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    Clinical Trial Results:
    A Multicenter, Single-blind, Randomized Parallel-group Study to Assess the Short- and Long-term Efficacy of Certolizumab Pegol Plus Methotrexate Compared with Adalimumab Plus Methotrexate in Subjects With Moderate To Severe Rheumatoid Arthritis Responding Inadequately to Methotrexate

    Summary
    EudraCT number
    2011-002067-20
    Trial protocol
    DE   GB   HU   PT   AT   IE   CZ   ES   BG   FR   IT   GR  
    Global end of trial date
    13 Jan 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    27 Apr 2017
    First version publication date
    09 Dec 2016
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    RA0077
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01500278
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma SA
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, B-1070
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.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
    17 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To demonstrate the superiority of short-term (Week 12) treatment in Certolizumab pegol (CZP)+ Methotrexate (MTX)-randomized subjects as compared with Adalimumab (ADA)+MTX-randomized subjecs • To demonstrate the superiority of long-term (Week 104) treatment in CZP+MTX-randomized subjects as compared with ADA+MTX-randomized subjects, with subjects who switch treatment (Week 12 Non-Responders) counted as treatment failures
    Protection of trial subjects
    Not applicable.
    Background therapy
    All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. The same dosing regimen (dose and route) was maintained from Baseline through Week 52. At Week 52, subjects were allowed to switch regimens (dose and/or route), but had to continue with an MTX dose of 15 to 25mg/week through Week 104 and were not allowed to change the MTX regimen after Week 52. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously. All subjects were responsible for providing their own MTX, consistent with their provision for such at entry. Other background therapy as permitted in the protocol.
    Evidence for comparator
    Adalimumab is a well established anti-TNF.
    Actual start date of recruitment
    14 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 27
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Bulgaria: 78
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Czech Republic: 118
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 62
    Country: Number of subjects enrolled
    Hungary: 58
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Mexico: 38
    Country: Number of subjects enrolled
    Poland: 130
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Romania: 52
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 226
    Worldwide total number of subjects
    915
    EEA total number of subjects
    603
    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)
    737
    From 65 to 84 years
    178
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll patients in December 2011 and concluded in January 2016.

    Pre-assignment
    Screening details
    Participant Flow refers to the Randomized Treatment Group (RTG) that consisted of all subjects randomized into the study.

    Period 1
    Period 1 title
    Week 0 - Week 12
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CZP+MTX (RTG)
    Arm description
    Subjects received loading doses of CZP 400mg (200mg/PFS, ie, 2 injections) at Baseline, and Weeks 2 and 4; and CZP 200mg at Weeks 6, 8, and 10. Week 12 Responders continued CZP 200mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to receive ADA 40mg at Week 12 and every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued ADA treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CZP+MTX group: Subcutaneous injections of CZP 400 mg at Baseline, Week 2 and Week 4, followed by a maintenance dose of 200 mg every 2 Weeks until week 102 for Week 12 Responders. ADA+MTX group: Subcutaneous injections of CZP 400 mg at Week 12, 14 and 16 followed by a maintenance dose of 200 mg every 2 Weeks until week 102 for Week 12 ADA+MTX Non-Responders.

    Arm title
    ADA+MTX (RTG)
    Arm description
    Subjects received ADA 40mg (40mg/PFS, ie, 1 injection) at Baseline and then every 2 weeks through Week 10. In order to preserve the blind (ie, use of 2 injections) until Week 12, subjects received an injection of PBO in addition to ADA at Baseline, and Weeks 2 and 4. Week 12 Responders continued ADA 40mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to a loading dose of CZP 400mg at Weeks 12, 14, and 16 followed by CZP 200mg every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued CZP treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    ADA
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ADA+MTX group: Subcutaneous injections of ADA 40mg at Baseline and then every 2 weeks through Week 102 for Week 12 Responders. CZP+MTX group: Subcutaneous injections of ADA 40mg at Week 12 and every 2 weeks through Week 102 for Week 12 CZP+MTX Non-Responders.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects in group ADA+MTX received an injection of PBO in addition to ADA at Baseline, and Weeks 2 and 4.

