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    Clinical Trial Results:
    Efficacy and Safety Study of a Sequential Therapy of Tocilizumab (TCZ) and, if Initially Inadequately Responded to Tocilizumab (TCZ), Followed by Rituximab (RTX) in DMARD-IR Patients With Rheumatoid Arthritis (MIRAI)

    Summary
    EudraCT number
    2010-022049-88
    Trial protocol
    DE  
    Global end of trial date
    19 Feb 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    21 Jul 2016
    First version publication date
    16 Mar 2016
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Errors have been identified that need to be corrected.

    Trial information

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    Trial identification
    Sponsor protocol code
    ML22985
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01332994
    WHO universal trial number (UTN)
    -
    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 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, 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
    19 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This open-label, national, multicenter, two-arm, non-controlled, nonrandomized study evaluated the efficacy and safety of TCZ with or without sequential RTX in participants with moderate to severe active rheumatoid arthritis (RA) with inadequate response to disease-modifying antirheumatic drugs (DMARD-IR) at the time of enrollment. Participants were treated with TCZ and, if applicable, with subsequent RTX in combination with traditional disease-modifying antirheumatic drugs (DMARDs) taken before study entry.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the Declaration of Helsinki (version 1996) as amended, international Good Clinical Practice (ICH-GCP) standards, and local laws and regulations concerning clinical studies.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Mar 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    9 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 519
    Worldwide total number of subjects
    519
    EEA total number of subjects
    519
    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)
    388
    From 65 to 84 years
    131
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    After a screening period of up to 4 weeks, eligible participants were treated according to a predefined treatment algorithm based on disease response. In certain cases a re-screening was allowed. Participants were enrolled into the study with the administration of their first dose.

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

    Arms
    Arm title
    TCZ/TCZ or TCZ/RTX
    Arm description
    All participants were assigned to receive TCZ 8 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Clinical response was assessed at Week 16 using Disease Activity Score Based on 28-Joint Count (DAS28) to determine subsequent treatment assignment. Participants who achieved early remission, defined as a DAS28 score of less than (<) 2.6, were transferred to clinical routine care and no longer received study medication. Participants who were considered partial responders, defined as a decrease from Baseline in DAS28 score greater than (>) 1.2 or a score between 2.6 and 3.2, inclusive, received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 additional infusions from Week 16 to 28. Those with assessed as having no response, defined as a decrease from Baseline in DAS28 score less than or equal to (≤) 1.2 or a score >3.2, received RTX 1000 milligrams (mg) via IV infusion at Weeks 16 and 18.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Participants with a partial response received an additional 4 infusions of TCZ 8 mg/kg every 4 weeks from Week 16 to 28.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants assessed as having no response received RTX 1000 mg via IV infusion at Weeks 16 and 18.

    Number of subjects in period 1
    TCZ/TCZ or TCZ/RTX
    Started
    519
    Completed Week 16
    463
    Completed Week 32 (TCZ/TCZ)
    200 [1]
    Completed Week 32 (TCZ/RTX)
    26 [2]
    Completed Week 66 (TCZ/RTX)
    25 [3]
    Completed
    448
    Not completed
    71
         Death
    1
         Protocol violation
    6
         Adverse event
    34
         Lack of efficacy
    1
         Not specified
    8
         Administrative problem
    2
         Consent withdrawn by subject
    15
         Lost to follow-up
    4
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only select participants continued assessment visits through the end of safety follow-up (Week 66). Participants achieving early remission or partial response could complete the study earlier.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only select participants continued assessment visits through the end of safety follow-up (Week 66). Participants achieving early remission or partial response could complete the study earlier.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only select participants continued assessment visits through the end of safety follow-up (Week 66). Participants achieving early remission or partial response could complete the study earlier.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TCZ/TCZ or TCZ/RTX
    Reporting group description
    All participants were assigned to receive TCZ 8 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Clinical response was assessed at Week 16 using Disease Activity Score Based on 28-Joint Count (DAS28) to determine subsequent treatment assignment. Participants who achieved early remission, defined as a DAS28 score of less than (<) 2.6, were transferred to clinical routine care and no longer received study medication. Participants who were considered partial responders, defined as a decrease from Baseline in DAS28 score greater than (>) 1.2 or a score between 2.6 and 3.2, inclusive, received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 additional infusions from Week 16 to 28. Those with assessed as having no response, defined as a decrease from Baseline in DAS28 score less than or equal to (≤) 1.2 or a score >3.2, received RTX 1000 milligrams (mg) via IV infusion at Weeks 16 and 18.

    Reporting group values
    TCZ/TCZ or TCZ/RTX Total
    Number of subjects
    519 519
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.7 ± 11.9 -
    Gender categorical
    Units: Subjects
        Female
    352 352
        Male
    167 167

    End points

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    End points reporting groups
    Reporting group title
    TCZ/TCZ or TCZ/RTX
    Reporting group description
    All participants were assigned to receive TCZ 8 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Clinical response was assessed at Week 16 using Disease Activity Score Based on 28-Joint Count (DAS28) to determine subsequent treatment assignment. Participants who achieved early remission, defined as a DAS28 score of less than (<) 2.6, were transferred to clinical routine care and no longer received study medication. Participants who were considered partial responders, defined as a decrease from Baseline in DAS28 score greater than (>) 1.2 or a score between 2.6 and 3.2, inclusive, received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 additional infusions from Week 16 to 28. Those with assessed as having no response, defined as a decrease from Baseline in DAS28 score less than or equal to (≤) 1.2 or a score >3.2, received RTX 1000 milligrams (mg) via IV infusion at Weeks 16 and 18.

    Primary: Percentage of Participants Achieving Remission at Week 16 According to DAS28

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    End point title
    Percentage of Participants Achieving Remission at Week 16 According to DAS28 [1]
    End point description
    The DAS28 was calculated as [0.28 times (x) the square root of number of swollen joints] plus (+) [0.56 x the square root of number of tender joints] + [0.7 x the natural log of erythrocyte sedimentation rate (ESR)] + [0.014 x Visual Analog Scale (VAS) patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. Main Intent-to-Treat (ITT) Population: All participants who received at least one dose of TCZ.
    End point type
    Primary
    End point timeframe
    Week 16
    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: Statistical analysis could not be entered due to system limitations for a single-arm study. An exact one-sided binomial test on single proportions was performed, with a significance level of alpha equals (=) 0.025. Null hypothesis: Proportion of participants reaching DAS28 remission (<2.6) at Week 16 is ≤45 percent (%). The result was p-value = 0.1648.
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    519
    Units: percentage of participants
        number (confidence interval 95%)
    42.8 (38.5 to 47.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Remission According to DAS28 at Weeks 4, 8, and 12

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    End point title
    Percentage of Participants Achieving Remission According to DAS28 at Weeks 4, 8, and 12
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, and 12
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    519
    Units: percentage of participants
    number (confidence interval 95%)
        Week 4
    21.6 (18.1 to 25.4)
        Week 8
    40.1 (35.8 to 44.4)
        Week 12
    43.2 (38.9 to 47.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Remission According to DAS28 at Weeks 16, 20, 24, and 28 Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Percentage of Participants Achieving Remission According to DAS28 at Weeks 16, 20, 24, and 28 Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. ITT2 Population: All participants who received at least one dose of TCZ in the first treatment period with at least one efficacy measurement under TCZ, receiving TCZ in the second treatment period.
    End point type
    Secondary
    End point timeframe
    Weeks 16, 20, 24, and 28
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    213
    Units: percentage of participants
    number (confidence interval 95%)
        Week 16
    1.4 (0.3 to 4.1)
        Week 20
    41.3 (34.6 to 48.2)
        Week 24
    51.2 (44.3 to 58.1)
        Week 28
    55.9 (48.9 to 62.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Remission According to DAS28 at Week 32 Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Percentage of Participants Achieving Remission According to DAS28 at Week 32 Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Week 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    213
    Units: percentage of participants
        number (confidence interval 95%)
    54.9 (48 to 61.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Low Disease Activity Score (LDAS) According to DAS28

