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    Clinical Trial Results:
    Open-Label, Phase IIIb Study to Evaluate the Efficacy and Safety of Subcutaneous (SC) Tocilizumab Monotherapy or Combination Therapy with Methotrexate (MTX) or Other Non-Biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) in Patients With Active Rheumatoid Arthritis (RA) Who Have an Inadequate Response to Current Non-Biologic DMARD Therapy or the First Anti-Tumour Necrosis Factor (Anti-TNF) Biologic Agent

    Summary
    EudraCT number
    2013-000054-22
    Trial protocol
    GB  
    Global end of trial date
    04 Aug 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    10 Jun 2018
    First version publication date
    21 Jul 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    ML28641
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02046603
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Hoffmann-La Roche: ACT-MOVE
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.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
    04 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the efficacy of switching to subcutaneous (SC) tocilizumab (as monotherapy or in combination with methotrexate or other non-biologic disease modifying antirheumatic drugs [DMARDs]) in participants who had an inadequate response to current non-biologic methotrexate therapy or the first anti-tumor necrosis factor (anti-TNF) biologic agent (as monotherapy or in combination with methotrexate or other non-biologic DMARDs).
    Protection of trial subjects
    The study was conducted in accordance with the principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice according to the regulations and procedures described in the study protocol.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Mar 2014
    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
    United Kingdom: 161
    Worldwide total number of subjects
    161
    EEA total number of subjects
    161
    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)
    126
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 162 participants were enrolled. One participant who did not receive a dose of tocilizumab was excluded from the full analysis set (FAS) and the results are reported for 161 participants.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tocilizumab Monotherapy
    Arm description
    Participants received a weekly SC injection of tocilizumab 162 milligrams (mg) as monotherapy for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab 162 mg was administered once a week by SC injection and as a single fixed dose, irrespective of body weight, for the treatment duration of 52 weeks.

    Arm title
    Tocilizumab in Combination With Methotrexate or Other DMARDs
    Arm description
    Participants received a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab 162 mg was administered once a week by SC injection and as a single fixed dose, irrespective of body weight, for the treatment duration of 52 weeks.

    Number of subjects in period 1
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Started
    21
    140
    Completed
    7
    65
    Not completed
    14
    75
         Death
    -
    1
         Protocol deviation
    -
    1
         Physician decision
    1
    1
         Unspecified
    11
    66
         Adverse Event
    -
    1
         Lost to follow-up
    1
    2
         Participant/legal guardian decision
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tocilizumab Monotherapy
    Reporting group description
    Participants received a weekly SC injection of tocilizumab 162 milligrams (mg) as monotherapy for 52 weeks.

    Reporting group title
    Tocilizumab in Combination With Methotrexate or Other DMARDs
    Reporting group description
    Participants received a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.

    Reporting group values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs Total
    Number of subjects
    21 140 161
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    53.9 ± 13.63 55.3 ± 10.76 -
    Gender Categorical
    Units: Subjects
        Female
    16 104 120
        Male
    5 36 41

    End points

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    End points reporting groups
    Reporting group title
    Tocilizumab Monotherapy
    Reporting group description
    Participants received a weekly SC injection of tocilizumab 162 milligrams (mg) as monotherapy for 52 weeks.

    Reporting group title
    Tocilizumab in Combination With Methotrexate or Other DMARDs
    Reporting group description
    Participants received a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.

    Primary: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 2

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    End point title
    Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 2 [1]
    End point description
    DAS28 was calculated from swollen joint count (SJC) and tender joint count (TJC) using 28 joints count, erythrocyte sedimentation rate (ESR; millimeters per hour [mm/hour]), and patient’s global assessment of disease activity (measured on 0 to 100 mm Visual Analog Scale [VAS] where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56×square root of TJC] + [0.28×square root of SJC] + [0.70×natural log (ESR)] + [0.014×VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR greater than or equal to (≥) 2.6 to less than or equal to (≤) 3.2 implied low disease activity, greater than (>) 3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and less than (<)2.6 implied clinical remission. FAS population included all participants who received at least 1 dose of SC tocilizumab. “Number of subjects analysed”=participants evaluable for this outcome. “n”=participants evaluable at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    139
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=21, 139)
    5.52 ± 1.014
    5.53 ± 1.257
        Change at Week 2 (n=21, 137)
    -1.41 ± 0.994
    -1.22 ± 1.131
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 4

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    End point title
    Change From Baseline in DAS28-ESR at Week 4 [2]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    Notes
    [2] - 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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    137
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.86 ± 1.016
    -2.11 ± 1.215
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 8

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    End point title
    Change From Baseline in DAS28-ESR at Week 8 [3]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    18
    131
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.42 ± 1.352
    -2.62 ± 1.482
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 12

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    End point title
    Change From Baseline in DAS28-ESR at Week 12 [4]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    Notes
    [4] - 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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    19
    128
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.33 ± 1.522
    -2.99 ± 1.510
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 16

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    End point title
    Change From Baseline in DAS28-ESR at Week 16 [5]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    18
    125
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.93 ± 1.218
    -3.07 ± 1.532
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 20

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    End point title
    Change From Baseline in DAS28-ESR at Week 20 [6]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 20
    Notes
    [6] - 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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    19
    121
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.17 ± 1.346
    -3.13 ± 1.525
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 24

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    End point title
    Change From Baseline in DAS28-ESR at Week 24 [7]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    19
    117
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.28 ± 1.379
    -3.33 ± 1.470
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 28

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    End point title
    Change From Baseline in DAS28-ESR at Week 28 [8]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 28
    Notes
    [8] - 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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    19
    115
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.54 ± 1.260
    -3.32 ± 1.552
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 32

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    End point title
    Change From Baseline in DAS28-ESR at Week 32 [9]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 32
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    19
    115
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.19 ± 1.418
    -3.54 ± 1.448
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 36

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    End point title
    Change From Baseline in DAS28-ESR at Week 36 [10]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 36
    Notes
    [10] - 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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    18
    114
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.57 ± 1.358
    -3.55 ± 1.589
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 40

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    End point title
    Change From Baseline in DAS28-ESR at Week 40 [11]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 40
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    17
    111
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.82 ± 1.143
    -3.64 ± 1.524
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 44

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    End point title
    Change From Baseline in DAS28-ESR at Week 44 [12]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 44
    Notes
    [12] - 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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    17
    107
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.61 ± 1.325
    -3.65 ± 1.574
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 48