    Number of subjects in period 1
    CZP+MTX (RTG) ADA+MTX (RTG)
    Started
    457
    458
    Completed
    426
    428
    Not completed
    31
    30
         Investigator decision
    1
    -
         Protocol deviation
    10
    16
         Adverse event (AE), not fatal
    7
    8
         Exclusion criteria not met
    1
    -
         Lack of efficacy
    -
    1
         Other serious disease
    -
    1
         Consent withdrawn by subject
    7
    2
         Protocol violation on screening X-ray
    1
    -
         Personal reason
    -
    1
         Patient decision
    1
    -
         Lost to follow-up
    1
    1
         Prior history of serious disease
    1
    -
         Sponsor decision
    1
    -
    Period 2
    Period 2 title
    Week 13 - Week 104
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Investigator [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CZP+MTX (RTG)
    Arm description
    Subjects received loading doses of CZP 400mg (200mg/PFS, ie, 2 injections) at Baseline, and Weeks 2 and 4; and CZP 200mg at Weeks 6, 8, and 10. Week 12 Responders continued CZP 200mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to receive ADA 40mg at Week 12 and every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued ADA treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    ADA
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ADA+MTX group: Subcutaneous injections of ADA 40mg at Baseline and then every 2 weeks through Week 102 for Week 12 Responders. CZP+MTX group: Subcutaneous injections of ADA 40mg at Week 12 and every 2 weeks through Week 102 for Week 12 CZP+MTX Non-Responders.

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CZP+MTX group: Subcutaneous injections of CZP 400 mg at Baseline, Week 2 and Week 4, followed by a maintenance dose of 200 mg every 2 Weeks until week 102 for Week 12 Responders. ADA+MTX group: Subcutaneous injections of CZP 400 mg at Week 12, 14 and 16 followed by a maintenance dose of 200 mg every 2 Weeks until week 102 for Week 12 ADA+MTX Non-Responders.

    Arm title
    ADA+MTX (RTG)
    Arm description
    Subjects received ADA 40mg (40mg/PFS, ie, 1 injection) at Baseline and then every 2 weeks through Week 10. In order to preserve the blind (ie, use of 2 injections) until Week 12, subjects received an injection of PBO in addition to ADA at Baseline, and Weeks 2 and 4. Week 12 Responders continued ADA 40mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to a loading dose of CZP 400mg at Weeks 12, 14, and 16 followed by CZP 200mg every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued CZP treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.
    Arm type
    Active comparator

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CZP+MTX group: Subcutaneous injections of CZP 400 mg at Baseline, Week 2 and Week 4, followed by a maintenance dose of 200 mg every 2 Weeks until week 102 for Week 12 Responders. ADA+MTX group: Subcutaneous injections of CZP 400 mg at Week 12, 14 and 16 followed by a maintenance dose of 200 mg every 2 Weeks until week 102 for Week 12 ADA+MTX Non-Responders.

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    ADA
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ADA+MTX group: Subcutaneous injections of ADA 40mg at Baseline and then every 2 weeks through Week 102 for Week 12 Responders. CZP+MTX group: Subcutaneous injections of ADA 40mg at Week 12 and every 2 weeks through Week 102 for Week 12 CZP+MTX Non-Responders.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Period 2 of the study (Week 13 – Week 104) was single blinded, as only investigators were blinded, subjects were not.
    Number of subjects in period 2
    CZP+MTX (RTG) ADA+MTX (RTG)
    Started
    426
    428
    Completed
    287
    302
    Not completed
    139
    126
         Protocol deviation
    6
    6
         Withdrawn in error
    1
    -
         Sponsor request
    4
    -
         Lack of efficacy
    11
    12
         Exclusion criteria not met
    1
    -
         Patient declined Safety Follow Up Visit
    1
    -
         Abnormal questionable chest X-ray
    -
    2
         Adverse event, serious fatal
    2
    4
         Principal investigator retiring
    1
    -
         Relocation
    -
    1
         Recurrent infections
    1
    -
         False positive test
    1
    2
         Not completed
    -
    1
         Consent withdrawn by subject
    22
    13
         Non/bad compliance
    7
    5
         Week 24 Non-Responder
    20
    16
         Protocol violation
    1
    -
         Personal reason
    -
    1
         Adverse event, non-fatal
    54
    54
         Medical monitor decision
    -
    2
         Sponsor decision
    -
    2
         Lost to follow-up
    6
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CZP+MTX (RTG)
    Reporting group description
    Subjects received loading doses of CZP 400mg (200mg/PFS, ie, 2 injections) at Baseline, and Weeks 2 and 4; and CZP 200mg at Weeks 6, 8, and 10. Week 12 Responders continued CZP 200mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to receive ADA 40mg at Week 12 and every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued ADA treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.