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    End point title
    Percentage of Participants Achieving Low Disease Activity Score (LDAS) According to DAS28
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x the patient global assessment of disease activity using a VAS]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. LDAS was defined as a DAS28 score <3.2 at the assessment visit. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    519
    Units: percentage of participants
        number (confidence interval 95%)
    68.8 (64.6 to 72.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Clinically Relevant Reduction From Baseline in DAS28 at Week 16

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    End point title
    Percentage of Participants Achieving a Clinically Relevant Reduction From Baseline in DAS28 at Week 16
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Reductions >1.2 points from Baseline to the assessment visit were considered clinically relevant. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    519
    Units: percentage of participants
        number (confidence interval 95%)
    86.1 (82.9 to 89)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Clinically Relevant Reduction From Baseline in DAS28 at Weeks 4, 8, and 12

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    End point title
    Percentage of Participants Achieving a Clinically Relevant Reduction From Baseline in DAS28 at Weeks 4, 8, and 12
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Reductions >1.2 points from Baseline to the assessment visit were considered clinically relevant. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, and 12
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    519
    Units: percentage of participants
    number (confidence interval 95%)
        Week 4
    74.6 (70.6 to 78.3)
        Week 8
    81.5 (77.9 to 84.8)
        Week 12
    83.4 (79.9 to 86.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Clinically Relevant Reduction in DAS28 From Week 16 to Week 32 Among Nonresponding Participants Treated With Rituximab

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    End point title
    Percentage of Participants Achieving a Clinically Relevant Reduction in DAS28 From Week 16 to Week 32 Among Nonresponding Participants Treated With Rituximab
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Reductions >1.2 points from the reference visit (Week 16) to the assessment visit were considered clinically relevant. ITT3 Population: All participants who received at least one dose of TCZ in the first treatment period and at least one dose of RTX in the second treatment period with at least one efficacy measurement under RTX.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    27
    Units: percentage of participants
        number (confidence interval 95%)
    37 (19.4 to 57.6)
    No statistical analyses for this end point

    Secondary: DAS28 Scores During and After Treatment

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    End point title
    DAS28 Scores During and After Treatment
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    516 [2]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=516)
    5.7 ± 1
        Week 4 (n=508)
    3.6 ± 1.3
        Week 8 (n=491)
    3 ± 1.4
        Week 12 (n=483)
    2.8 ± 1.4
        Week 16 (n=485)
    2.6 ± 1.3
    Notes
    [2] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: DAS28 Scores During Safety Follow-Up Among Nonresponding Participants Treated With Rituximab

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    End point title
    DAS28 Scores During Safety Follow-Up Among Nonresponding Participants Treated With Rituximab
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 40, 48, 56, and 66
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    26 [3]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 40 (n=26)
    3.9 ± 1.5
        Week 48 (n=25)
    3.9 ± 1.2
        Week 56 (n=22)
    4.1 ± 1.8
        Week 66 (n=25)
    3.9 ± 1.5
    Notes
    [3] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Response According to European League Against Rheumatism (EULAR) Criteria at Weeks 4, 8, 12 and 16

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    End point title
    Percentage of Participants Achieving a Response According to European League Against Rheumatism (EULAR) Criteria at Weeks 4, 8, 12 and 16
    End point description
    Response was determined using EULAR criteria based upon DAS28 absolute scores at the assessment visit and the DAS28 reduction from Baseline. Participants with a score ≤3.2 and reduction of >1.2 points were assessed as having a 'good' response. Participants with a score >3.2 with reduction of >1.2 points, or a score ≤5.1 with reduction of >0.6 to ≤1.2 points, were assessed as having a 'moderate' response. Participants with a score >5.1 with reduction of >0.6 to ≤1.2 points, or any score with reduction ≤0.6 points, were assessed as nonresponders with response recorded as 'none.' Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, and 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    519
    Units: percentage of participants
    number (confidence interval 95%)
        Week 4, Good
    36 (31.9 to 40.3)
        Week 4, Moderate
    47.8 (43.4 to 52.2)
        Week 4, None
    16.2 (13.1 to 19.6)
        Week 8, Good
    56.1 (51.7 to 60.4)
        Week 8, Moderate
    30.6 (26.7 to 34.8)
        Week 8, None
    13.3 (10.5 to 16.5)
        Week 12, Good
    61.1 (56.7 to 65.3)
        Week 12, Moderate
    25.6 (21.9 to 29.6)
        Week 12, None
    13.3 (10.5 to 16.5)
        Week 16, Good
    68.2 (64 to 72.2)
        Week 16, Moderate
    20.2 (16.9 to 23.9)
        Week 16, None
    11.6 (8.9 to 14.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Response According to EULAR Criteria at Week 32 Compared to Week 16 Among Nonresponding Participants Treated With Rituximab

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    End point title
    Percentage of Participants Achieving a Response According to EULAR Criteria at Week 32 Compared to Week 16 Among Nonresponding Participants Treated With Rituximab
    End point description
    Response was determined using EULAR criteria based upon DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit (Week 16). Participants with a score ≤3.2 and reduction of >1.2 points were assessed as having a 'good' response. Participants with a score >3.2 with reduction of >1.2 points, or a score ≤5.1 with reduction of >0.6 to ≤1.2 points, were assessed as having a 'moderate' response. Participants with a score >5.1 with reduction of >0.6 to ≤1.2 points, or any score with reduction ≤0.6 points, were assessed as nonresponders with response recorded as 'none.' ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    27
    Units: percentage of participants
    number (confidence interval 95%)
        Good
    25.9 (11.1 to 46.3)
        Moderate
    29.6 (13.8 to 50.2)
        None
    44.4 (25.5 to 64.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Response According to EULAR Criteria at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Percentage of Participants Achieving a Response According to EULAR Criteria at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    Response was determined using EULAR criteria based upon DAS28 absolute scores at the assessment visit and the DAS28 reduction from Baseline. Participants with a score ≤3.2 and reduction of >1.2 points were assessed as having a 'good' response. Participants with a score >3.2 with reduction of >1.2 points, or a score ≤5.1 with reduction of >0.6 to ≤1.2 points, were assessed as having a 'moderate' response. Participants with a score >5.1 with reduction of >0.6 to ≤1.2 points, or any score with reduction ≤0.6 points, were assessed as nonresponders with response recorded as 'none.' ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 20, 24, 28, and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    213
    Units: percentage of participants
    number (confidence interval 95%)
        Week 20, Good
    65.3 (58.5 to 71.6)
        Week 20, Moderate
    30 (24 to 36.7)
        Week 20, None
    4.7 (2.3 to 8.5)
        Week 24, Good
    68.1 (61.4 to 74.3)
        Week 24, Moderate
    23.9 (18.4 to 30.3)
        Week 24, None
    8 (4.7 to 12.5)
        Week 28, Good
    72.8 (66.3 to 78.6)
        Week 28, Moderate
    19.2 (14.2 to 25.2)
        Week 28, None
    8 (4.7 to 12.5)
        Week 32, Good
    66.7 (59.9 to 73)
        Week 32, Moderate
    20.7 (15.4 to 26.7)
        Week 32, None
    12.7 (8.5 to 17.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Response According to American College of Rheumatology (ACR) Criteria at Weeks 4, 8, 12, and 16