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    End point title
    Change From Baseline in DAS28-ESR at Week 48 [13]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 48
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    16
    107
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.54 ± 1.146
    -3.65 ± 1.552
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Week 52

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    End point title
    Change From Baseline in DAS28-ESR at Week 52 [14]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    Notes
    [14] - 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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    15
    107
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.75 ± 1.361
    -3.67 ± 1.592
    No statistical analyses for this end point

    Primary: Change From Baseline in DAS28-ESR at Early Withdrawal

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    End point title
    Change From Baseline in DAS28-ESR at Early Withdrawal [15]
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    Baseline, early withdrawal (up to Week 52)
    Notes
    [15] - 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: No statistical analysis was planned for this end point.
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    5
    28
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.88 ± 1.236
    -1.63 ± 1.480
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response

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    End point title
    Number of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response
    End point description
    A participant had an ACR20 response if there was at least a 20 percent (%) improvement, ie, reduction from Baseline, in TJC (68 joints) and SJC (66 joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, averaged to 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either C-reactive protein [CRP] or ESR). FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: participants
    number (not applicable)
        Week 2 (n=21, 137)
    6
    23
        Week 4 (n=21, 137)
    6
    68
        Week 8 (n=18, 132)
    11
    69
        Week 12 (n=19, 128)
    10
    83
        Week 16 (n=19, 125)
    13
    83
        Week 20 (n=19, 122)
    15
    86
        Week 24 (n=19, 117)
    15
    90
        Week 28 (n=19, 115)
    14
    87
        Week 32 (n=19, 115)
    13
    89
        Week 36 (n=18, 114)
    12
    92
        Week 40 (n=17, 111)
    13
    91
        Week 44 (n=17, 108)
    12
    88
        Week 48 (n=16, 107)
    12
    87
        Week 52 (n=16, 107)
    12
    88
        Early withdrawal (n=5, 29)
    3
    10
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving an ACR50 Response

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    End point title
    Number of Participants Achieving an ACR50 Response
    End point description
    A participant had an ACR50 response if there was at least a 50% improvement, ie, reduction from Baseline, in TJC (68 joints) and SJC (66 joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, averaged to 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: participants
    number (not applicable)
        Week 2 (n=21, 137)
    0
    5
        Week 4 (n=21, 137)
    3
    20
        Week 8 (n=18, 132)
    6
    43
        Week 12 (n=19, 128)
    8
    54
        Week 16 (n=19, 125)
    7
    62
        Week 20 (n=19, 122)
    9
    61
        Week 24 (n=19, 117)
    9
    64
        Week 28 (n=19, 115)
    13
    68
        Week 32 (n=19, 115)
    8
    69
        Week 36 (n=18, 114)
    9
    74
        Week 40 (n=17, 111)
    9
    71
        Week 44 (n=17, 108)
    10
    72
        Week 48 (n=16, 107)
    11
    73
        Week 52 (n=16, 107)
    8
    73
        Early withdrawal (n=5, 29)
    2
    4
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving an ACR70 Response

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    End point title
    Number of Participants Achieving an ACR70 Response
    End point description
    A participant had an ACR70 response if there was at least a 70% improvement, ie, reduction from Baseline, in TJC (68 joints) and SJC (66 joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, averaged to 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: participants
    number (not applicable)
        Week 2 (n=21, 137)
    0
    0
        Week 4 (n=21, 137)
    1
    9
        Week 8 (n=18, 132)
    4
    19
        Week 12 (n=19, 128)
    3
    30
        Week 16 (n=19, 125)
    3
    32
        Week 20 (n=19, 122)
    7
    37
        Week 24 (n=19, 117)
    5
    38
        Week 28 (n=19, 115)
    6
    44
        Week 32 (n=19, 115)
    6
    47
        Week 36 (n=18, 114)
    7
    48
        Week 40 (n=17, 111)
    8
    49
        Week 44 (n=17, 108)
    6
    53
        Week 48 (n=16, 107)
    8
    56
        Week 52 (n=16, 107)
    7
    54
        Early withdrawal (n=5, 29)
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR

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    End point title
    Number of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR
    End point description
    DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (VAS: 0 mm=no disease activity to 100 mm=maximum disease activity). DAS28-ESR scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28-ESR based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on extent of change from baseline and level of disease activity reached. Good responders had a change from baseline >1.2 with a DAS28 score ≤3.2; moderate responders had a change from baseline >1.2 with a DAS28 score >3.2 or a change from baseline >0.6 to ≤1.2 with a DAS28 score ≤5.1. Participants with change from baseline >0.6 to ≤1.2 with a DAS28 score >5.1, or any score with change from baseline ≤0.6, were assessed as non-responders. FAS population. “n”=participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: participants
    number (not applicable)
        Week 2 (n=21, 137): No response
    4
    56
        Week 2 (n=21, 137): Moderate response
    10
    56
        Week 2 (n=21, 137): Good response
    7
    25
        Week 4 (n=21, 137): No response
    3
    22
        Week 4 (n=21, 137): Moderate response
    7
    58
        Week 4 (n=21, 137): Good response
    11
    57
        Week 8 (n=18, 131): No response
    1
    11
        Week 8 (n=18, 131): Moderate response
    9
    48
        Week 8 (n=18, 131): Good response
    8
    72
        Week 12 (n=19, 128): No response
    4
    11
        Week 12 (n=19, 128): Moderate response
    3
    34
        Week 12 (n=19, 128): Good response
    12
    83
        Week 16 (n=18, 125): No response
    1
    9
        Week 16 (n=18, 125): Moderate response
    4
    30
        Week 16 (n=18, 125): Good response
    13
    86
        Week 20 (n=19, 121): No response
    0
    9
        Week 20 (n=19, 121): Moderate response
    5
    27
        Week 20 (n=19, 121): Good response
    14
    85
        Week 24 (n=19, 117): No response
    1
    7
        Week 24 (n=19, 117): Moderate response
    2
    21
        Week 24 (n=19, 117): Good response
    16
    89
        Week 28 (n=19, 115): No response
    1
    5
        Week 28 (n=19, 115): Moderate response
    0
    24
        Week 28 (n=19, 115): Good response
    18
    86
        Week 32 (n=19, 115): No response
    1
    3
        Week 32 (n=19, 115): Moderate response
    2
    21
        Week 32 (n=19, 115): Good response
    16
    91
        Week 36 (n=18, 114): No response
    0
    4
        Week 36 (n=18, 114): Moderate response
    3
    19
        Week 36 (n=18, 114): Good response
    15
    91
        Week 40 (n=17, 111): No response
    0
    2
        Week 40 (n=17, 111): Moderate response
    1
    15
        Week 40 (n=17, 111): Good response
    16
    94
        Week 44 (n=17, 107): No response
    0
    5
        Week 44 (n=17, 107): Moderate response
    2
    15
        Week 44 (n=17, 107): Good response
    15
    87
        Week 48 (n=16, 107): No response
    0
    4
        Week 48 (n=16, 107): Moderate response
    2
    13
        Week 48 (n=16, 107): Good response
    14
    90
        Week 52 (n=15, 107): No response
    0
    5
        Week 52 (n=15, 107): Moderate response
    3
    12
        Week 52 (n=15, 107): Good response
    12
    90
        Early Withdrawal (n=5, 28): No response
    0
    11
        Early Withdrawal (n=5, 28): Moderate response
    1
    8
        Early Withdrawal (n=5, 28): Good response
    4
    9
    No statistical analyses for this end point

    Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

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    End point title
    Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal
    End point description
    The SDAI is the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, patient and physician global assessment of disease activity assessed on 0-10 centimeter (cm) VAS (0 cm= no disease activity and 10 cm= worst disease activity), and CRP in milligrams per liter (mg/L). SDAI total score = 0-86. SDAI ≤3.3 indicates clinical remission, >3.3 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high (or severe) disease activity. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    136
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=21, 136)
    31.23 ± 11.892
    32.33 ± 11.620
        Change at Week 2 (n=21, 132)
    -9.80 ± 10.406
    -6.94 ± 9.710
        Change at Week 4 (n=19, 131)
    -12.64 ± 10.502
    -13.92 ± 10.666
        Change at Week 8 (n=17, 127)
    -19.75 ± 12.978
    -17.21 ± 12.900
        Change at Week 12 (n=16, 120)
    -14.65 ± 15.003
    -20.26 ± 12.739
        Change at Week 16 (n=16, 118)
    -19.48 ± 9.649
    -21.16 ± 11.945
        Change at Week 20 (n=18, 115)
    -23.67 ± 14.015
    -20.50 ± 11.630
        Change at Week 24 (n=19, 112)
    -24.31 ± 13.469
    -23.48 ± 12.417
        Change at Week 28 (n=19, 109)
    -24.87 ± 12.554
    -23.26 ± 12.418
        Change at Week 32 (n=19, 109)
    -22.98 ± 12.850
    -24.94 ± 11.399
        Change at Week 36 (n=18, 107)
    -26.32 ± 12.795
    -24.65 ± 11.268
        Change at Week 40 (n=17, 106)
    -27.29 ± 13.280
    -25.46 ± 12.210
        Change at Week 44 (n=16, 101)
    -27.71 ± 12.851
    -26.08 ± 11.835
        Change at Week 48 (n=16, 102)
    -26.83 ± 13.615
    -26.13 ± 11.189
        Change at Week 52 (n=15, 104)
    -27.45 ± 14.351
    -26.15 ± 12.791
        Change at early withdrawal (n=5, 28)
    -18.94 ± 14.681
    -9.45 ± 12.533
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

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    End point title
    Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal
    End point description
    The CDAI is the numerical sum of four outcome parameters: TJC and SJC based on a 28-joint assessment, patient and physician’s global assessment of disease activity assessed on 0-10 cm VAS (0 cm= no disease activity and 10 cm= worst disease activity). CDAI total score = 0-76. CDAI ≤2.8 indicates clinical remission, >2.8 to 10 = low disease activity, >10 to 22 = moderate disease activity, and >22 = high (or severe) disease activity. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    139
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=21, 139)
    29.69 ± 11.209
    30.88 ± 10.953
        Change at Week 2 (n=21, 137)
    -8.35 ± 10.433
    -5.16 ± 9.323
        Change at Week 4 (n=21, 137)
    -11.87 ± 10.062
    -12.26 ± 10.137
        Change at Week 8 (n=18, 130)
    -17.74 ± 12.289
    -15.63 ± 11.873
        Change at Week 12 (n=19, 128)
    -15.39 ± 14.216
    -18.66 ± 11.895
        Change at Week 16 (n=19, 125)
    -20.70 ± 11.694
    -19.51 ± 11.124
        Change at Week 20 (n=18, 121)
    -22.19 ± 13.545
    -19.23 ± 11.433
        Change at Week 24 (n=19, 117)
    -22.88 ± 12.720
    -21.96 ± 11.825
        Change at Week 28 (n=19, 115)
    -23.43 ± 11.573
    -21.48 ± 11.585
        Change at Week 32 (n=19, 115)
    -21.55 ± 12.019
    -23.20 ± 10.842
        Change at Week 36 (n=18, 114)
    -24.86 ± 11.854
    -23.10 ± 11.263
        Change at Week 40 (n=17, 111)
    -25.74 ± 12.488
    -24.01 ± 11.282
        Change at Week 44 (n=17, 106)
    -25.42 ± 11.971
    -24.42 ± 11.186
        Change at Week 48 (n=16, 106)
    -25.36 ± 12.718
    -24.59 ± 10.645
        Change at Week 52 (n=16, 107)
    -25.48 ± 13.049
    -24.42 ± 12.599
        Change at early withdrawal (n=5, 29)
    -17.78 ± 14.667
    -8.68 ± 11.909
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total TJC on 68 Joints at Week 52

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    End point title
    Percent Change From Baseline in Total TJC on 68 Joints at Week 52
    End point description
    Number of tender joints was determined by examining 68 joints and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 68. A reduction in number of tender joints compared to baseline indicates improvement. The outcome is reported as the percent change from baseline to end of treatment (52 weeks). FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    15
    106
    Units: percent change
        arithmetic mean (standard deviation)
    -83.12 ± 26.607
    -80.44 ± 41.226
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total TJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