    Reporting group title
    ADA+MTX (RTG)
    Reporting group description
    Subjects received ADA 40mg (40mg/PFS, ie, 1 injection) at Baseline and then every 2 weeks through Week 10. In order to preserve the blind (ie, use of 2 injections) until Week 12, subjects received an injection of PBO in addition to ADA at Baseline, and Weeks 2 and 4. Week 12 Responders continued ADA 40mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to a loading dose of CZP 400mg at Weeks 12, 14, and 16 followed by CZP 200mg every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued CZP treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.

    Reporting group values
    CZP+MTX (RTG) ADA+MTX (RTG) Total
    Number of subjects
    457 458 915
    Age Categorical
    Units: Subjects
        <=18 years
    0 1 1
        Between 18 and 65 years
    364 372 736
        >=65 years
    93 85 178
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    53.5 ± 12.3 52.9 ± 12.8 -
    Gender Categorical
    Units: Subjects
        Female
    360 363 723
        Male
    97 95 192

    End points

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    End points reporting groups
    Reporting group title
    CZP+MTX (RTG)
    Reporting group description
    Subjects received loading doses of CZP 400mg (200mg/PFS, ie, 2 injections) at Baseline, and Weeks 2 and 4; and CZP 200mg at Weeks 6, 8, and 10. Week 12 Responders continued CZP 200mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to receive ADA 40mg at Week 12 and every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued ADA treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.

    Reporting group title
    ADA+MTX (RTG)
    Reporting group description
    Subjects received ADA 40mg (40mg/PFS, ie, 1 injection) at Baseline and then every 2 weeks through Week 10. In order to preserve the blind (ie, use of 2 injections) until Week 12, subjects received an injection of PBO in addition to ADA at Baseline, and Weeks 2 and 4. Week 12 Responders continued ADA 40mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to a loading dose of CZP 400mg at Weeks 12, 14, and 16 followed by CZP 200mg every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued CZP treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.
    Reporting group title
    CZP+MTX (RTG)
    Reporting group description
    Subjects received loading doses of CZP 400mg (200mg/PFS, ie, 2 injections) at Baseline, and Weeks 2 and 4; and CZP 200mg at Weeks 6, 8, and 10. Week 12 Responders continued CZP 200mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to receive ADA 40mg at Week 12 and every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued ADA treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.

    Reporting group title
    ADA+MTX (RTG)
    Reporting group description
    Subjects received ADA 40mg (40mg/PFS, ie, 1 injection) at Baseline and then every 2 weeks through Week 10. In order to preserve the blind (ie, use of 2 injections) until Week 12, subjects received an injection of PBO in addition to ADA at Baseline, and Weeks 2 and 4. Week 12 Responders continued ADA 40mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to a loading dose of CZP 400mg at Weeks 12, 14, and 16 followed by CZP 200mg every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued CZP treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.

    Subject analysis set title
    CZP+MTX (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of Certolizumab pegol (CZP). All adverse events that occurred when the subject was receiving CZP treatment are summarized in this group.

    Subject analysis set title
    ADA+MTX (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of Adalimumab (ADA). All adverse events that occurred when the subject was receiving ADA treatment are summarized in this group.

    Subject analysis set title
    CZP+MTX (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received loading doses of CZP 400mg (200mg/PFS, ie, 2 injections) at Baseline, and Weeks 2 and 4; and CZP 200mg at Weeks 6, 8, and 10. Week 12 Responders continued CZP 200mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to receive ADA 40mg at Week 12 and every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued ADA treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.