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    End point title
    Percentage of Participants Achieving a Response According to American College of Rheumatology (ACR) Criteria at Weeks 4, 8, 12, and 16
    End point description
    Response was determined using ACR criteria based upon assessment of 66 joints for swelling and 68 joints for tenderness; joints were classified dichotomously as swollen or not swollen and tender or not tender. Respectively, these assessments were used to generate a swollen joint count (SJC) ranging from 0 to 66 swollen joints and a tender joint count (TJC) ranging from 0 to 68 tender joints. Response was defined as a reduction from Baseline of at least 20% for one of the following: VAS scores for patient-reported pain, patient global assessment of disease activity, or physician global assessment of disease activity, Health Assessment Questionnaire Disability Index (HAQ-DI), or C-reactive protein (CRP); plus a reduction in individual SJC and TJC of 20% (ACR20), 50% (ACR50), or 70% (ACR70). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, and 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    519
    Units: percentage of participants
    number (confidence interval 95%)
        Week 4, ACR20
    39.1 (34.9 to 43.5)
        Week 4, ACR50
    15 (12.1 to 18.4)
        Week 4, ACR70
    5.8 (3.9 to 8.1)
        Week 8, ACR20
    61.1 (56.7 to 65.3)
        Week 8, ACR50
    33.5 (29.5 to 37.8)
        Week 8, ACR70
    15.2 (12.2 to 18.6)
        Week 12, ACR20
    64 (59.7 to 68.1)
        Week 12, ACR50
    42.8 (38.5 to 47.2)
        Week 12, ACR70
    20.2 (16.9 to 23.9)
        Week 16, ACR20
    67.1 (62.8 to 71.1)
        Week 16, ACR50
    45.7 (41.3 to 50.1)
        Week 16, ACR70
    24.5 (20.8 to 28.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Response According to ACR Criteria at Week 32 Compared to Week 16 Among Nonresponding Participants Treated With Rituximab

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    End point title
    Percentage of Participants Achieving a Response According to ACR Criteria at Week 32 Compared to Week 16 Among Nonresponding Participants Treated With Rituximab
    End point description
    Response was determined using ACR criteria based upon assessment of 66 joints for swelling and 68 joints for tenderness; joints were classified dichotomously as swollen or not swollen and tender or not tender. Respectively, these assessments were used to generate an SJC ranging from 0 to 66 swollen joints and a TJC ranging from 0 to 68 tender joints. Response was defined as a reduction from the reference visit (Week 16) of at least 20% for one of the following: VAS scores for patient-reported pain, patient global assessment of disease activity, or physician global assessment of disease activity, HAQDI, or CRP; plus a reduction in individual SJC and TJC of 20% (ACR20), 50% (ACR50), or 70% (ACR70). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    27
    Units: percentage of participants
    number (confidence interval 95%)
        ACR20
    40.7 (22.4 to 61.2)
        ACR50
    33.3 (16.5 to 54)
        ACR70
    22.2 (8.6 to 42.3)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Response According to ACR Criteria at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Percentage of Participants Achieving a Response According to ACR Criteria at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    Response was determined using ACR criteria based upon assessment of 66 joints for swelling and 68 joints for tenderness; joints were classified dichotomously as swollen or not swollen and tender or not tender. Respectively, these assessments were used to generate an SJC ranging from 0 to 66 swollen joints and a TJC ranging from 0 to 68 tender joints. Response was defined as a reduction from Baseline of at least 20% for one of the following: VAS scores for patient-reported pain, patient global assessment of disease activity, or physician global assessment of disease activity, HAQ-DI, or CRP; plus a reduction in individual SJC and TJC of 20% (ACR20), 50% (ACR50), or 70% (ACR70). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 20, 24, 28, and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    213
    Units: percentage of participants
    number (confidence interval 95%)
        Week 20, ACR20
    74.2 (67.8 to 79.9)
        Week 20, ACR50
    45.1 (38.3 to 52)
        Week 20, ACR70
    21.1 (15.8 to 27.2)
        Week 24, ACR20
    72.8 (66.3 to 78.6)
        Week 24, ACR50
    49.8 (42.9 to 56.7)
        Week 24, ACR70
    21.6 (16.3 to 27.7)
        Week 28, ACR20
    73.2 (66.8 to 79.1)
        Week 28, ACR50
    53.1 (46.1 to 59.9)
        Week 28, ACR70
    30.5 (24.4 to 37.2)
        Week 32, ACR20
    75.6 (69.2 to 81.2)
        Week 32, ACR50
    54.9 (48 to 61.7)
        Week 32, ACR70
    34.3 (27.9 to 41.1)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) Scores at Weeks 4, 8, 12, and 16

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    End point title
    Change From Baseline in Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) Scores at Weeks 4, 8, 12, and 16
    End point description
    The CDAI was calculated as [SJC + TJC + VAS patient global assessment of disease activity + VAS physician global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. The SDAI was determined by adding CRP level to the CDAI score. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. A reduction in either score at the assessment visit reflects improvement in disease. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, and 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    509 [4]
    Units: units of a scale
    arithmetic mean (standard deviation)
        CDAI, Week 4 (n=509)
    -10.9 ± 10.2
        CDAI, Week 8 (n=497)
    -16.5 ± 11.1
        CDAI, Week 12 (n=486)
    -18.3 ± 11.5
        CDAI, Week 16 (n=485)
    -19.4 ± 11.5
        SDAI, Week 4 (n=496)
    -12.3 ± 10.6
        SDAI, Week 8 (n=489)
    -17.9 ± 11.5
        SDAI, Week 12 (n=474)
    -19.7 ± 11.9
        SDAI, Week 16 (n=471)
    -20.7 ± 12.2
    Notes
    [4] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Week 16 to 32 in CDAI and SDAI Scores Among Nonresponding Participants Treated With Rituximab

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    End point title
    Change From Week 16 to 32 in CDAI and SDAI Scores Among Nonresponding Participants Treated With Rituximab
    End point description
    The CDAI was calculated as [SJC + TJC + VAS patient global assessment of disease activity + VAS physician global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. The SDAI was determined by adding CRP level to the CDAI score. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. A reduction in either score at the assessment visit reflects improvement in disease. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    25 [5]
    Units: units on a scale
    arithmetic mean (standard deviation)
        CDAI (n=25)
    -14.2 ± 12
        SDAI (n=24)
    -14 ± 12.5
    Notes
    [5] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in CDAI and SDAI Scores at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Change From Baseline in CDAI and SDAI Scores at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    The CDAI was calculated as [SJC + TJC + VAS patient global assessment of disease activity + VAS physician global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. The SDAI was determined by adding CRP level to the CDAI score. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. A reduction in either score at the assessment visit reflects improvement in disease. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 20, 24, 28, and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    208 [6]
    Units: units on a scale
    arithmetic mean (standard deviation)
        CDAI, Week 20 (n=208)
    -21.7 ± 11.7
        CDAI, Week 24 (n=199)
    -22.8 ± 11.4
        CDAI, Week 28 (n=200)
    -24.6 ± 12.5
        CDAI, Week 32 (n=194)
    -24 ± 13.4
        SDAI, Week 20 (n=200)
    -22.9 ± 12.5
        SDAI, Week 24 (n=190)
    -24.3 ± 12.1
        SDAI, Week 28 (n=195)
    -25.9 ± 13.2
        SDAI, Week 32 (n=189)
    -25.2 ± 14
    Notes
    [6] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemoglobin at Weeks 4, 8, 12, and 16

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    End point title
    Change From Baseline in Hemoglobin at Weeks 4, 8, 12, and 16
    End point description
    Blood samples for laboratory assessments, including hemoglobin level, were collected prior to each dose of study medication. The mean hemoglobin level was determined at Baseline and for assessment visits by averaging the observed hemoglobin level among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean hemoglobin at the assessment visit minus mean hemoglobin at Baseline] and expressed in grams per liter (g/L). Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, and 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    509 [7]
    Units: g/L
    arithmetic mean (standard deviation)
        Week 4 (n=509)
    4.9 ± 7.2
        Week 8 (n=496)
    6.4 ± 8.8
        Week 12 (n=483)
    6.9 ± 9.1
        Week 16 (n=477)
    7.5 ± 9.1
    Notes
    [7] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in CRP at Weeks 4, 8, 12, and 16