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    End point title
    Change From Baseline in Total TJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal
    End point description
    Number of tender joints was determined by examining 28 joints and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28. A reduction in number of tender joints compared to baseline indicates improvement. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    139
    Units: tender joints
    arithmetic mean (standard deviation)
        Baseline (n=21, 139)
    10.4 ± 6.46
    12.9 ± 7.06
        Change at Week 2 (n=21, 137)
    -3.4 ± 5.62
    -2.4 ± 5.63
        Change at Week 4 (n=21, 137)
    -3.9 ± 5.80
    -5.4 ± 6.14
        Change at Week 8 (n=18, 132)
    -6.6 ± 6.41
    -6.4 ± 6.94
        Change at Week 12 (n=19, 128)
    -6.0 ± 6.71
    -8.0 ± 7.35
        Change at Week 16 (n=19, 125)
    -7.9 ± 6.35
    -8.2 ± 7.05
        Change at Week 20 (n=19, 122)
    -8.5 ± 6.59
    -8.3 ± 7.09
        Change at Week 24 (n=19, 117)
    -8.3 ± 7.41
    -9.3 ± 7.53
        Change at Week 28 (n=19, 115)
    -8.7 ± 6.26
    -9.2 ± 7.04
        Change at Week 32 (n=19, 115)
    -7.6 ± 6.64
    -10.1 ± 6.76
        Change at Week 36 (n=18, 114)
    -9.4 ± 6.25
    -9.7 ± 7.23
        Change at Week 40 (n=17, 111)
    -10.1 ± 6.64
    -10.3 ± 6.74
        Change at Week 44 (n=17, 108)
    -9.7 ± 6.46
    -10.4 ± 6.63
        Change at Week 48 (n=16, 107)
    -9.6 ± 6.36
    -10.5 ± 6.70
        Change at Week 52 (n=16, 107)
    -9.4 ± 7.15
    -10.4 ± 8.01
        Change at early withdrawal (n=5, 29)
    -7.0 ± 6.24
    -3.3 ± 7.46
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total SJC on 66 Joints at Week 52

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    End point title
    Percent Change From Baseline in Total SJC on 66 Joints at Week 52
    End point description
    Number of swollen joints was determined by examination of 66 joints and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 66. A reduction in number of swollen joints compared to baseline indicates improvement. The outcome is reported as the percent change from baseline to end of treatment (52 weeks). FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    16
    102
    Units: percent change
        arithmetic mean (standard deviation)
    -89.31 ± 20.059
    -74.77 ± 66.277
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total SJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

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    End point title
    Change From Baseline in Total SJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal
    End point description
    Number of swollen joints was determined by examination of 28 joints and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. A reduction in number of swollen joints compared to baseline indicates improvement. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    139
    Units: swollen joints
    arithmetic mean (standard deviation)
        Baseline (n=21, 139)
    7.0 ± 4.64
    5.6 ± 4.43
        Change at Week 2 (n=21, 137)
    -2.5 ± 4.31
    -0.8 ± 3.95
        Change at Week 4 (n=21, 137)
    -4.2 ± 3.79
    -2.5 ± 3.81
        Change at Week 8 (n=18, 132)
    -4.8 ± 4.21
    -3.2 ± 4.40
        Change at Week 12 (n=19, 128)
    -4.2 ± 4.37
    -3.8 ± 4.36
        Change at Week 16 (n=19, 125)
    -5.3 ± 4.67
    -3.9 ± 4.41
        Change at Week 20 (n=19, 122)
    -5.6 ± 5.08
    -4.2 ± 4.60
        Change at Week 24 (n=19, 117)
    -5.9 ± 5.12
    -4.7 ± 4.21
        Change at Week 28 (n=19, 115)
    -6.4 ± 4.90
    -4.4 ± 4.63
        Change at Week 32 (n=19, 115)
    -5.4 ± 5.10
    -4.8 ± 4.37
        Change at Week 36 (n=18, 114)
    -6.5 ± 4.57
    -4.9 ± 4.41
        Change at Week 40 (n=17, 111)
    -6.6 ± 5.12
    -5.0 ± 4.82
        Change at Week 44 (n=17, 108)
    -6.6 ± 5.28
    -5.2 ± 4.71
        Change at Week 48 (n=16, 107)
    -6.4 ± 4.83
    -5.0 ± 4.48
        Change at Week 52 (n=16, 107)
    -6.3 ± 4.81
    -5.1 ± 4.51
        Change at early withdrawal (n=5, 29)
    -5.8 ± 5.59
    -1.7 ± 4.43
    No statistical analyses for this end point

    Secondary: Number of Participants Who Achieved Low Disease Activity as Defined by DAS28-ESR ≤3.2

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    End point title
    Number of Participants Who Achieved Low Disease Activity as Defined by DAS28-ESR ≤3.2
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity. FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: participants
    number (not applicable)
        Baseline (n=21, 139)
    0
    5
        Week 2 (n=21, 137)
    7
    18
        Week 4 (n=21, 137)
    9
    30
        Week 8 (n=18, 131)
    3
    25
        Week 12 (n=19, 128)
    6
    23
        Week 16 (n=18, 125)
    3
    20
        Week 20 (n=19, 121)
    3
    15
        Week 24 (n=19, 117)
    2
    15
        Week 28 (n=19, 115)
    4
    15
        Week 32 (n=19, 115)
    5
    14
        Week 36 (n=18, 114)
    1
    14
        Week 40 (n=17, 111)
    3
    14
        Week 44 (n=17, 107)
    5
    10
        Week 48 (n=16, 107)
    3
    12
        Week 52 (n=15, 107)
    0
    11
        Early withdrawal (n=5, 29)
    2
    4
    No statistical analyses for this end point

    Secondary: Number of Participants Who Achieved Remission as Defined by DAS28-ESR <2.6

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    End point title
    Number of Participants Who Achieved Remission as Defined by DAS28-ESR <2.6
    End point description
    DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR <2.6 implied clinical remission. FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: participants
    number (not applicable)
        Baseline (n=21, 139)
    0
    3
        Week 2 (n=21, 137)
    1
    15
        Week 4 (n=21, 137)
    2
    34
        Week 8 (n=18, 131)
    5
    53
        Week 12 (n=19, 128)
    6
    66
        Week 16 (n=18, 125)
    10
    72
        Week 20 (n=19, 121)
    11
    75
        Week 24 (n=19, 117)
    14
    76
        Week 28 (n=19, 115)
    14
    73
        Week 32 (n=19, 115)
    12
    80
        Week 36 (n=18, 114)
    14
    80
        Week 40 (n=17, 111)
    13
    81
        Week 44 (n=17, 107)
    10
    80
        Week 48 (n=16, 107)
    11
    78
        Week 52 (n=15, 107)
    12
    80
        Early withdrawal (n=5, 29)
    3
    7
    No statistical analyses for this end point