    Subject analysis set title
    ADA+MTX (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received ADA 40mg (40mg/PFS, ie, 1 injection) at Baseline and then every 2 weeks through Week 10. In order to preserve the blind (ie, use of 2 injections) until Week 12, subjects received an injection of PBO in addition to ADA at Baseline, and Weeks 2 and 4. Week 12 Responders continued ADA 40mg at Week 12 and every 2 weeks thereafter through Week 102. Week 12 Non-Responders were switched to a loading dose of CZP 400mg at Weeks 12, 14, and 16 followed by CZP 200mg every 2 weeks through Week 22. At Week 24, Week 12 Non-Responders who did not have DAS28(ESR) LDA or a DAS28(ESR) change from Week 12 reduction of ≥1.2 discontinued CZP treatment and were withdrawn from the Treatment Period. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.

    Subject analysis set title
    CZP+MTX (Week 12 Responder Set)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    CZP 400 mg at Baseline, Week 2 and Week 4, followed by a maintenance dose of 200 mg every 2 Weeks until Week 102. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.

    Subject analysis set title
    ADA+MTX (Week 12 Responder Set)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ADA 40 mg at Baseline and then every 2 Weeks until Week 102. Subjects received PBO in addition to ADA at baseline and weeks 2 and 4 in order to maintain the blinding. All subjects received Methotrexate 15 to 25mg/week orally or subcutaneously from Baseline through Week 104. Regimens could have been changed at Week 52 only. Subjects who could not tolerate these doses could receive MTX at a minimum dose of 10mg/week orally or subcutaneously.

    Primary: Percentage of subjects who met the American College of Rheumatology 20 % (ACR20) criteria at Week 12

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    End point title
    Percentage of subjects who met the American College of Rheumatology 20 % (ACR20) criteria at Week 12
    End point description
    Subjects who met the ACR20 criteria were those subjects with at least 20% improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS).
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    CZP+MTX (FAS) ADA+MTX (FAS)
    Number of subjects analysed
    454
    454
    Units: Percentage of subjects
    number (not applicable)
        Percentage of subjects
    69.2
    71.4
    Statistical analysis title
    Odds Ratio for Difference in Responders
    Comparison groups
    CZP+MTX (FAS) v ADA+MTX (FAS)
    Number of subjects included in analysis
    908
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.467 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    1.2
    Notes
    [1] - The odds ratio, CI, and p-value are from a logistic regression model with RTG, gender, Baseline duration of RA (<2 years or >=2 years), and geographic region as factors and age as a covariate.

    Primary: Percentage of subjects who had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 104

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    End point title
    Percentage of subjects who had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 104
    End point description
    DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity.
    End point type
    Primary
    End point timeframe
    Week 104
    End point values
    CZP+MTX (FAS) ADA+MTX (FAS)
    Number of subjects analysed
    454
    454
    Units: Percentage of subjects
    number (not applicable)
        Percentage of subjects
    35.5
    33.5
    Statistical analysis title
    Odds Ratio for Difference in Responders
    Comparison groups
    CZP+MTX (FAS) v ADA+MTX (FAS)
    Number of subjects included in analysis
    908
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.532 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.45
    Notes
    [2] - The odds ratio, CI and p-value are from a logistic regression model with RTG, gender, Baseline duration of RA (<2 years or >=2 years), and geographic region as factors and Baseline DAS28(ESR) and age as covariates.

    Secondary: Percentage of Week 12 responders who had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 104

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    End point title
    Percentage of Week 12 responders who had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 104
    End point description
    DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity. The definition of Week 12 responders was DAS28[ESR] Low Disease Activity (LDA) (ie ≤ 3.2) or an improvement of ≥ 1.2 in DAS28[ESR] relative to Baseline.
    End point type
    Secondary
    End point timeframe
    Week 104
    End point values
    CZP+MTX (Week 12 Responder Set) ADA+MTX (Week 12 Responder Set)
    Number of subjects analysed
    353
    361
    Units: Percentage of subjects
    number (not applicable)
        Percentage of subjects
    45.6
    42.4
    No statistical analyses for this end point

    Secondary: Percentage of subjects who met the American College of Rheumatology 20 % (ACR20) criteria at Week 6

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    End point title
    Percentage of subjects who met the American College of Rheumatology 20 % (ACR20) criteria at Week 6
    End point description
    Subjects who met the ACR20 criteria were those subjects with at least 20% improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS).
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    CZP+MTX (FAS) ADA+MTX (FAS)
    Number of subjects analysed
    454
    454
    Units: Percentage of subjects
    number (not applicable)
        Percentage of subjects
    64.5
    60.8
    No statistical analyses for this end point