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    End point title
    Change From Baseline in CRP at Weeks 4, 8, 12, and 16
    End point description
    Blood samples for laboratory assessments, including CRP level, were collected prior to each dose of study medication. The mean CRP level was determined at Baseline and for assessment visits by averaging the observed CRP level among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean CRP at the assessment visit minus mean CRP at Baseline] and expressed in milligrams per deciliter (mg/dL). Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, and 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    497 [8]
    Units: mg/dL
    arithmetic mean (standard deviation)
        Week 4 (n=497)
    -1.4 ± 1.9
        Week 8 (n=492)
    -1.4 ± 1.9
        Week 12 (n=476)
    -1.4 ± 1.9
        Week 16 (n=471)
    -1.3 ± 1.9
    Notes
    [8] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in ESR at Weeks 4, 8, 12, and 16

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    End point title
    Change From Baseline in ESR at Weeks 4, 8, 12, and 16
    End point description
    Blood samples for laboratory assessments, including ESR, were collected prior to each dose of study medication. The mean ESR was determined at Baseline and for assessment visits by averaging the observed ESR among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean ESR at the assessment visit minus mean ESR at Baseline] and expressed in millimeters per hour (mm/h). Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, and 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    507 [9]
    Units: mm/h
    arithmetic mean (standard deviation)
        Week 4 (n=507)
    -25.2 ± 18.1
        Week 8 (n=494)
    -26.6 ± 18.9
        Week 12 (n=484)
    -26.3 ± 19.1
        Week 16 (n=484)
    -27.5 ± 18.7
    Notes
    [9] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change in Hemoglobin From Week 16 to 32 Among Nonresponding Participants Treated With Rituximab

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    End point title
    Change in Hemoglobin From Week 16 to 32 Among Nonresponding Participants Treated With Rituximab
    End point description
    Blood samples for laboratory assessments, including hemoglobin level, were collected prior to each dose of study medication. The mean hemoglobin level was determined at Baseline and for assessment visits by averaging the observed hemoglobin level among all participants providing evaluable blood samples. Change was calculated as [mean hemoglobin at Week 32 minus mean hemoglobin at Week 16] and expressed in g/L. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    26 [10]
    Units: g/L
        arithmetic mean (standard deviation)
    -2 ± 8.3
    Notes
    [10] - Participants with evaluable data at the designated visit were included.
    No statistical analyses for this end point

    Secondary: Change in CRP From Week 16 to 32 Among Nonresponding Participants Treated With Rituximab

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    End point title
    Change in CRP From Week 16 to 32 Among Nonresponding Participants Treated With Rituximab
    End point description
    Blood samples for laboratory assessments, including CRP level, were collected prior to each dose of study medication. The mean CRP level was determined at Baseline and for assessment visits by averaging the observed CRP level among all participants providing evaluable blood samples. Change was calculated as [mean CRP at Week 32 minus mean CRP at Week 16] and expressed in mg/dL. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    25 [11]
    Units: mg/dL
        arithmetic mean (standard deviation)
    0.7 ± 1.7
    Notes
    [11] - Participants with evaluable data at the designated visit were included.
    No statistical analyses for this end point

    Secondary: Change in ESR From Week 16 to 32 Among Nonresponding Participants Treated With Rituximab

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    End point title
    Change in ESR From Week 16 to 32 Among Nonresponding Participants Treated With Rituximab
    End point description
    Blood samples for laboratory assessments, including ESR, were collected prior to each dose of study medication. The mean ESR was determined at Baseline and for assessment visits by averaging the observed ESR among all participants providing evaluable blood samples. Change was calculated as [mean ESR at Week 32 minus mean ESR at Week 16] and expressed in mm/h. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    26 [12]
    Units: mm/h
        arithmetic mean (standard deviation)
    11.5 ± 17.9
    Notes
    [12] - Participants with evaluable data at the designated visit were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemoglobin at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Change From Baseline in Hemoglobin at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    Blood samples for laboratory assessments, including hemoglobin level, were collected prior to each dose of study medication. The mean hemoglobin level was determined at Baseline and for assessment visits by averaging the observed hemoglobin level among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean hemoglobin at the assessment visit minus mean hemoglobin at Baseline] and expressed in g/L. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 20, 24, 28, and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    207 [13]
    Units: g/L
    arithmetic mean (standard deviation)
        Week 20 (n=207)
    5.5 ± 9
        Week 24 (n=198)
    6.6 ± 9.4
        Week 28 (n=197)
    6.9 ± 9.5
        Week 32 (n=197)
    8.3 ± 10.4
    Notes
    [13] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in CRP at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Change From Baseline in CRP at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    Blood samples for laboratory assessments, including CRP level, were collected prior to each dose of study medication. The mean CRP level was determined at Baseline and for assessment visits by averaging the observed CRP level among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean CRP at the assessment visit minus mean CRP at Baseline] and expressed in mg/dL. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 20, 24, 28, and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    200 [14]
    Units: mg/dL
    arithmetic mean (standard deviation)
        Week 20 (n=200)
    -1.3 ± 1.9
        Week 24 (n=191)
    -1.4 ± 1.9
        Week 28 (n=195)
    -1.3 ± 1.9
        Week 32 (n=192)
    -1.3 ± 1.9
    Notes
    [14] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in ESR at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Change From Baseline in ESR at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    Blood samples for laboratory assessments, including ESR, were collected prior to each dose of study medication. The mean ESR was determined at Baseline and for assessment visits by averaging the observed ESR among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean ESR at the assessment visit minus mean ESR at Baseline] and expressed in mm/h. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 20, 24, 28, and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    206 [15]
    Units: mm/h
    arithmetic mean (standard deviation)
        Week 20 (n=206)
    -28.6 ± 17.6
        Week 24 (n=197)
    -29.4 ± 18
        Week 28 (n=200)
    -29.4 ± 18.1
        Week 32 (n=196)
    -28.6 ± 20.2
    Notes
    [15] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Withdrawing From the Study for Insufficient Therapeutic Response

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    End point title
    Percentage of Participants Withdrawing From the Study for Insufficient Therapeutic Response
    End point description
    Study discontinuation was documented by reason for each participant prematurely withdrawing from the study. The percentage of participants was calculated as the number withdrawing for insufficient therapeutic response divided by the total number of participants who began treatment. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    485 [16]
    Units: percentage of participants
        number (confidence interval 95%)
    0.2 (0 to 1.1)
    Notes
    [16] - Participants who withdrew from the study for other reasons were excluded from the analysis.
    No statistical analyses for this end point

    Secondary: Percentage of B-Cells at Baseline by B-Cell Subpopulation Among Participants With Early Remission

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    End point title
    Percentage of B-Cells at Baseline by B-Cell Subpopulation Among Participants With Early Remission
    End point description
    Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional (cluster of differentiation [CD] 19-positive, immunoglobulin (Ig) D-positive, CD38 medium, CD10-positive); naive (CD19-positive, IgD-positive, CD38 medium, CD27-negative); preswitch memory (CD19-positive, CD27-positive, IgD-positive); post-switch memory (CD19-positive, CD27-positive, IgD-negative); IgG-positive class-switched (CD19-positive, IgG-positive); IgA-positive class-switched (CD19-positive, IgA-positive); double-negative memory (CD19-positive, IgD-negative, CD27-negative); and plasmablasts (CD19-positive, IgD-negative, CD38 high, CD27 high). Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. ITT1 Population: Those who received at least one dose of TCZ in the first treatment period and completed at Week 16 reaching remission.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    196 [17]
    Units: percentage of B-cells
    median (full range (min-max))
        Naive B-cell compartment (n=196)
    61.1 (5.3 to 102.9)
        Transitional B-cells (n=196)
    1.4 (0.1 to 18.8)
        Naive B-cells (n=196)
    58.1 (3.4 to 94.2)
        Memory including double-negative (n=46)
    56.4 (20.2 to 103.5)
        Memory excluding double-negative (n=194)
    46.5 (5.6 to 125.8)
        Pre-switch memory B-cells (n=196)
    11.1 (1.3 to 73.6)
        Post-switch memory B-cells (n=196)
    16.4 (0.8 to 58.1)
        IgG-positive class-switched B-cells (n=195)
    9.9 (0.3 to 42)
        IgA-positive class-switched B-cells (n=194)
    7.4 (0.7 to 35.6)
        Double-negative B-cells (n=46)
    6.1 (2.5 to 16.3)
        Plasmablasts (n=196)
    0.3 (0 to 19.9)
    Notes
    [17] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Spearman's Rank Correlation Coefficient Between Percentage of B-Cells at Baseline and Difference in DAS28 Scores Between Baseline and Week 16 Among Participants With Early Remission