    Secondary: Number of Participants With Non-Biologic DMARD/Corticosteroid Dose Reductions and/or Discontinuation

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    End point title
    Number of Participants With Non-Biologic DMARD/Corticosteroid Dose Reductions and/or Discontinuation
    End point description
    Results are reported for number of participants who had non-biologic DMARD/corticosteroid dose reductions and/or discontinuation by reasons for dose reductions or discontinuation (safety reasons, discomfort, lack of efficacy, other reasons, and unknown reasons). Participants may be included under more than one reason. FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, at early withdrawal (up to Week 52), follow-up Week 4 (up to Week 56), and follow-up Week 8 (up to Week 60)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: participants
    number (not applicable)
        Baseline: Safety (n=21, 140)
    0
    1
        Baseline: Discomfort (n=21, 140)
    0
    0
        Baseline: Lack of efficacy (n=21, 140)
    0
    1
        Baseline: Other (n=21, 140)
    0
    2
        Baseline: Unknown (n=21, 140)
    0
    0
        Week 2: Safety (n=21, 137)
    0
    4
        Week 2: Discomfort (n=21, 137)
    0
    0
        Week 2: Lack of efficacy (n=21, 137)
    0
    0
        Week 2: Other (n=21, 137)
    0
    7
        Week 2: Unknown (n=21, 137)
    0
    0
        Week 4: Safety (n=21, 137)
    0
    6
        Week 4: Discomfort (n=21, 137)
    0
    0
        Week 4: Lack of efficacy (n=21, 137)
    0
    1
        Week 4: Other (n=21, 137)
    1
    9
        Week 4: Unknown (n=21, 137)
    0
    1
        Week 8: Safety (n=18, 132)
    0
    8
        Week 8: Discomfort (n=18, 132)
    0
    0
        Week 8: Lack of efficacy (n=18, 132)
    0
    0
        Week 8: Other (n=18, 132)
    1
    13
        Week 8: Unknown (n=18, 132)
    0
    1
        Week 12: Safety (n=19, 128)
    0
    6
        Week 12: Discomfort (n=19, 128)
    0
    2
        Week 12: Lack of efficacy (n=19, 128)
    0
    0
        Week 12: Other (n=19, 128)
    2
    14
        Week 12: Unknown (n=19, 128)
    0
    0
        Week 16: Safety (n=19, 126)
    0
    7
        Week 16: Discomfort (n=19, 126)
    0
    0
        Week 16: Lack of efficacy (n=19, 126)
    0
    1
        Week 16: Other (n=19, 126)
    2
    13
        Week 16: Unknown (n=19, 126)
    0
    0
        Week 20: Safety (n=19, 122)
    0
    6
        Week 20: Discomfort (n=19, 122)
    0
    0
        Week 20: Lack of efficacy (n=19, 122)
    0
    0
        Week 20: Other (n=19, 122)
    2
    9
        Week 20: Unknown (n=19, 122)
    0
    1
        Week 24: Safety (n=19, 117)
    0
    5
        Week 24:Discomfort (n=19, 117)
    0
    0
        Week 24: Lack of efficacy (n=19, 117)
    0
    0
        Week 24: Other (n=19, 117)
    1
    13
        Week 24: Unknown (n=19, 117)
    0
    1
        Week 28: Safety (n=19, 116)
    0
    3
        Week 28: Discomfort (n=19, 116)
    0
    0
        Week 28: Lack of efficacy (n=19, 116)
    0
    1
        Week 28: Other (n=19, 116)
    1
    7
        Week 28: Unknown (n=19, 116)
    0
    0
        Week 32: Safety (n=19, 115)
    0
    4
        Week 32: Discomfort (n=19, 115)
    0
    0
        Week 32: Lack of efficacy (n=19, 115)
    0
    2
        Week 32: Other (n=19, 115)
    1
    11
        Week 32: Unknown (n=19, 115)
    0
    0
        Week 36: Safety (n=18, 114)
    0
    3
        Week 36: Discomfort (n=18, 114)
    0
    1
        Week 36: Lack of efficacy (n=18, 114)
    0
    0
        Week 36: Other (n=18, 114)
    2
    3
        Week 36: Unknown (n=18, 114)
    0
    0
        Week 40: Safety (n=17, 111)
    0
    4
        Week 40: Discomfort (n=17, 111)
    0
    1
        Week 40: Lack of efficacy (n=17, 111)
    0
    1
        Week 40: Other (n=17, 111)
    1
    1
        Week 40: Unknown (n=17, 111)
    0
    0
        Week 44: Safety (n=17, 108)
    0
    3
        Week 44: Discomfort (n=17, 108)
    0
    0
        Week 44: Lack of efficacy (n=17, 108)
    0
    0
        Week 44: Other (n=17, 108)
    0
    7
        Week 44: Unknown (n=17, 108)
    0
    0
        Week 48: Safety (n=16, 107)
    0
    3
        Week 48: Discomfort (n=16, 107)
    0
    0
        Week 48: Lack of efficacy (n=16, 107)
    0
    1
        Week 48: Other (n=16, 107)
    1
    3
        Week 48: Unknown (n=16, 107)
    0
    0
        Week 52: Safety (n=16, 107)
    0
    0
        Week 52: Discomfort (n=16, 107)
    0
    0
        Week 52: Lack of efficacy (n=16, 107)
    0
    0
        Week 52: Other (n=16, 107)
    0
    1
        Week 52: Unknown (n=16, 107)
    0
    0
        Early withdrawal: Safety (n=5, 30)
    0
    0
        Early withdrawal: Discomfort (n=5, 30)
    0
    0
        Early withdrawal: Lack of efficacy (n=5, 30)
    0
    0
        Early withdrawal: Other (n=5, 30)
    1
    8
        Early withdrawal: Unknown (n=5, 30)
    0
    0
        Follow-up Week 4: Safety (n=8, 70)
    0
    0
        Follow-up Week 4: Discomfort (n=8, 70)
    0
    0
        Follow-up Week 4: Lack of efficacy (n=8, 70)
    0
    0
        Follow-up Week 4: Other (n=8, 70)
    0
    2
        Follow-up Week 4: Unknown (n=8, 70)
    0
    1
        Follow-up Week 8: Safety (n=9, 65)
    0
    0
        Follow-up Week 8: Discomfort (n=9, 65)
    0
    0
        Follow-up Week 8: Lack of efficacy (n=9, 65)
    0
    0
        Follow-up Week 8: Other (n=9, 65)
    0
    0
        Follow-up Week 8: Unknown (n=9, 65)
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Methotrexate Adherence as Assessed by Methotrexate Adherence Questionnaire