    Secondary: Percentage of subjects who had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 6

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    End point title
    Percentage of subjects who had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 6
    End point description
    DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    CZP+MTX (FAS) ADA+MTX (FAS)
    Number of subjects analysed
    454
    454
    Units: Percentage of subjects
    number (not applicable)
        Percentage of subjects
    20.5
    18.1
    No statistical analyses for this end point

    Secondary: Percentage of subjects who had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 12

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    End point title
    Percentage of subjects who had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 12
    End point description
    DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    CZP+MTX (FAS) ADA+MTX (FAS)
    Number of subjects analysed
    454
    454
    Units: Percentage of subjects
    number (not applicable)
        Percentage of subjects
    30.4
    29.7
    No statistical analyses for this end point

    Secondary: Percentage of subjects with a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 104, in subjects responding at both Week 6 and Week 12

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    End point title
    Percentage of subjects with a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 104, in subjects responding at both Week 6 and Week 12
    End point description
    DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity. The definition of Week 6/12 responders was DAS28[ESR] Low Disease Activity (LDA) (ie ≤ 3.2) or an improvement of ≥ 1.2 in DAS28[ESR] relative to Baseline.
    End point type
    Secondary
    End point timeframe
    Week 104
    End point values
    CZP+MTX (Week 12 Responder Set) ADA+MTX (Week 12 Responder Set)
    Number of subjects analysed
    310
    298
    Units: Percentage of subjects
    number (not applicable)
        Percentage of subjects
    47.7
    46.6
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 104

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    End point title
    Change from Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 104
    End point description
    HAQ-DI was derived based on the mean of individual scores in 8 categories of daily living actives (using 20 questions). Each question was scored 0-3 (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do), and the total HAQ-DI was scored on the scale of 0-3 as well. Change from Baseline was computed as the value at Week 104 minus the Baseline value. A negative value in Change from Baseline indicates an improvement.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 104
    End point values
    CZP+MTX (FAS) ADA+MTX (FAS)
    Number of subjects analysed
    454
    454
    Units: Units on a Scale
    least squares mean (standard error)
        Least squares mean
    -0.62 ± 0.03
    -0.72 ± 0.03
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimates of Proportion of Subjects Who Discontinued After Response at Week 12

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    End point title
    Kaplan-Meier Estimates of Proportion of Subjects Who Discontinued After Response at Week 12
    End point description
    Response at Week 12 means that a subject had either a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 12 or had a reduction of DAS28 [ESR] ≥ 1.2 from Baseline to Week 12. Kaplan-Meier Estimates of Proportion of Subjects Discontinued are presented per study week (days relative to Week 12 visit).
    End point type
    Secondary
    End point timeframe
    From Week 12 up to Week 104
    End point values
    CZP+MTX (Week 12 Responder Set) ADA+MTX (Week 12 Responder Set)
    Number of subjects analysed
    353
    361
    Units: proportion of subjects
    number (not applicable)
        Week 13 (Day 7)
    0
    0.0028
        Week 26 (Day 98)
    0.0198
    0.0332
        Week 39 (Day 189)
    0.0453
    0.0609
        Week 52 (Day 280)
    0.0963
    0.0886
        Week 65 (Day 371)
    0.1643
    0.1607
        Week 78 (Day 462)
    0.2181
    0.1967
        Week 91 (Day 553)
    0.2408
    0.2105
        Week 104 (Day 644)
    0.2635
    0.2247
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the entire study period (From Week -4 to Week 104).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    CZP+MTX (SS)
    Reporting group description
    All subjects who received at least 1 dose of Certolizumab pegol (CZP). All adverse events that occurred when the subject was receiving CZP treatment are summarized in this group.

    Reporting group title
    ADA+MTX (SS)
    Reporting group description
    All subjects who received at least 1 dose of Adalimumab (ADA). All adverse events that occurred when the subject was receiving ADA treatment are summarized in this group.