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    End point title
    Spearman's Rank Correlation Coefficient Between Percentage of B-Cells at Baseline and Difference in DAS28 Scores Between Baseline and Week 16 Among Participants With Early Remission
    End point description
    Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional, naïve, pre-switch memory, post-switch memory, IgG-positive class-switched, IgA-positive class-switched, double-negative memory, and plasmablasts. Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. Extent of disease response, using change from Baseline to Week 16 in DAS28 score, was correlated to the percentage of B-cells within each subpopulation at Baseline. Correlation is indicated by a correlation coefficient (r) >0.2, with greater values indicating a stronger correlation. ITT1 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    217 [18]
    Units: coefficient
    number (not applicable)
        Naive B-cell compartment (n=192)
    -0.02258
        Transitional B-cells (n=192)
    -0.00949
        Naive B-cells (n=192)
    -0.0192
        Memory B-cells (n=62)
    -0.03148
        Pre-switch memory B-cells (n=192)
    0.03221
        Post-switch memory B-cells (n=192)
    0.05419
        IgG-positive class-switched B-cells (n=192)
    0.08864
        IgA-positive class-switched B-cells (n=192)
    0.01041
        Double-negative B-cells (n=62)
    -0.02134
        Plasmablasts (n=192)
    0.00397
    Notes
    [18] - n = number of data pairs included in the analysis.
    No statistical analyses for this end point

    Secondary: Spearman's Rank Correlation Coefficient Between Percentage of B-Cells at Baseline and Difference in DAS28 Scores Between Baseline and Weeks 16, 24, and 32 Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Spearman's Rank Correlation Coefficient Between Percentage of B-Cells at Baseline and Difference in DAS28 Scores Between Baseline and Weeks 16, 24, and 32 Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional, naïve, pre-switch memory, post-switch memory, IgG-positive class-switched, IgA-positive class-switched, double-negative memory, and plasmablasts. Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. Extent of disease response, using change from Baseline in DAS28 score, was correlated to the percentage of B-cells within each subpopulation at Baseline. Correlation is indicated by a correlation coefficient (r) >0.2, with greater values indicating a stronger correlation. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 16, 24, and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    213 [19]
    Units: coefficient
    number (not applicable)
        Week 16, Naive B-cell compartment (n=199)
    0.00007
        Week 16, Transitional B-cells (n=199)
    -0.06529
        Week 16, Naive B-cells (n=199)
    0.02334
        Week 16, Memory B-cells (n=75)
    -0.03478
        Week 16, Pre-switch memory B-cells (n=199)
    -0.01889
        Week 16, Post-switch memory B-cells (n=199)
    -0.04161
        Week 16, IgG-positive class-switched (n=199)
    -0.06235
        Week 16, IgA-positive class-switched (n=199)
    -0.06492
        Week 16, Double-negative B-cells (n=75)
    -0.04352
        Week 16, Plasmablasts (n=199)
    -0.13161
        Week 24, Naive B-cell compartment (n=162)
    -0.18469
        Week 24, Transitional B-cells (n=162)
    -0.21966
        Week 24, Naive B-cells (n=162)
    -0.15683
        Week 24, Memory B-cells (n=76)
    0.15135
        Week 24, Pre-switch memory B-cells (n=162)
    0.08074
        Week 24, Post-switch memory B-cells (n=162)
    0.10798
        Week 24, IgG-positive class-switched (n=161)
    0.10752
        Week 24, IgA-positive class-switched (n=162)
    0.11023
        Week 24, Double-negative B-cells (n=76)
    0.05609
        Week 24, Plasmablasts (n=162)
    0.07468
        Week 32, Naive B-cell compartment (n=179)
    -0.12635
        Week 32, Transitional B-cells (n=179)
    -0.09234
        Week 32, Naive B-cells (n=179)
    -0.11114
        Week 32, Memory B-cells (n=88)
    0.05361
        Week 32, Pre-switch memory B-cells (n=179)
    0.12265
        Week 32, Post-switch memory B-cells (n=179)
    0.05867
        Week 32, IgG-positive class-switched (n=181)
    0.06381
        Week 32, IgA-positive class-switched (n=181)
    0.06036
        Week 32, Double-negative B-cells (n=90)
    -0.0631
        Week 32, Plasmablasts (n=179)
    0.02205
    Notes
    [19] - n = number of data pairs included in the analysis.
    No statistical analyses for this end point

    Secondary: Spearman's Rank Correlation Coefficient Between Percentage of B-Cells at Baseline and Difference in DAS28 Scores Between Baseline and Weeks 16, 32, 40, 48, and 66 Among Nonresponding Participants Treated With Rituximab

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    End point title
    Spearman's Rank Correlation Coefficient Between Percentage of B-Cells at Baseline and Difference in DAS28 Scores Between Baseline and Weeks 16, 32, 40, 48, and 66 Among Nonresponding Participants Treated With Rituximab
    End point description
    Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional, naïve, pre-switch memory, post-switch memory, IgG-positive class-switched, IgA-positive class-switched, double-negative memory, and plasmablasts. Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. Extent of disease response, using change from Baseline in DAS28 score, was correlated to the percentage of B-cells within each subpopulation at Baseline. Correlation is indicated by a correlation coefficient (r) >0.2, with greater values indicating a stronger correlation. ITT3 Population. (99999 = not estimable because participants in this population were followed for changes in DAS28 up to Week 16 compared to Baseline, and for changes up to Week 66 compared to Week 16; 9999 = not estimable for 0 pairs; 999 = not estimable for 1 pair.)
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 16, 32, 40, 48, and 66
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    27 [20]
    Units: coefficient
    number (not applicable)
        Week 16, Naive B-cell compartment (n=24)
    0.09611
        Week 16, Transitional B-cells (n=24)
    0.08571
        Week 16, Naive B-cells (n=24)
    0.0087
        Week 16, Memory B-cells (n=6)
    -0.6
        Week 16, Pre-switch memory B-cells (n=24)
    -0.15217
        Week 16, Post-switch memory B-cells (n=24)
    -0.04004
        Week 16, IgG-positive class-switched (n=24)
    -0.07528
        Week 16, IgA-positive class-switched (n=24)
    0.27049
        Week 16, Double-negative B-cells (n=6)
    -0.14286
        Week 16, Plasmablasts (n=24)
    0.13232
        Week 32, Naive B-cell compartment (n=0)
    99999
        Week 32, Transitional B-cells (n=0)
    99999
        Week 32, Naive B-cells (n=0)
    99999
        Week 32, Memory B-cells (n=0)
    99999
        Week 32, Pre-switch memory B-cells (n=0)
    99999
        Week 32, Post-switch memory B-cells (n=0)
    99999
        Week 32, IgG-positive class-switched (n=0)
    99999
        Week 32, IgA-positive class-switched (n=0)
    99999
        Week 32, Double-negative B-cells (n=0)
    99999
        Week 32, Plasmablasts (n=0)
    99999
        Week 40, Naive B-cell compartment (n=2)
    1
        Week 40, Transitional B-cells (n=2)
    -1
        Week 40, Naive B-cells (n=2)
    1
        Week 40, Memory B-cells (n=0)
    9999
        Week 40, Pre-switch memory B-cells (n=2)
    1
        Week 40, Post-switch memory B-cells (n=2)
    1
        Week 40, IgG-positive class-switched (n=2)
    1
        Week 40, IgA-positive class-switched (n=2)
    1
        Week 40, Double-negative B-cells (n=0)
    9999
        Week 40, Plasmablasts (n=2)
    1
        Week 48, Naive B-cell compartment (n=5)
    0.3
        Week 48, Transitional B-cells (n=5)
    -0.6
        Week 48, Naive B-cells (n=5)
    0.3
        Week 48, Memory B-cells (n=1)
    999
        Week 48, Pre-switch memory B-cells (n=5)
    0.6
        Week 48, Post-switch memory B-cells (n=5)
    0.2
        Week 48, IgG-positive class-switched (n=5)
    0.2
        Week 48, IgA-positive class-switched (n=5)
    0.5
        Week 48, Double-negative B-cells (n=1)
    999
        Week 48, Plasmablasts (n=5)
    0.1
        Week 66, Naive B-cell compartment (n=10)
    0.12727
        Week 66, Transitional B-cells (n=10)
    -0.0303
        Week 66, Naive B-cells (n=10)
    0.04242
        Week 66, Memory B-cells (n=3)
    1
        Week 66, Pre-switch memory B-cells (n=10)
    -0.0303
        Week 66, Post-switch memory B-cells (n=10)
    0.16364
        Week 66, IgG-positive class-switched (n=10)
    0.07295
        Week 66, IgA-positive class-switched (n=10)
    0.12805
        Week 66, Double-negative B-cells (n=3)
    1
        Week 66, Plasmablasts (n=10)
    0.30909
    Notes
    [20] - n = number of data pairs included in the analysis.
    No statistical analyses for this end point