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    End point title
    Percentage of Methotrexate Adherence as Assessed by Methotrexate Adherence Questionnaire [16]
    End point description
    Methotrexate adherence was determined from responses to the question ‘Over the last 3 months you were prescribed 12 doses of methotrexate, how many (approximately) have you taken?’ Adherence (%) was calculated as: (Approximate number of doses taken/12)*100. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 52, and at early withdrawal (up to Week 52)
    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: No statisticaResults are provided for single arm as participants in “Tocilizumab Monotherapy” arm did not receive methotrexate.l analysis was planned for this end point.
    End point values
    Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    97
    Units: percentage of methotrexate adherence
    arithmetic mean (standard deviation)
        Baseline (n=97)
    96.82 ± 7.747
        Week 12 (n=80)
    92.92 ± 14.412
        Week 24 (n=65)
    91.54 ± 20.915
        Week 36 (n=60)
    90.14 ± 21.456
        Week 52 (n=60)
    95.28 ± 11.417
        Early withdrawal (n=17)
    90.69 ± 18.367
    No statistical analyses for this end point

    Secondary: Patient Global Assessment of Disease Activity VAS Score

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    End point title
    Patient Global Assessment of Disease Activity VAS Score
    End point description
    Patient global assessment of disease activity was measured on a 0 to 100 mm horizontal VAS where 0 mm=no disease activity and 100 mm=maximum disease activity. FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: mm
    arithmetic mean (standard deviation)
        Baseline (n=21, 139)
    59.6 ± 26.94
    62.3 ± 20.72
        Week 2 (n=21, 137)
    50.3 ± 24.01
    54.5 ± 22.12
        Week 4 (n=21, 137)
    46.4 ± 26.43
    42.3 ± 23.22
        Week 8 (n=18, 131)
    35.8 ± 24.73
    36.2 ± 24.43
        Week 12 (n=19, 128)
    41.3 ± 27.67
    32.1 ± 23.91
        Week 16 (n=19, 126)
    29.6 ± 21.59
    29.2 ± 22.55
        Week 20 (n=19, 122)
    25.7 ± 23.77
    29.9 ± 22.99
        Week 24 (n=19, 117)
    23.8 ± 19.55
    26.6 ± 21.92
        Week 28 (n=19, 116)
    23.2 ± 16.47
    26.7 ± 23.12
        Week 32 (n=19, 115)
    24.0 ± 17.81
    24.3 ± 21.66
        Week 36 (n=18, 114)
    24.1 ± 19.13
    22.3 ± 21.86
        Week 40 (n=17, 111)
    22.5 ± 19.31
    21.4 ± 20.81
        Week 44 (n=17, 107)
    22.7 ± 20.62
    22.0 ± 22.83
        Week 48 (n=16, 107)
    22.9 ± 23.31
    18.9 ± 20.57
        Week 52 (n=16, 107)
    20.6 ± 18.96
    21.4 ± 23.07
        Early withdrawal (n=5, 30)
    30.8 ± 28.78
    52.4 ± 24.88
    No statistical analyses for this end point

    Secondary: Patient Pain VAS Score

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    End point title
    Patient Pain VAS Score
    End point description
    This assessment represents the participant’s assessment of his/her current level of pain on a 100 mm horizontal VAS where 0 mm= no pain to 100 mm= unbearable pain. FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: mm
    arithmetic mean (standard deviation)
        Baseline (n=21, 139)
    50.5 ± 23.78
    57.5 ± 21.06
        Week 2 (n=21, 137)
    46.1 ± 22.43
    51.1 ± 22.58
        Week 4 (n=21, 137)
    47.0 ± 26.69
    42.4 ± 23.80
        Week 8 (n=18, 131)
    37.8 ± 25.75
    35.3 ± 24.30
        Week 12 (n=19, 128)
    40.9 ± 29.56
    30.8 ± 23.29
        Week 16 (n=19, 126)
    29.7 ± 20.83
    26.8 ± 22.61
        Week 20 (n=19, 122)
    27.6 ± 25.48
    28.6 ± 23.74
        Week 24 (n=19, 117)
    29.9 ± 22.76
    25.2 ± 22.16
        Week 28 (n=19, 116)
    24.8 ± 19.15
    25.6 ± 23.18
        Week 32 (n=19, 115)
    25.1 ± 17.92
    22.6 ± 21.30
        Week 36 (n=18, 114)
    29.6 ± 20.03
    22.1 ± 21.68
        Week 40 (n=17, 111)
    27.6 ± 22.70
    20.9 ± 21.24
        Week 44 (n=17, 107)
    26.7 ± 24.25
    20.0 ± 21.26
        Week 48 (n=16, 107)
    28.6 ± 28.98
    17.6 ± 19.66
        Week 52 (n=16, 107)
    22.4 ± 19.70
    19.0 ± 19.83
        Early withdrawal (n=5, 30)
    30.4 ± 29.57
    51.6 ± 26.03
    No statistical analyses for this end point

    Secondary: Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

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    End point title
    Health Assessment Questionnaire-Disability Index (HAQ-DI) Score
    End point description
    The HAQ-DI questionnaire measures functional status (disability) and health-related quality of life. It measures the participant's ability to perform everyday tasks. The index consists of 20 questions regarding the function of the upper and lower extremities. These questions are summarized in 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common activities over past week. Each question is evaluated according to the degree of severity on a 4-point scale. Total score for HAQ-DI was the average of all questions and ranges from 0 = without any difficulty to 3 = unable to do. FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=21, 139)
    1.806 ± 0.5551
    1.738 ± 0.6406
        Week 2 (n=20, 137)
    1.558 ± 0.7319
    1.659 ± 0.6210
        Week 4 (n=21, 137)
    1.616 ± 0.7720
    1.546 ± 0.7351
        Week 8 (n=18, 132)
    1.508 ± 0.7597
    1.404 ± 0.8115
        Week 12 (n=19, 128)
    1.488 ± 0.9304
    1.333 ± 0.8272
        Week 16 (n=19, 126)
    1.351 ± 0.9586
    1.312 ± 0.8621
        Week 20 (n=19, 119)
    1.409 ± 0.9071
    1.318 ± 0.8608
        Week 24 (n=19, 117)
    1.330 ± 0.8379
    1.261 ± 0.8915
        Week 28 (n=19, 116)
    1.330 ± 0.9412
    1.221 ± 0.8730
        Week 32 (n=19, 114)
    1.351 ± 0.8816
    1.232 ± 0.8870
        Week 36 (n=18, 113)
    1.432 ± 0.9048
    1.170 ± 0.8757
        Week 40 (n=17, 111)
    1.479 ± 0.8975
    1.199 ± 0.8908
        Week 44 (n=17, 108)
    1.442 ± 0.9392
    1.130 ± 0.9206
        Week 48 (n=16, 107)
    1.361 ± 0.9685
    1.114 ± 0.8815
        Week 52 (n=16, 107)
    1.338 ± 0.9796
    1.154 ± 0.9187
        Early withdrawal (n=5, 30)
    1.252 ± 1.1232
    1.756 ± 0.7820
    No statistical analyses for this end point