    Serious adverse events
    CZP+MTX (SS) ADA+MTX (SS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    67 / 516 (12.98%)
    58 / 523 (11.09%)
         number of deaths (all causes)
    3
    3
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (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 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Osteosynthesis
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 516 (0.19%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 516 (0.19%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Borderline mucinous tumour of ovary
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         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 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 516 (0.19%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy with contraceptive device
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Impaired healing
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (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
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         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
    Cervical dysplasia
         subjects affected / exposed
    0 / 516 (0.00%)
    2 / 523 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural heamatoma
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (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
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         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 / 516 (0.39%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (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 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ancle fracture
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         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 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         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
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         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 / 516 (0.39%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 516 (0.19%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 516 (0.19%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 516 (0.39%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 516 (0.19%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 516 (0.39%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         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
    Anaemia
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haematoma
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (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
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         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
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ophthalmic vein thrombosis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Obstruction gastric
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal stenosis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal varices
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (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
    Nephrolithiasis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 516 (0.19%)
    2 / 523 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 516 (0.00%)
    4 / 523 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone disorder
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invertebral disc protrusion
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torticollis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 516 (0.39%)
    1 / 523 (0.19%)
         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
    3 / 516 (0.58%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 516 (0.19%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Mycobacterial infection
         subjects affected / exposed
    2 / 516 (0.39%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 516 (0.00%)
    2 / 523 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oophoritis
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 516 (0.19%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 516 (1.16%)
    5 / 523 (0.96%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 516 (0.19%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 516 (0.39%)
    0 / 523 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 516 (0.39%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 516 (0.00%)
    1 / 523 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    CZP+MTX (SS) ADA+MTX (SS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    269 / 516 (52.13%)
    244 / 523 (46.65%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    37 / 516 (7.17%)
    31 / 523 (5.93%)
         occurrences all number
    42
    34
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 516 (4.07%)
    28 / 523 (5.35%)
         occurrences all number
    26
    35
    Nervous system disorders
    Headache
         subjects affected / exposed
    55 / 516 (10.66%)
    47 / 523 (8.99%)
         occurrences all number
    62
    77
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    31 / 516 (6.01%)
    23 / 523 (4.40%)
         occurrences all number
    36
    26
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    79 / 516 (15.31%)
    67 / 523 (12.81%)
         occurrences all number
    116
    106
    Urinary tract infection
         subjects affected / exposed
    43 / 516 (8.33%)
    51 / 523 (9.75%)
         occurrences all number
    58
    65
    Upper respiratory tract infection
         subjects affected / exposed
    53 / 516 (10.27%)
    60 / 523 (11.47%)
         occurrences all number
    74
    80
    Latent tuberculosis
         subjects affected / exposed
    31 / 516 (6.01%)
    27 / 523 (5.16%)
         occurrences all number
    31
    27
    Sinusitis
         subjects affected / exposed
    31 / 516 (6.01%)
    21 / 523 (4.02%)
         occurrences all number
    35
    31
    Bronchitis
         subjects affected / exposed
    29 / 516 (5.62%)
    25 / 523 (4.78%)
         occurrences all number
    33
    26

