose of study drug during the LT period.
    End point type
    Secondary
    End point timeframe
    Days 169, 729, 1261, 1821
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1365
    Units: Subjects
        Day 169 (n=1357)
    1087
        Day 729 (n=1187)
    973
        Day 1261 (n=1068)
    904
        Day 1821 (n=421)
    356
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses at Days 169, 729, 1261, 1821

    Close Top of page
    End point title
    Open-Label LT Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses at Days 169, 729, 1261, 1821
    End point description
    The ACR 50 definition of improvement is a 50% improvement from baseline in the number of tender and swollen joint counts, and a 50% improvement from baseline in 3 of the remaining 5 core set measures: subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function and acute phase reactant value (C-reactive protein). ACR 70 is defined similarly with 70% improvements from baseline for tender and swollen joint counts and 3 out of 5 core measures. All subjects who entered the LT period and received at least 1 dose of study drug during the LT period were summarized.
    End point type
    Secondary
    End point timeframe
    Days 169, 729, 1261, 1821
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1365
    Units: Subjects
        Day 169 ACR 50 (n=1362)
    724
        Day 729 ACR 50 (n=1185)
    720
        Day 1261 ACR 50(n=1069)
    672
        Day 1821 ACR 50 (n=423)
    277
        Day 169 ACR 70 (n=1362)
    371
        Day 729 ACR 70 (n=1186)
    443
        Day 1261 ACR 70 (n=1070)
    438
        Day 1821 ACR 70 (n=425)
    191
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Mean Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Using C-reactive Protein (CRP) at Days 169, 729, 1261, 1821

    Close Top of page
    End point title
    Open-Label LT Period: Mean Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Using C-reactive Protein (CRP) at Days 169, 729, 1261, 1821
    End point description
    The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and subject assessment of global health (by marking a visual analog scale 100 mm line from "very good" to "very bad"). A higher DAS28 score indicates worse control of disease. High disease activity is > 5.1, low disease activity is < 3.2 and remission is < 2.6. A clinically significant response= decrease in DAS28 score of >1.2 from baseline. All subjects who entered the LT period and received at least 1 dose of study drug during the LT period were summarized.
    End point type
    Secondary
    End point timeframe
    Days 169, 729, 1261, 1821
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1365
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Day 169 (n=1353)
    -2.65 (-2.71 to -2.58)
        Day 729 (n=1181)
    -2.94 (-3.01 to -2.86)
        Day 1261 (n=1063)
    -3.09 (-3.17 to -3)
        Day 1821 (n=413)
    -3.24 (-3.38 to -3.11)
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Number of Subjects Achieving DAS 28 Remission at Days 169, 729, 1261, 1821

    Close Top of page
    End point title
    Open-Label LT Period: Number of Subjects Achieving DAS 28 Remission at Days 169, 729, 1261, 1821
    End point description
    The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and subject assessment of global health (by marking a visual analog scale 100 mm line from "very good" to "very bad"). A higher DAS28 score indicates worse control of disease. High disease activity is > 5.1, low disease activity is < 3.2 and remission is < 2.6. All subjects who entered the LT period and received at least 1 dose of study drug during the LT period were summarised.
    End point type
    Secondary
    End point timeframe
    Days 169, 729, 1261, 1821
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1365
    Units: Subjects
        Day 169 (n=1355)
    334
        Day 729 (n=1183)
    411
        Day 1261 (n=1064)
    425
        Day 1821 (n=413)
    169
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Number of Subjects Achieving DAS 28 Low Disease Activity (LDA) at Days 169, 729, 1261, 1821

    Close Top of page
    End point title
    Open-Label LT Period: Number of Subjects Achieving DAS 28 Low Disease Activity (LDA) at Days 169, 729, 1261, 1821
    End point description
    The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and subject assessment of global health (by marking a visual analog scale 100 mm line from "very good" to "very bad"). A higher DAS28 score indicates worse control of disease. High disease activity is > 5.1, low disease activity is < 3.2 and remission is < 2.6. All Subjects who entered the LT period and received at least 1 dose of study drug during the LT period were summarised.
    End point type
    Secondary
    End point timeframe
    Days 169, 729, 1261, 1821
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1365
    Units: Subjects
        Day 169 (n=1355)
    553
        Day 729 (n=1183)
    600
        Day 1261 (n=1064)
    585
        Day 1821 (n=413)
    238
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Number of Subjects With HAQ-DI Response at Days 169, 729, 1261, 1821