    Secondary: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score

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    End point title
    Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score
    End point description
    The FACIT-F score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-F score for a total possible score of 0 (worse score) to 52 (better score). FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=21, 139)
    18.4 ± 11.14
    24.3 ± 11.55
        Week 2 (n=21, 137)
    23.1 ± 12.37
    27.9 ± 11.03
        Week 4 (n=21, 136)
    25.1 ± 12.28
    30.7 ± 12.10
        Week 8 (n=18, 132)
    30.2 ± 11.58
    32.8 ± 11.91
        Week 12 (n=19, 128)
    28.4 ± 11.71
    33.7 ± 11.85
        Week 16 (n=19, 126)
    31.3 ± 13.80
    34.0 ± 12.53
        Week 20 (n=19, 121)
    33.2 ± 13.57
    34.1 ± 12.05
        Week 24 (n=19, 117)
    33.8 ± 15.28
    35.3 ± 10.98
        Week 28 (n=19, 115)
    32.9 ± 12.06
    35.5 ± 11.59
        Week 32 (n=19, 115)
    34.1 ± 12.68
    36.2 ± 11.32
        Week 36 (n=18, 114)
    30.3 ± 13.62
    36.8 ± 11.48
        Week 40 (n=17, 111)
    31.7 ± 12.87
    37.1 ± 11.69
        Week 44 (n=17, 106)
    31.0 ± 14.02
    37.2 ± 11.75
        Week 48 (n=16, 107)
    31.6 ± 14.63
    37.9 ± 11.73
        Week 52 (n=16, 106)
    33.4 ± 14.17
    38.1 ± 11.16
        Early withdrawal (n=4, 30)
    31.3 ± 2.63
    24.5 ± 12.08
    No statistical analyses for this end point

    Secondary: Number of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records

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    End point title
    Number of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records
    End point description
    A diary card was provided to participants to record home injections. Participants were asked to return all empty drug supply boxes, unused pre-filled syringe, and diary cards to the clinic at each visit as a measure of drug accountability and participant compliance. A participant was considered compliant if the participant correctly administered all scheduled doses of SC tocilizumab during the assessment period. FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: participants
    number (not applicable)
        Baseline (n=21, 139)
    21
    137
        Week 2 (n=21, 137)
    20
    126
        Week 4 (n=21, 137)
    20
    132
        Week 8 (n=18, 132)
    18
    124
        Week 12 (n=19, 128)
    18
    121
        Week 16 (n=19, 126)
    19
    120
        Week 20 (n=19, 122)
    18
    114
        Week 24 (n=19, 117)
    16
    107
        Week 28 (n=19, 116)
    19
    112
        Week 32 (n=19, 115)
    17
    111
        Week 36 (n=18, 114)
    17
    105
        Week 40 (n=17, 111)
    16
    104
        Week 44 (n=17, 108)
    16
    102
        Week 48 (n=16, 107)
    13
    107
        Week 52 (n=16, 107)
    16
    98
        Early withdrawal (n=5, 30)
    4
    27
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-Tocilizumab Antibodies

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    End point title
    Number of Participants With Anti-Tocilizumab Antibodies
    End point description
    FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups. "99999" indicates results are not reported as no participants were evaluable at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: participants
    number (not applicable)
        Baseline (n=20, 138)
    3
    6
        Week 12 (n=1, 0)
    0
    99999
        Week 24 (n=19, 116)
    0
    2
        Early withdrawal (n=5, 27)
    0
    0
        Follow-up visit (n=3, 21)
    0
    0
    No statistical analyses for this end point

    Secondary: Serum Levels of Tocilizumab

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    End point title
    Serum Levels of Tocilizumab
    End point description
    FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Baseline (n=20, 138)
    0.0000 ± 0.0000
    0.0082 ± 0.09619
        Week 12 (n=18, 125)
    35.3953 ± 22.69069
    40.2529 ± 21.05801
        Week 24 (n=19, 115)
    53.0416 ± 39.06367
    43.9047 ± 30.41603
        Early withdrawal (n=5, 25)
    44.7160 ± 38.81521
    17.6160 ± 22.92477
        Follow-up visit (n=3, 22)
    0.0597 ± 0.10335
    2.3123 ± 7.40931
    No statistical analyses for this end point

    Secondary: Serum Levels of Soluble Interleukin-6 Receptors (sIL-6Rs)

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    End point title
    Serum Levels of Soluble Interleukin-6 Receptors (sIL-6Rs)
    End point description
    FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks)
    End point values
    Tocilizumab Monotherapy Tocilizumab in Combination With Methotrexate or Other DMARDs
    Number of subjects analysed
    21
    140
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=8, 48)
    43.63 ± 10.947
    42.40 ± 12.087
        Week 12 (n=12, 57)
    577.42 ± 175.649
    548.70 ± 131.079
        Week 24 (n=12, 80)
    602.25 ± 158.541
    521.07 ± 160.464
        Early withdrawal (n=4, 18)
    639.75 ± 99.644
    327.95 ± 229.481
        Follow-up visit (n=3, 20)
    132.23 ± 93.048
    125.07 ± 211.038
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 60
    Adverse event reporting additional description
    FAS population
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Tocilizumab in Combination With Methotrexate or Other DMARDs
    Reporting group description
    Participants received a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.

    Reporting group title
    Tocilizumab Monotherapy
    Reporting group description
    Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy for 52 weeks.