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2012
    The main purpose was to address operational challenges, changes were considered practical, not to carry excess risk to the study subjects, and to have minimal impact on the study outcome. The changes included: •Washout Periods for analgesic and nonbiologic DMARDs were added to clarify subject eligibility. •Upper limit of eligibility for the liver function tests (LFTs) was increased to >1.5 times since many subjects in the targeted population were taking medications that can cause modest elevations in LFTs. RA is also an inflammatory process, whereby subjects may also have modestly elevated LFTs. •The definition of an inadequate response to MTX was revised to align with clinical practice. •Adjustments to MTX doses and oral corticosteroid doses were permitted during the study. •Revisions to the exclusion criterion that listed bacteria/fungal infections, due to false negative rate associated with various serological tests as well as the lack of specificity provided by chest x-rays with respect to granulomatous changes. •Clarification of the definitions of a positive and negative purified protein derivative test, to minimize the risk of missing a subject with possible LTB infection. •Addition of -cotinine level measurement, as a validated marker of exposure to smoking, since smoking exposure is linked to an increase risk of developing RA, and exposure to smoking also impedes the effectiveness of biologic DMARDs. -extra sampling time points for IMP antibody determination and in particular for the genomic analysis were included to allow for early detection of IMP antibodies and genomic biomarkers. •Since prior anti-TNF use was an exclusion criterion, this class of medication was removed as a covariate in the primary efficacy analysis. •Changes were implemented to minimize/eliminate the confounding effect of substance abuse, since recreational drugs frequently can induce expectations or effects that may enhance or mask a disease entity under study such as pain.
    19 Oct 2012
    The main purpose of this protocol amendment was to update all procedures related to tuberculosis (TB) detection and monitoring in line with the revised UCB policy. The amended changes also included updates of a number of eligibility criteria, specifically: •Clarification of the required clinical parameters to define moderate to severe RA disease at Screening and Baseline and the duration of the Washout Periods for analgesics and nonbiologic DMARDs. •The upper limit of eligibility for the LFTs was increased to >2.0 times since RA is an inflammatory process that may lead to modestly elevated LFTs and many subjects in the targeted population were taking medications, which can also cause modest elevations in LFTs. Study procedure revisions included: •Any safety laboratory parameter could be repeated when the result was considered erroneous in the judgment of the Investigator or if it was known that the sample could have been mishandled. •The number of sampling times for the genomic analysis was reduced. •The definition of an inadequate response to MTX was revised to emphasize that the decision was based on the Investigator’s clinical judgment.
    24 Jul 2013
    The main purpose was to provide further clarification to support interpretation. The clarifications included: •Dose adjustments of oral corticosteroids during the 28 days prior to Baseline were to be avoided unless clinically necessary. The respective language was updated for clarity. Guidelines for discontinuation/tapering of oral corticosteroids permitted during the study were amended with more details •Guidance to ensure an appropriate washout of prior medication was updated for clarity and also specified information regarding the washout of leflunomide •RA-related exclusion criteria were updated with more specific information regarding subjects with systemic lupus erythematosus, lupus nephritis, and Sjogren’s Syndrome •Duration of exclusionary periods for subjects with a history of chronic/recurrent infections was decreased to 6 months preceding the study for subjects with more than 3 episodes requiring antibiotics/antivirals and increased to 12 months prior to Baseline for subjects with recent serious/life-hreatening infection •Exclusion criterion related to a history/active systemic/respiratory infection was updated with more details regarding radiographic findings •Guidance for the exclusion of subjects with hepatitis B or C infection including assessments of hepatitis-related biomarkers and for subjects with any positive findings in the urine drug screen •Noncompliance with the protocol-defined visit schedule was a reason for withdrawal. This withdrawal criterion was updated to provide additional guidance •Amendment of inclusion criterions to further emphasize that abstinence was not considered an acceptable method •Addition of albumin and creatinine to the list of clinical chemistry parameters •Update of the -list of the most common adverse reactions in clinical studies of ADA to match the latest version of the ADA SmPC -section describing the handling of protocol deviations to reflect process related changes resulting from the Submission Excellence Program
    26 Mar 2014
    The main purposes were: •To clarify the timing of the primary endpoint analyses •To note how unblinding of individual treatment allocation codes were to be handled at the Week 104/WD visit The analysis of data for the Week 12 and Week 104 primary endpoints was changed to be done only at the completion of the study. The reason for this change was that knowledge of the Week 12 efficacy results could bias the way that the Investigators and/or subjects performed assessments or completed the study, which could compromise the interpretation of the final results and/or conclusions. Once all the efficacy assessments were performed for an individual subject at Week 104/WD, the blinded team had the opportunity to unblind the treatment allocation code for that subject. The reason was to aid the Investigator’s decision regarding RA treatment after the study. To confirm that this by subject-unblinding did not impact the study results, a sensitivity analysis was added in which all subjects who had their TJC/SJC values at Week 104/WD changed post-visit were excluded. Other changes were: •Modification of text relating to storage and handling of study drugs. •Blood sampling for cotinine at withdrawal did not need to be done if the withdrawal was due to the subject being ineligible to continue in the study at Week 24. •Clarification that all chest radiographs had to be both read and reported by a qualified radiologist. •Addition of text regarding the method of documentation of RA treatment after Week 104/WD. •The ISRQ/SIAQ was performed throughout the study as planned. However, statistical analysis of these questionnaires might not be performed for data at later time points in the study, because the available commercial ADA had undergone an alteration of the needle gauge during this study, which could affect the responses of the subjects to these questionnaires. •Addition of analysis sets needed for selected analyses based on subjects that reached Week 12 and continued in the study.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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