    Secondary: Mean Number of Work Days Missed Per Week

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    End point title
    Mean Number of Work Days Missed Per Week
    End point description
    Work days missed were documented by reason (either RA or other reasons) for each participant over the preceding 7-day period. The mean number of work days missed was calculated by averaging the number of days missed per week among all participants. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    241 [21]
    Units: days
    arithmetic mean (standard deviation)
        Due to RA, Baseline (n=241)
    1.03 ± 2.3
        Due to RA, Week 16 (n=221)
    0.39 ± 1.51
        Due to other reasons, Baseline (n=233)
    0.14 ± 0.87
        Due to other reasons, Week 16 (n=222)
    0.32 ± 1.26
    Notes
    [21] - Employed participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Quality of Life as Assessed Using Short Form 36 (SF-36)

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    End point title
    Quality of Life as Assessed Using Short Form 36 (SF-36)
    End point description
    The SF-36 evaluates participant-rated quality of life using 8 domains: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for each section is the average of the individual question scores, which are scaled from 0 to 100, with higher scores indicating better functioning. The mean score at each timepoint was determined by averaging the scores among all participants. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    513 [22]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical functioning, Baseline (n=511)
    49.6 ± 23.7
        Physical functioning, Week 16 (n=473)
    64.1 ± 25.5
        Role (physical), Baseline (n=508)
    12.9 ± 18.1
        Role (physical), Week 16 (n=472)
    29.9 ± 21.4
        Bodily pain, Baseline (n=512)
    31.3 ± 18.2
        Bodily pain, Week 16 (n=474)
    55.3 ± 17.8
        General health, Baseline (n=504)
    43.6 ± 16.7
        General health, Week 16 (n=468)
    54.3 ± 18.3
        Vitality, Baseline (n=512)
    44 ± 19.7
        Vitality, Week 16 (n=474)
    58.1 ± 20.4
        Social functioning, Baseline (n=507)
    68.1 ± 24.8
        Social functioning, Week 16 (n=464)
    80.1 ± 21.6
        Role (emotional), Baseline (n=505)
    55.9 ± 45
        Role (emotional), Week 16 (n=472)
    70.9 ± 42.1
        Mental health, Baseline (n=513)
    63.5 ± 18.7
        Mental health, Week 16 (n=474)
    72.3 ± 17.9
    Notes
    [22] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Quality of Life as Assessed Using SF-36 at Week 16

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    End point title
    Change From Baseline in Quality of Life as Assessed Using SF-36 at Week 16
    End point description
    The SF-36 evaluates participant-rated quality of life using 8 domains: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for each section is the average of the individual question scores, which are scaled from 0 to 100, with higher scores indicating better functioning. The mean score at each timepoint was determined by averaging the scores among all participants, and the change in each domain score was calculated as [mean score at Week 16 minus mean score at Baseline]. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    470 [23]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical functioning (n=466)
    14.3 ± 21.8
        Role (physical) (n=461)
    17 ± 22
        Bodily pain (n=470)
    23.9 ± 21.1
        General health (n=454)
    10.4 ± 18.5
        Vitality (n=468)
    13.9 ± 19.3
        Social functioning (n=456)
    12 ± 23.8
        Role (emotional) (n=459)
    14.7 ± 46.1
        Mental health (n=468)
    8.7 ± 16.8
    Notes
    [23] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Week 16 to 32 in Quality of Life as Assessed Using SF-36 Scores Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Change From Week 16 to 32 in Quality of Life as Assessed Using SF-36 Scores Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    The SF-36 evaluates participant-rated quality of life using 8 domains: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for each section is the average of the individual question scores, which are scaled from 0 to 100, with higher scores indicating better functioning. The mean score at each timepoint was determined by averaging the scores among all participants, and the change in each domain score was calculated as [mean score at Week 32 minus mean score at Week 16]. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    188 [24]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical functioning (n=188)
    3.6 ± 16.6
        Role (physical) (n=187)
    2 ± 20.6
        Bodily pain (n=188)
    3.2 ± 16.5
        General health (n=184)
    2.6 ± 14.3
        Vitality (n=186)
    2.7 ± 14.2
        Social functioning (n=184)
    -0.3 ± 19.6
        Role (emotional) (n=184)
    5.5 ± 42.3
        Mental health (n=186)
    0.7 ± 15.3
    Notes
    [24] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Quality of Life as Assessed Using HAQ-DI

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    End point title
    Quality of Life as Assessed Using HAQ-DI
    End point description
    The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. The mean index score at each timepoint was determined by averaging the scores among all participants. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    513 [25]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=513)
    1.24 ± 0.67
        Week 16 (n=472)
    0.75 ± 0.67
    Notes
    [25] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Quality of Life as Assessed Using HAQ-DI at Week 16

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    End point title
    Change From Baseline in Quality of Life as Assessed Using HAQ-DI at Week 16
    End point description
    The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. The mean index score at each timepoint was determined by averaging the scores among all participants, and the change in score was calculated as [mean score at Week 16 minus mean score at Baseline]. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    466 [26]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.48 ± 0.58
    Notes
    [26] - Participants with evaluable data at the designated visit were included.
    No statistical analyses for this end point

    Secondary: Change From Week 16 to 32 in Quality of Life as Assessed Using HAQ-DI Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Change From Week 16 to 32 in Quality of Life as Assessed Using HAQ-DI Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. The mean index score at each timepoint was determined by averaging the scores among all participants, and the change in score was calculated as [mean score at Week 32 minus the mean score at Week 16]. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    187 [27]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.06 ± 0.34
    Notes
    [27] - Participants with evaluable data at the designated visit were included.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Response According to HAQ-DI Criteria

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    End point title
    Percentage of Participants Achieving a Response According to HAQ-DI Criteria
    End point description
    The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Response was defined as a change in index score >0.22 from Baseline to Week 16. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    519
    Units: percentage of participants
        number (not applicable)
    61.1
    No statistical analyses for this end point