    Close Top of page
    End point title
    Open-Label LT Period: Number of Subjects With HAQ-DI Response at Days 169, 729, 1261, 1821
    End point description
    The disability section of the full HAQ includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI overall score ranges from a minimum of 0 to a maximum of 3.0. HAQ response was defined as an improvement (reduction) from baseline (Day 1) of at least 0.3 units in the HAQ score. All subjects who entered the LT period, received at least 1 dose of study drug during the LT period, and had HAD-QI scores at baseline and at specified days were summarised.
    End point type
    Secondary
    End point timeframe
    Days 169, 729, 1261, 1821
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1365
    Units: Subjects
        Day 169 (n=1364)
    962
        Day 729 (n=1190)
    853
        Day 1261 (n=1068)
    780
        Day 1821 (n=427)
    315
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

    Close Top of page
    End point title
    Open-Label LT Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation
    End point description
    AE=any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Treatment-related SAE=possibly, probably, or certainly related to study drug. The analysis was performed in all the subjects who entered the LT Period and received at least 1 dose of study drug during the LT Period.
    End point type
    Secondary
    End point timeframe
    End of ST Period (Day 169) to last dose plus 85 days, up to 5 years (September 2014)
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1373
    Units: Subjects
        Death
    41
        SAE
    353
        Treatment-related SAE
    88
        SAEs leading to Discontinuation
    73
        Treatment-related AEs
    632
        AEs leading to Discontinuation
    97
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Number of Subjects With Adverse Events (AEs) of Special Interest

    Close Top of page
    End point title
    Open-Label LT Period: Number of Subjects With Adverse Events (AEs) of Special Interest
    End point description
    AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs: all infections, serious infections, and opportunistic infections; autoimmune disorders; malignancies; system injection reactions, and local injection site reactions. The analysis was performed in all the subjects who entered the LT Period and received at least 1 dose of study drug during the LT Period.
    End point type
    Secondary
    End point timeframe
    End of ST Period (Day 169) to last dose plus 85 days, up to 5 years (September 2014)
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1373
    Units: Subjects
        All Infections
    962
        Serious Infections
    85
        Infections leading to Discontinuation
    25
        Serious Infections leading to Discontinuation
    16
        Malignancies
    56
        Autoimmune Disorders
    67
        Local Injection Site Reactions
    33
        Systemic Injection Reactions
    161
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements

    Close Top of page
    End point title
    Open-Label LT Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements
    End point description
    Vital sign assessments were performed in the LT period at 12-week intervals and at a yearly visit (at 16-week intervals) and, for subjects who withdrew from the study prematurely, 7 days after the last dose of SC abatacept. Vital signs included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator. The analysis was performed in all the subjects who entered the LT Period and received at least 1 dose of study drug during the LT Period.
    End point type
    Secondary
    End point timeframe
    End of ST Period (Day 169) to last dose plus 7 days, up to 5 years (September 2014)
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1373
    Units: Subjects
    0
    No statistical analyses for this end point

    Secondary: Open-Label LT Period: Number of Subjects With Clinically Significant Laboratory Abnormalities

    Close Top of page
    End point title
    Open-Label LT Period: Number of Subjects With Clinically Significant Laboratory Abnormalities
    End point description
    Laboratory assessments were performed in the LT period at 12-week intervals and at a yearly visit and, for subjects who withdrew from the study prematurely, 7 days after the last dose of SC abatacept. Abnormalities were determined to be clinically significant by the investigator. The analysis was performed in all the subjects who entered the LT Period and received at least 1 dose of study drug during the LT Period.
    End point type
    Secondary
    End point timeframe
    End of ST Period (Day 169) to last dose plus 7 days, up to 5 years (September 2014)
    End point values
    Subcutaneous (SC) Abatacept
    Number of subjects analysed
    1373
    Units: Subjects
    0
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    First dose (Day 1) in ST period to last dose in LT period plus 85 days, up to 5 years (September 2014)
    Adverse event reporting additional description
    Population includes both Main Study and Anti-TNF Failure Sub-study. Sub-study was terminated early and subjects could enter LT Period of Main study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    IV Abatacept
    Reporting group description
    During the Main study Double Blind ST Period, subjects received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter for 6 months. A double-dummy design was used to protect the blind, thus, subjects also received SC injections of placebo (SC Placebo). An Anti-TNF Failure Sub-study was initiated (recruited separately from Main study) using the same treatment as the Main study in order to assess the immunogenicity and safety in the Anti-TNF Failure population. The Sub-study terminated due to low recruitment and subjects were permitted to roll into the LT Open Label Period. During the Open Label LT Period, subjects in both the Main Study and the Anti-TNF Failure Sub-study could switch to SC abatacept until the SC formulation became commercially available on a country basis or the Sponsor terminated the study.