    Serious adverse events
    Tocilizumab in Combination With Methotrexate or Other DMARDs Tocilizumab Monotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 140 (5.00%)
    3 / 21 (14.29%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Knee arthroplasty
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 21 (4.76%)
         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)
    Prostate cancer
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Costochondritis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 21 (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
    0 / 140 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Tocilizumab in Combination With Methotrexate or Other DMARDs Tocilizumab Monotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    135 / 140 (96.43%)
    19 / 21 (90.48%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    13 / 140 (9.29%)
    2 / 21 (9.52%)
         occurrences all number
    17
    2
    Fall
         subjects affected / exposed
    14 / 140 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    14
    1
    Laceration
         subjects affected / exposed
    7 / 140 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    10
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    31 / 140 (22.14%)
    2 / 21 (9.52%)
         occurrences all number
    50
    4
    Neutrophil count decreased
         subjects affected / exposed
    13 / 140 (9.29%)
    0 / 21 (0.00%)
         occurrences all number
    15
    0
    Blood cholesterol increased
         subjects affected / exposed
    5 / 140 (3.57%)
    3 / 21 (14.29%)
         occurrences all number
    5
    3
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    14 / 140 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    15
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    27 / 140 (19.29%)
    3 / 21 (14.29%)
         occurrences all number
    33
    4
    Cough
         subjects affected / exposed
    21 / 140 (15.00%)
    4 / 21 (19.05%)
         occurrences all number
    22
    5
    Productive cough
         subjects affected / exposed
    3 / 140 (2.14%)
    2 / 21 (9.52%)
         occurrences all number
    6
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 140 (9.29%)
    4 / 21 (19.05%)
         occurrences all number
    20
    4
    Dizziness
         subjects affected / exposed
    8 / 140 (5.71%)
    2 / 21 (9.52%)
         occurrences all number
    9
    2
    Migraine
         subjects affected / exposed
    7 / 140 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    13
    1
    Paraesthesia
         subjects affected / exposed
    6 / 140 (4.29%)
    2 / 21 (9.52%)
         occurrences all number
    6
    2
    Lethargy
         subjects affected / exposed
    7 / 140 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    7
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 140 (8.57%)
    1 / 21 (4.76%)
         occurrences all number
    12
    1
    Injection site bruising
         subjects affected / exposed
    12 / 140 (8.57%)
    3 / 21 (14.29%)
         occurrences all number
    14
    5
    Injection site erythema
         subjects affected / exposed
    11 / 140 (7.86%)
    1 / 21 (4.76%)
         occurrences all number
    49
    4
    Influenza like illness
         subjects affected / exposed
    8 / 140 (5.71%)
    1 / 21 (4.76%)
         occurrences all number
    9
    1
    Peripheral swelling
         subjects affected / exposed
    8 / 140 (5.71%)
    1 / 21 (4.76%)
         occurrences all number
    9
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    32 / 140 (22.86%)
    2 / 21 (9.52%)
         occurrences all number
    41
    2
    Nausea
         subjects affected / exposed
    21 / 140 (15.00%)
    0 / 21 (0.00%)
         occurrences all number
    26
    0
    Mouth ulceration
         subjects affected / exposed
    18 / 140 (12.86%)
    1 / 21 (4.76%)
         occurrences all number
    23
    3
    Vomiting
         subjects affected / exposed
    16 / 140 (11.43%)
    2 / 21 (9.52%)
         occurrences all number
    21
    2
    Abdominal pain
         subjects affected / exposed
    7 / 140 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    9
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    18 / 140 (12.86%)
    0 / 21 (0.00%)
         occurrences all number
    22
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 140 (8.57%)
    1 / 21 (4.76%)
         occurrences all number
    13
    1
    Pain in extremity
         subjects affected / exposed
    11 / 140 (7.86%)
    0 / 21 (0.00%)
         occurrences all number
    11
    0
    Back pain
         subjects affected / exposed
    10 / 140 (7.14%)
    3 / 21 (14.29%)
         occurrences all number
    10
    4
    Rheumatoid arthritis
         subjects affected / exposed
    11 / 140 (7.86%)
    0 / 21 (0.00%)
         occurrences all number
    13
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    33 / 140 (23.57%)
    5 / 21 (23.81%)
         occurrences all number
    40
    6
    Lower respiratory tract infection
         subjects affected / exposed
    25 / 140 (17.86%)
    6 / 21 (28.57%)
         occurrences all number
    27
    11
    Urinary tract infection
         subjects affected / exposed
    16 / 140 (11.43%)
    5 / 21 (23.81%)
         occurrences all number
    25
    6
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 140 (14.29%)
    2 / 21 (9.52%)
         occurrences all number
    31
    3
    Oral herpes
         subjects affected / exposed
    10 / 140 (7.14%)
    1 / 21 (4.76%)
         occurrences all number
    13
    1
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 140 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Sep 2013
    The major changes were corrections to ensure consistent wording for participant withdrawal criteria throughout the protocol and clarification regarding post-study follow-up visits. Minor formatting changes were also made to improve clarity and consistency.
    06 May 2014
    The major changes were the reduction in sample size from 260 participants to 160 participants, expansion of the target population to include those participants who had not experienced an adequate response to their current non-biologic DMARD therapy or the first anti-TNF agent and clarification that eligible participants were required to have “active” (not severe) rheumatoid arthritis. The reduction in sample size only increased the 95% confidence interval (CI) width by 0.09 for ESR and by 0.8 for CDAI. The expected precision of the CI widths around the mean change from baseline for a sample of 160 participants was still deemed to be clinically sufficient and a reasonable target to be able to draw conclusions from the study. The addition of DMARD inadequate response participants was not expected to compromise the power of the study as data from other studies indicate their responses are no worse and not more variable than those of the original study population. Details regarding study treatment, concomitant medications and assessments were updated for clarification. Administrative changes and additional minor changes were made to improve clarity and consistency.
    10 Dec 2014
    The major change was amendment of the target participant population to remove the window (previously 12 to 32 weeks) during which a participant who was receiving their first anti-TNF therapy would have to be assessed for an inadequate response to anti-TNF treatment. The rationale for this change was based on the feedback received from the sites, which indicated that such a protocol requirement was extremely difficult to implement and not aligned with local hospital protocols for assessing inadequate response to anti-TNF treatment. It was also clarified that inadequate response to non-biologic DMARD therapy was to be assessed according to local guidelines and that participants needed to be eligible for biologic therapy according to local guidelines. Language regarding pregnancy testing was also clarified in this amendment and names of relevant Roche personnel were updated. Additional minor changes were made to improve clarity and consistency.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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