    Secondary: Quality of Life as Assessed Using Functional Assessment of Chronic Illness Therapy (FACIT)

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    End point title
    Quality of Life as Assessed Using Functional Assessment of Chronic Illness Therapy (FACIT)
    End point description
    The FACIT-F evaluates quality of life using 5 categories: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and fatigue (FS). Participants answer each item on a 5-point scale from 0 to 4. The total score is the sum of individual responses across all 5 categories and may range from 0 to 160. The FACIT-General (FACIT-G; range 0 to 108) is the sum of scores for PWB, SWB, EWB, and FWB; the FACIT-Fatigue (FACIT-F) trial outcome index (TOI; range 0 to 108) is the sum of scores for PWB, FWB, and FS; and the FACIT-F fatigue (range 0 to 52) is the sum of scores for the FS only. For derivations of the FACIT-F reported here, higher scores indicate better quality of life. The mean score at each timepoint was determined by averaging scores among all participants. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    510 [28]
    Units: units on a scale
    arithmetic mean (standard deviation)
        FACIT-F TOI, Baseline (n=498)
    66.2 ± 20.6
        FACIT-F TOI, Week 16 (n=460)
    80.8 ± 19.3
        FACIT-G total, Baseline (n=498)
    71.1 ± 15.7
        FACIT-G total, Week 16 (n=462)
    82.6 ± 15.9
        FACIT-F total, Baseline (n=494)
    103.8 ± 25.5
        FACIT-F total, Week 16 (n=458)
    121.9 ± 25.3
        FACIT-F fatigue, Baseline (n=510)
    32.7 ± 11.6
        FACIT-F fatigue, Week 16 (n=475)
    39.2 ± 10.6
    Notes
    [28] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Quality of Life as Assessed Using FACIT at Week 16

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    End point title
    Change From Baseline in Quality of Life as Assessed Using FACIT at Week 16
    End point description
    The FACIT-F evaluates quality of life using 5 categories: PWB, SWB, EWB, FWB, and FS. Participants answer each item on a 5-point scale from 0 to 4. The total score is the sum of individual responses across all 5 categories and may range from 0 to 160. The FACIT-G (range 0 to 108) is the sum of scores for PWB, SWB, EWB, and FWB; the FACIT-F TOI (range 0 to 108) is the sum of scores for PWB, FWB, and FS; and the FACIT-F fatigue (range 0 to 52) is the sum of scores for the FS only. For derivations of the FACIT-F reported here, higher scores indicate better quality of life. The mean score at each timepoint was determined by averaging scores among all participants, and the change in score was calculated as [mean score at Week 16 minus mean score at Baseline]. Main ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    467 [29]
    Units: units on a scale
    arithmetic mean (standard deviation)
        FACIT-F TOI (n=445)
    14.2 ± 17.9
        FACIT-G total (n=445)
    10.8 ± 13.6
        FACIT-F total (n=439)
    17.5 ± 21.8
        FACIT-F fatigue (n=467)
    6.6 ± 9.9
    Notes
    [29] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Week 16 to 32 in Quality of Life as Assessed Using FACIT Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Change From Week 16 to 32 in Quality of Life as Assessed Using FACIT Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    The FACIT-F evaluates quality of life using 5 categories: PWB, SWB, EWB, FWB, and FS. Participants answer each item on a 5-point scale from 0 to 4. The total score is the sum of individual responses across all 5 categories and may range from 0 to 160. The FACIT-G (range 0 to 108) is the sum of scores for PWB, SWB, EWB, and FWB; the FACIT-F TOI (range 0 to 108) is the sum of scores for PWB, FWB, and FS; and the FACIT-F fatigue (range 0 to 52) is the sum of scores for the FS only. For derivations of the FACIT-F reported here, higher scores indicate better quality of life. The mean score at each timepoint was determined by averaging scores among all participants, and the change in score was calculated as [mean score at Week 32 minus mean score at Week 16]. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    186 [30]
    Units: units on a scale
    arithmetic mean (standard deviation)
        FACIT-F TOI (n=172)
    1.7 ± 12.9
        FACIT-G total (n=174)
    1.1 ± 9.2
        FACIT-F total (n=170)
    2 ± 15.1
        FACIT-F fatigue (n=186)
    0.8 ± 7.4
    Notes
    [30] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Remission According to DAS28 at Week 32 Among Nonresponding Participants Treated With Rituximab

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    End point title
    Percentage of Participants Achieving Remission According to DAS28 at Week 32 Among Nonresponding Participants Treated With Rituximab
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Week 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    27
    Units: percentage of participants
        number (confidence interval 95%)
    14.8 (4.2 to 33.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving LDAS According to DAS28 Among Nonresponding Participants Treated With Rituximab

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    End point title
    Percentage of Participants Achieving LDAS According to DAS28 Among Nonresponding Participants Treated With Rituximab
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x the patient global assessment of disease activity using a VAS]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. LDAS was defined as a DAS28 score <3.2 at the assessment visit. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Week 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    27
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (16.5 to 54)
    No statistical analyses for this end point

    Secondary: DAS28 Scores During and After Treatment Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    DAS28 Scores During and After Treatment Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    213 [31]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=213)
    6 ± 0.9
        Week 4 (n=213)
    4 ± 1.2
        Week 8 (n=205)
    3.4 ± 1.2
        Week 12 (n=207)
    3.3 ± 1.1
        Week 16 (n=213)
    3.3 ± 0.6
        Week 20 (n=206)
    2.8 ± 1
        Week 24 (n=197)
    2.6 ± 1.1
        Week 28 (n=200)
    2.4 ± 1.1
        Week 32 (n=193)
    2.5 ± 1.2
    Notes
    [31] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: DAS28 Scores During and After Treatment Among Nonresponding Participants Treated With Rituximab

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    End point title
    DAS28 Scores During and After Treatment Among Nonresponding Participants Treated With Rituximab
    End point description
    The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, 16, 24, and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    27 [32]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=27)
    5.7 ± 1
        Week 4 (n=27)
    4.5 ± 1.2
        Week 8 (n=26)
    4.2 ± 1.5
        Week 12 (n=27)
    4.8 ± 1.6
        Week 16 (n=27)
    5.1 ± 1.2
        Week 24 (n=26)
    4.6 ± 1.4
        Week 32 (n=26)
    4 ± 1.5
    Notes
    [32] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Percentage of B-Cells at Baseline by B-Cell Subpopulation Among Participants Treated With 8 Courses of Tocilizumab

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    End point title
    Percentage of B-Cells at Baseline by B-Cell Subpopulation Among Participants Treated With 8 Courses of Tocilizumab
    End point description
    Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional (cluster of differentiation [CD] 19-positive, immunoglobulin (Ig) D-positive, CD38 medium, CD10-positive); naive (CD19-positive, IgD-positive, CD38 medium, CD27-negative); pre-switch memory (CD19-positive, CD27-positive, IgD-positive); post-switch memory (CD19-positive, CD27-positive, IgD-negative); IgG-positive class-switched (CD19-positive, IgG-positive); IgA-positive class-switched (CD19-positive, IgA-positive); double-negative memory (CD19-positive, IgD-negative, CD27-negative); and plasmablasts (CD19-positive, IgD-negative, CD38 high, CD27 high). Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. ITT2 Population.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    197 [33]
    Units: percentage of B-cells
    median (full range (min-max))
        Naive B-cell compartment (n=197)
    57.1 (5.6 to 91.2)
        Transitional B-cells (n=197)
    1.3 (0 to 13.4)
        Naive B-cells (n=197)
    55.5 (4.7 to 87.1)
        Memory including double-negative (n=57)
    63.2 (18.8 to 113.7)
        Memory excluding double-negative (n=196)
    49.7 (10.9 to 120.1)
        Pre-switch memory B-cells (n=197)
    11.6 (0.9 to 74.1)
        Post-switch memory B-cells (n=197)
    17.2 (2.8 to 52.7)
        IgG-positive class-switched B-cells (n=196)
    10 (0.2 to 38.4)
        IgA-positive class-switched B-cells (n=196)
    8 (1.4 to 34.4)
        Double-negative B-cells (n=57)
    6.6 (1.2 to 19.1)
        Plasmablasts (n=197)
    0.3 (0 to 7.6)
    Notes
    [33] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Percentage of B-Cells at Baseline by B-Cell Subpopulation Among Nonresponding Participants Treated With Rituximab