    Reporting group title
    SC Abatacept
    Reporting group description
    During the Main Study Double Blind ST Period, subjects received 125 mg weekly SC abatacept injections for 6 months (with an IV abatacept loading dose on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, subjects also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment. An Anti-TNF Failure Sub-study was initiated (recruited separately from Main study) using the same treatment as the Main study in order to assess the immunogenicity and safety in the Anti-TNF Failure population. The Sub-study terminated due to low recruitment and subjects were permitted to roll into the LT Open Label Period. During the Open Label LT Period, subjects in both the Main Study and the Anti-TNF Failure Sub-study could continue SC abatacept until the SC formulation became commercially available on a country basis or the Sponsor terminated the study.

    Serious adverse events
    IV Abatacept SC Abatacept
    Total subjects affected by serious adverse events
         subjects affected / exposed
    206 / 731 (28.18%)
    199 / 744 (26.75%)
         number of deaths (all causes)
    22
    19
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angiopathy
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 731 (0.14%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Mammoplasty
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma stage 0
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Ovarian epithelial cancer
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal cancer
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 731 (0.14%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrous histiocytoma
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    7 / 731 (0.96%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 731 (0.00%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucoepidermoid carcinoma of salivary gland
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    2 / 731 (0.27%)
    4 / 744 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary cancer metastatic
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic myelomonocytic leukaemia
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenosquamous cell lung cancer
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroma
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder cancer metastatic
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    6 / 731 (0.82%)
    4 / 744 (0.54%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adhesion
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embedded device
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pyrexia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pacemaker generated arrhythmia
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic haematoma
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenomyosis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian mass
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    2 / 731 (0.27%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    2 / 731 (0.27%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Contusion
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Median nerve injury
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    3 / 731 (0.41%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    3 / 731 (0.41%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac function disturbance postoperative
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Enterococcus test positive
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 731 (0.14%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 731 (0.00%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 731 (0.14%)
    5 / 744 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myocardial infarction
         subjects affected / exposed
    5 / 731 (0.68%)
    11 / 744 (1.48%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 12
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 731 (0.14%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Metatarsus primus varus
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial septal defect
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary toxicity
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary bulla
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 731 (0.00%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Haemoptysis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 731 (0.27%)
    6 / 744 (0.81%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lung disorder
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Tracheal stenosis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypersplenism
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 731 (0.27%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising granulomatous lymphadenitis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nervous system disorders
    Brain stem stroke
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 731 (0.27%)
    4 / 744 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basilar migraine
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral artery embolism
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery aneurysm
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Demyelinating polyneuropathy
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 731 (0.41%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 731 (0.27%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculitis lumbosacral
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical cord compression
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Keratitis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular fibrosis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blindness
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal infarction
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 731 (0.27%)
    4 / 744 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ischaemia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal angiodysplasia haemorrhagic
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 731 (0.00%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocele
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    3 / 731 (0.41%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    3 / 731 (0.41%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Stress urinary incontinence
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder prolapse
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice hepatocellular
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    3 / 731 (0.41%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 731 (0.14%)
    4 / 744 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    4 / 731 (0.55%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 731 (0.27%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin wrinkling