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    End point title
    Percentage of B-Cells at Baseline by B-Cell Subpopulation Among Nonresponding Participants Treated With Rituximab
    End point description
    Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional (cluster of differentiation [CD] 19-positive, immunoglobulin (Ig) D-positive, CD38 medium, CD10-positive); naive (CD19-positive, IgD-positive, CD38 medium, CD27-negative); pre-switch memory (CD19-positive, CD27-positive, IgD-positive); post-switch memory (CD19-positive, CD27-positive, IgD-negative); IgG-positive class-switched (CD19-positive, IgG-positive); IgA-positive class-switched (CD19-positive, IgA-positive); double-negative memory (CD19-positive, IgD-negative, CD27-negative); and plasmablasts (CD19-positive, IgD-negative, CD38 high, CD27 high). Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    25 [34]
    Units: percentage of B-cells
    median (full range (min-max))
        Naive B-cell compartment (n=25)
    65.9 (9.8 to 85)
        Transitional B-cells (n=25)
    1.6 (0.2 to 7)
        Naive B-cells (n=25)
    61.9 (5.8 to 83.4)
        Memory including double-negative (n=4)
    45.1 (37.1 to 86.7)
        Memory excluding double-negative (n=25)
    41.5 (21.6 to 139.6)
        Pre-switch memory B-cells (n=25)
    9.1 (2.4 to 36.2)
        Post-switch memory B-cells (n=25)
    16.1 (6.9 to 64.1)
        IgG-positive class-switched B-cells (n=25)
    8.7 (5 to 32.7)
        IgA-positive class-switched B-cells (n=25)
    7.7 (3.4 to 29.3)
        Double-negative B-cells (n=4)
    7.5 (5.9 to 9.1)
        Plasmablasts (n=25)
    0.3 (0 to 3.2)
    Notes
    [34] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Week 16 to 32 in Quality of Life as Assessed Using SF-36 Scores Among Nonresponding Participants Treated With Rituximab

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    End point title
    Change From Week 16 to 32 in Quality of Life as Assessed Using SF-36 Scores Among Nonresponding Participants Treated With Rituximab
    End point description
    The SF-36 evaluates participant-rated quality of life using 8 domains: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for each section is the average of the individual question scores, which are scaled from 0 to 100, with higher scores indicating better functioning. The mean score at each timepoint was determined by averaging the scores among all participants, and the change in each domain score was calculated as [mean score at Week 32 minus mean score at Week 16]. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    26 [35]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical functioning (n=26)
    2.5 ± 20
        Role (physical) (n=24)
    -1 ± 21.5
        Bodily pain (n=26)
    10.6 ± 20.8
        General health (n=24)
    5.2 ± 18.1
        Vitality (n=26)
    1 ± 9.3
        Social functioning (n=24)
    -3.1 ± 17.4
        Role (emotional) (n=24)
    2.8 ± 35.3
        Mental health (n=26)
    3.4 ± 10.7
    Notes
    [35] - Participants with evaluable data at the designated visit (number shown = n) were included.
    No statistical analyses for this end point

    Secondary: Change From Week 16 to 32 in Quality of Life as Assessed Using HAQ-DI Among Nonresponding Participants Treated With Rituximab

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    End point title
    Change From Week 16 to 32 in Quality of Life as Assessed Using HAQ-DI Among Nonresponding Participants Treated With Rituximab
    End point description
    The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. The mean index score at each timepoint was determined by averaging the scores among all participants, and the change in score was calculated as [mean score at Week 32 minus the mean score at Week 16]. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    26 [36]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.1 ± 0.39
    Notes
    [36] - Participants with evaluable data at the designated visit were included.
    No statistical analyses for this end point

    Secondary: Change From Week 16 to 32 in Quality of Life as Assessed Using FACIT Among Nonresponding Participants Treated With Rituximab

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    End point title
    Change From Week 16 to 32 in Quality of Life as Assessed Using FACIT Among Nonresponding Participants Treated With Rituximab
    End point description
    The FACIT-F evaluates quality of life using 5 categories: PWB, SWB, EWB, FWB, and FS. Participants answer each item on a 5-point scale from 0 to 4. The total score is the sum of individual responses across all 5 categories and may range from 0 to 160. The FACIT-G (range 0 to 108) is the sum of scores for PWB, SWB, EWB, and FWB; the FACIT-F TOI (range 0 to 108) is the sum of scores for PWB, FWB, and FS; and the FACIT-F fatigue (range 0 to 52) is the sum of scores for the FS only. For derivations of the FACIT-F reported here, higher scores indicate better quality of life. The mean score at each timepoint was determined by averaging scores among all participants, and the change in score was calculated as [mean score at Week 32 minus mean score at Week 16]. ITT3 Population.
    End point type
    Secondary
    End point timeframe
    Weeks 16 and 32
    End point values
    TCZ/TCZ or TCZ/RTX
    Number of subjects analysed
    26 [37]
    Units: units on a scale
    arithmetic mean (standard deviation)
        FACIT-F TOI
    2.9 ± 9.8
        FACIT-G total
    3 ± 8.3
        FACIT-F total
    4.4 ± 12.5
        FACIT-F fatigue
    1.4 ± 5.8
    Notes
    [37] - Participants with evaluable data at the designated visit were included.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 66 weeks
    Adverse event reporting additional description
    Adverse events (AEs) were assessed at each treatment visit from Baseline to Week 16, at which point participants having achieved early remission completed the study. Those who did not achieve early remission continued to receive treatment, and AEs were assessed until 4 weeks after last dose (TCZ/TCZ) or until Week 66 (TCZ/RTX).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    TCZ/TCZ or TCZ/RTX
    Reporting group description
    All participants were assigned to receive TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Clinical response was assessed at Week 16 using DAS28 to determine subsequent treatment assignment. Participants who achieved early remission, defined as a DAS28 score of <2.6, were transferred to clinical routine care and no longer received study medication. Participants who were considered partial responders, defined as a decrease from Baseline in DAS28 score >1.2 or a score between 2.6 and 3.2, inclusive, received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 additional infusions from Week 16 to 28. Those with assessed as having no response, defined as a decrease from Baseline in DAS28 score ≤1.2 or a score >3.2, received RTX 1000 mg via IV infusion at Weeks 16 and 18.

    Serious adverse events
    TCZ/TCZ or TCZ/RTX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 519 (10.40%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 519 (0.39%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Fall
         subjects affected / exposed
    2 / 519 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Contusion
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fibrin D dimer increased
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Allergic cough
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperventilation
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial haematoma
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 519 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    3 / 519 (0.58%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 519 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Joint destruction
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sacroiliitis
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 519 (0.58%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 519 (0.39%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 519 (0.39%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 519 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    TCZ/TCZ or TCZ/RTX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    104 / 519 (20.04%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    30 / 519 (5.78%)
         occurrences all number
    32
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    77 / 519 (14.84%)
         occurrences all number
    91

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Feb 2012
    The protocol was amended to clarify inclusion and exclusion criteria, and to allow the enrollment of participants receiving methotrexate and leflunomide up to 4 weeks prior to Baseline. Safety follow-up was also planned for participants who withdrew from the study early. Definitions and procedures for TCZ-related hypersensitivity were implemented, and the reporting requirements for AEs were also modified.

    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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