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Facet joint syndrome
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament disorder
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint contracture
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 731 (0.27%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    3 / 731 (0.41%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    12 / 731 (1.64%)
    16 / 744 (2.15%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 731 (0.14%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 731 (0.27%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    12 / 731 (1.64%)
    14 / 744 (1.88%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetes mellitus
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective tenosynovitis
         subjects affected / exposed
    2 / 731 (0.27%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    0 / 731 (0.00%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urosepsis
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Encephalitis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal tuberculosis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 731 (0.41%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 731 (0.41%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 731 (0.00%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Abscess oral
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atypical pneumonia
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 731 (0.00%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ludwig angina
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral hepatitis carrier
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 731 (1.64%)
    8 / 744 (1.08%)
         occurrences causally related to treatment / all
    9 / 13
    4 / 8
         deaths causally related to treatment / all
    1 / 3
    2 / 3
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 731 (0.00%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 731 (0.27%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Herpes zoster
         subjects affected / exposed
    2 / 731 (0.27%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 731 (0.14%)
    2 / 744 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 731 (0.96%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    7 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 731 (0.00%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sepsis
         subjects affected / exposed
    1 / 731 (0.14%)
    3 / 744 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 731 (0.14%)
    1 / 744 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tetanus
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 744 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    IV Abatacept SC Abatacept
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    544 / 731 (74.42%)
    567 / 744 (76.21%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    85 / 731 (11.63%)
    96 / 744 (12.90%)
         occurrences all number
    103
    114
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    74 / 731 (10.12%)
    72 / 744 (9.68%)
         occurrences all number
    108
    91
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 731 (3.56%)
    55 / 744 (7.39%)
         occurrences all number
    65
    32
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    40 / 731 (5.47%)
    37 / 744 (4.97%)
         occurrences all number
    52
    43
    Headache
         subjects affected / exposed
    88 / 731 (12.04%)
    86 / 744 (11.56%)
         occurrences all number
    156
    120
    Psychiatric disorders
    Depression
         subjects affected / exposed
    40 / 731 (5.47%)
    37 / 744 (4.97%)
         occurrences all number
    42
    40
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    27 / 731 (3.69%)
    39 / 744 (5.24%)
         occurrences all number
    37
    46
    Abdominal pain upper
         subjects affected / exposed
    47 / 731 (6.43%)
    43 / 744 (5.78%)
         occurrences all number
    53
    45
    Diarrhoea
         subjects affected / exposed
    89 / 731 (12.18%)
    96 / 744 (12.90%)
         occurrences all number
    128
    129
    Gastritis
         subjects affected / exposed
    30 / 731 (4.10%)
    40 / 744 (5.38%)
         occurrences all number
    36
    43
    Nausea
         subjects affected / exposed
    53 / 731 (7.25%)
    79 / 744 (10.62%)
         occurrences all number
    74
    96
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    76 / 731 (10.40%)
    76 / 744 (10.22%)
         occurrences all number
    99
    95
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    120 / 731 (16.42%)
    109 / 744 (14.65%)
         occurrences all number
    182
    183
    Gastroenteritis
         subjects affected / exposed
    48 / 731 (6.57%)
    60 / 744 (8.06%)
         occurrences all number
    57
    72
    Influenza
         subjects affected / exposed
    55 / 731 (7.52%)
    51 / 744 (6.85%)
         occurrences all number
    82
    74
    Nasopharyngitis
         subjects affected / exposed
    143 / 731 (19.56%)
    149 / 744 (20.03%)
         occurrences all number
    250
    248
    Pharyngitis
         subjects affected / exposed
    80 / 731 (10.94%)
    74 / 744 (9.95%)
         occurrences all number
    127
    109
    Sinusitis
         subjects affected / exposed
    50 / 731 (6.84%)
    69 / 744 (9.27%)
         occurrences all number
    77
    122
    Upper respiratory tract infection
         subjects affected / exposed
    131 / 731 (17.92%)
    130 / 744 (17.47%)
         occurrences all number
    205
    228
    Urinary tract infection
         subjects affected / exposed
    133 / 731 (18.19%)
    150 / 744 (20.16%)
         occurrences all number
    210
    243

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2007
    The target percentage for subcutaneous abatacept was increased to preserve the intravenous abatacept benefit over placebo to 70%. In accordance, the following revisions were made: • non-inferiority margin reduced to -7.5 • total sample size increased to 1440 • randomization ratio changed to 1:1.
    25 Apr 2008
    The purpose of this amendment was further clarification on target population to be methotrexate inadequate responders, introducing a limit of subjects with prior exposure to anti-TNF therapy to 10% of the study population, implementing stratification by weight and shifting the collection interval for Pharmacokinetic (PK) samples of the Full PK Profile.
    25 Sep 2008
    Incorporates changes in the main protocol that result from the implementation of the anti-TNF failure substudy at selected sites, like the increase of the total sample size. In addition, some minor clarifications and updates on the protocol document were added.

    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
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA