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    Clinical Trial Results:
    A randomised, double-blind, parallel-group study of safety and the effect on clinical outcome of tocilizumab subcutaneous (SC) versus placebo SC in combination with traditional disease modifying anti-rheumatic drugs (DMARDs), in patients with moderate to severe active rheumatoid arthritis.

    Summary
    EudraCT number
    		 2010-019912-18
    Trial protocol
    		 ES   GR   HU   BG  
    Global end of trial date
    27 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2016
    First version publication date
    08 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NA25220
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01232569
    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
    27 Nov 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 May 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This randomised, parallel-group, placebo-controlled, multicenter study will evaluate the reduction in disease activity and the safety of tocilizumab (RoActemra/Actemra) in combination with traditional disease-modifying anti-rheumatic drugs (DMARDs) in patients with active, moderate to severe rheumatoid arthritis. In the double-blind part of the study, patients will be randomised to receive either 162 mg tocilizumab or placebo subcutaneously every 2 weeks for 24 weeks using a pre-filled syringe. In the open-label part of the study, patients who reach Week 24 on their randomised treatment will be rerandomised to receive 162 mg tocilizumab subcutaneously every 2 weeks from Week 24 to Week 96 using a pre-filled syringe or an auto-injector. Patients with inadequate efficacy had the option to escape to treatment with tocilizumab 162 mg subcutaneously once weekly. The analysis of the endpoints occurred at Week 24. No analyses were planned at Week 96, so none are presented.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 99
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Bulgaria: 27
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Argentina: 29
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Brazil: 98
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Colombia: 17
    Country: Number of subjects enrolled
    Guatemala: 9
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Malaysia: 7
    Country: Number of subjects enrolled
    Mexico: 106
    Country: Number of subjects enrolled
    Panama: 6
    Country: Number of subjects enrolled
    Philippines: 11
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    South Africa: 11
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    United States: 114
    Worldwide total number of subjects
    656
    EEA total number of subjects
    149
    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)
    575
    From 65 to 84 years
    81
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of the 656 patients randomised into the study (437 to the tocilizumab arm and 219 to the placebo arm), 438 patients received tocilizumab as their first dose and 218 received placebo as their first dose because of a dose administration error with 1 patient.

    Pre-assignment
    Screening details
    		 The target population for this study was patients with moderate to severe rheumatoid arthritis who were inadequate responders to disease-modifying anti-rheumatic drugs that may include one or more anti−tumor necrosis factor-α agents.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tocilizumab 162 mg sc
    Arm description
    		 Patients received tocilizumab 162 mg subcutaneously (sc) every 2 weeks for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab was supplied in a ready-to-use, single-use, pre-filled syringe. Patients and/or caregivers were trained to administer the injection.

    Arm title
    		 Placebo sc
    Arm description
    		 Patients received placebo sc every 2 weeks for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was supplied in a ready-to-use, single-use, pre-filled syringe. Patients and/or caregivers were trained to administer the injection.

    Number of subjects in period 1
    		Tocilizumab 162 mg sc Placebo sc
    Started
    438
    218
    Completed
    410
    209
    Not completed
    28
    9
         Physician decision
    1
    -
         Death
    2
    -
         Withdrawal by Subject
    9
    2
         Escape
    2
    2
         Lost to follow-up
    4
    -
         Adverse Event (Except Anaphylaxis)
    9
    3
         Lack of efficacy
    1
    2
    Period 2
    Period 2 title
    Open-label extension
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tocilizumab pre-filled syringe
    Arm description
    		 Patients received tocilizumab 162 mg sc via a pre-filled syringe every 2 weeks for 72 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab was supplied in a ready-to-use, single-use, pre-filled syringe. Patients and/or caregivers were trained to administer the injection.

    Arm title
    		 Tocilizumab auto-injector
    Arm description
    		 Patients received tocilizumab 162 mg sc via auto-injector every 2 weeks for 72 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab was supplied in a ready-to-use, single-use, auto-injector. Patients and/or caregivers were trained to administer the injection.

    Number of subjects in period 2 [1]
    		Tocilizumab pre-filled syringe Tocilizumab auto-injector
    Started
    230
    227
    Completed
    203
    200
    Not completed
    27
    27
         Reason not specified
    27
    27
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some participants who completed the double-blind treatment period did not enter the open-label period. Only participants who reached week 24 on their randomised treatment were rerandomised into the open-label period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tocilizumab 162 mg sc
    Reporting group description
    		 Patients received tocilizumab 162 mg subcutaneously (sc) every 2 weeks for 24 weeks.

    Reporting group title
    Placebo sc
    Reporting group description
    		 Patients received placebo sc every 2 weeks for 24 weeks.

    Reporting group values
    		 Tocilizumab 162 mg sc Placebo sc Total
    Number of subjects
    		 438 218 656
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 383 192 575
        From 65-84 years
    		 55 26 81
    Age continuous
    Baseline Characteristics are reported for the safety population which included all patients who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. One patient who received tocilizumab had no post-baseline safety data and was excluded from the safety population.
    Units: years
        arithmetic mean (standard deviation)
    		 120 ( 60 ) 120 ( 60 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 0 0 0
        Not recorded
    		 438 218 656
    Subject analysis sets

    Subject analysis set title
    Tocilizumab 162 mg sc
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Baseline Characteristics are reported for the safety population which included all patients who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. One patient who received tocilizumab had no post-baseline safety data and was excluded from the safety population.

    Subject analysis set title
    Placebo sc
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Baseline Characteristics are reported for the safety population which included all patients who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. One patient who received tocilizumab had no post-baseline safety data and was excluded from the safety population.

    Subject analysis sets values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects
    437
    218
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
    Age continuous
    Baseline Characteristics are reported for the safety population which included all patients who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. One patient who received tocilizumab had no post-baseline safety data and was excluded from the safety population.
    Units: years
        arithmetic mean (standard deviation)
    52.1 ( 11.49 )
    52 ( 11.67 )
    Gender categorical
    Units: Subjects
        Female
    375
    180
        Male
    62
    38
        Not recorded
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Tocilizumab 162 mg sc
    Reporting group description
    		 Patients received tocilizumab 162 mg subcutaneously (sc) every 2 weeks for 24 weeks.

    Reporting group title
    Placebo sc
    Reporting group description
    		 Patients received placebo sc every 2 weeks for 24 weeks.
    Reporting group title
    Tocilizumab pre-filled syringe
    Reporting group description
    		 Patients received tocilizumab 162 mg sc via a pre-filled syringe every 2 weeks for 72 weeks.

    Reporting group title
    Tocilizumab auto-injector
    Reporting group description
    		 Patients received tocilizumab 162 mg sc via auto-injector every 2 weeks for 72 weeks.

    Subject analysis set title
    Tocilizumab 162 mg sc
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Baseline Characteristics are reported for the safety population which included all patients who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. One patient who received tocilizumab had no post-baseline safety data and was excluded from the safety population.

    Subject analysis set title
    Placebo sc
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Baseline Characteristics are reported for the safety population which included all patients who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. One patient who received tocilizumab had no post-baseline safety data and was excluded from the safety population.

    Primary: Percentage of patients with an American College of Rheumatology 20 (ACR20) response at Week 24

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    End point title
    		 Percentage of patients with an American College of Rheumatology 20 (ACR20) response at Week 24
    End point description
    A patient had an ACR20 response if there was at least a 20% improvement, ie, reduction from baseline, in tender and swollen joint counts (28 assessed joints) and in at least 3 of the following 5 parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, left end=no disease activity [symptom-free and no arthritis symptoms], right end=maximum disease activity; patient assessment of pain in previous 24 hours on a VAS (left end=no pain and right end=unbearable pain); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and acute-phase reactant (either C-reactive protein or erythrocyte sedimentation rate).
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    437
    219
    Units: Percentage of patients
        number (confidence interval 95%)
    60.9 (56.3 to 65.4)
    31.5 (25.4 to 37.7)
    Statistical analysis title
    		 Tocilizumab vs placebo
    Comparison groups
    Tocilizumab 162 mg sc v Placebo sc
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    29.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22
         upper limit
    		 37

    Secondary: Percentage of patients with ACR50 and ACR70 responses at Week 24

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    End point title
    		 Percentage of patients with ACR50 and ACR70 responses at Week 24
    End point description
    A patient had an ACR50 response if there was at least a 50% improvement in the ACR scores. A patient had an ACR70 response if there was at least a 70% improvement in the ACR scores.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    437
    219
    Units: Percentage of patients
    number (confidence interval 95%)
        ACR50
    39.8 (35.2 to 44.4)
    12.3 (8 to 16.7)
        ACR70
    19.7 (16 to 23.4)
    5 (2.1 to 7.9)
    No statistical analyses for this end point

    Secondary: Time to onset of ACR20, ACR50, and ACR70 responses

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    End point title
    		 Time to onset of ACR20, ACR50, and ACR70 responses
    End point description
    Time to first ACR response was calculated as the number of days between the date of the first ACR response minus the date of the first dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    437 [1]
    219 [2]
    Units: Days
    median (confidence interval 95%)
        ACR20
    57 (57 to 58)
    86 (85 to 113)
        ACR50
    115 (113 to 141)
    999 (999 to 999)
        ACR70
    174 (172 to 999)
    999 (999 to 999)
    Notes
    [1] - Only patients with available data were included in the analysis. 999.0 = NA due to too few events
    [2] - 999.0 = Not calculable due to too few events.
    No statistical analyses for this end point

    Secondary: Change from baseline in tender joint count (TJC) and swollen joint count (SJC) at Week 24

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    End point title
    		 Change from baseline in tender joint count (TJC) and swollen joint count (SJC) at Week 24
    End point description
    Joints (28 joints) will be assessed and classified as swollen/not swollen and tender/not tender by pressure and joint manipulation on physical examination.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    432 [3]
    219
    Units: Joint count
    arithmetic mean (standard deviation)
        Tender joint count
    -14.8 ( 15 )
    -8.1 ( 14.2 )
        Swollen joint count
    -9.6 ( 9.7 )
    -5.9 ( 10.2 )
    Notes
    [3] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in C-reactive protein at Week 24

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    End point title
    		 Change from baseline in C-reactive protein at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    345 [4]
    124 [5]
    Units: mg/dL
        arithmetic mean (standard deviation)
    -1.7 ( 2.6 )
    -0.1 ( 1.8 )
    Notes
    [4] - Only patients with available data were included in the analysis.
    [5] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in erythrocyte sedimentation rate at Week 24

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    End point title
    		 Change from baseline in erythrocyte sedimentation rate at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    347 [6]
    124 [7]
    Units: mm/hrmm/hr
        arithmetic mean (standard deviation)
    -36.4 ( 23.6 )
    -9.5 ( 22.7 )
    Notes
    [6] - Only patients with available data were included in the analysis.
    [7] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in the patient’s and the physician’s global assessment of disease activity visual analog score

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    End point title
    		 Change from baseline in the patient’s and the physician’s global assessment of disease activity visual analog score
    End point description
    Patients and physicians assessed the patient’s disease activity in the previous 24 hours on a 100 mm visual analog scale, where the extreme left end of the line represented “no disease activity” (symptom-free and no arthritis symptoms) and the extreme right end represented “maximum disease activity”. Scores ranged from 0 to 100 with a higher score indicating more disease activity. A negative change score indicated less disease activity.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    348 [8]
    124 [9]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Patient's Global Assessment VAS, N=346, 123
    -32 ( 27.6 )
    -20.9 ( 25.2 )
        Physician's Global Assessment VAS, N=348, 124
    -36.9 ( 22.5 )
    -30.7 ( 25.8 )
    Notes
    [8] - Only patients with available data were included in the analysis.
    [9] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in the patient’s pain visual analog score

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    End point title
    		 Change from baseline in the patient’s pain visual analog score
    End point description
    Patients assessed their pain in the previous 24 hours on a visual analog scale, where the extreme left end of the line represented “no pain” and the extreme right end represented “unbearable pain”. Scores ranged from 0 to 100 with a higher score indicating more pain. A negative change score indicated less pain.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    346 [10]
    123 [11]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -28.1 ( 27.2 )
    -15 ( 28.3 )
    Notes
    [10] - Only patients with available data were included in the analysis.
    [11] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24

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    End point title
    		 Change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24
    End point description
    The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Patients completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    348 [12]
    124 [13]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -0.5 ( 0.6 )
    -0.3 ( 0.6 )
    Notes
    [12] - Only patients with available data were included in the analysis.
    [13] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Percentage of patients with an improvement of ≥ 0.3 units from baseline in the HAQ-DI score at Week 24

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    End point title
    		 Percentage of patients with an improvement of ≥ 0.3 units from baseline in the HAQ-DI score at Week 24
    End point description
    The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Patients completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    348 [14]
    124 [15]
    Units: Percentage of patients
        number (confidence interval 95%)
    58 (52.9 to 63.2)
    46.8 (38 to 55.6)
    Notes
    [14] - Only patients with available data were included in the analysis.
    [15] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in Disease Activity Score 28 (DAS28) at Week 24

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    End point title
    		 Change from baseline in Disease Activity Score 28 (DAS28) at Week 24
    End point description
    The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient’s global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    344 [16]
    123 [17]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -3.3 ( 1.4 )
    -1.8 ( 1.3 )
    Notes
    [16] - Only patients with available data were included in the analysis.
    [17] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Percentage of patients with a DAS28 score ≤ 3.2 (DAS28 low disease activity) at Week 24

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    End point title
    		 Percentage of patients with a DAS28 score ≤ 3.2 (DAS28 low disease activity) at Week 24
    End point description
    The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient’s global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    347 [18]
    124 [19]
    Units: Percentage of patients
        number (confidence interval 95%)
    45.2 (40 to 50.5)
    15.3 (9 to 21.7)
    Notes
    [18] - Only patients with available data were included in the analysis.
    [19] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Percentage of patients with a DAS28 score < 2.6 (DAS28 remission) at Week 24

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    End point title
    		 Percentage of patients with a DAS28 score < 2.6 (DAS28 remission) at Week 24
    End point description
    The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient’s global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    347 [20]
    124 [21]
    Units: Percentage of patients
        number (confidence interval 95%)
    32 (27.1 to 36.9)
    4 (0.6 to 7.5)
    Notes
    [20] - Only patients with available data were included in the analysis.
    [21] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Percentage of patients with good, moderate, or no European League Against Rheumatism (EULAR) responses at Week 24

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    End point title
    		 Percentage of patients with good, moderate, or no European League Against Rheumatism (EULAR) responses at Week 24
    End point description
    Change of the Disease Activity Score 28 score from baseline was used to determine EULAR responses of good, moderate, or no response. For a post-baseline score ≤ 3.2, a change from baseline of < -1.2 was a good response, < -0.6 to ≥ -1.2 was a moderate response, and ≥ -0.6 was no response. For a post-baseline score > 3.2 to ≤ 5.1, a change from baseline of < -0.6 was a moderate response and ≥ -0.6 was no response. For a post-baseline score > 5.1, a change from baseline < -1.2 was a moderate response and ≥ -1.2 was no response. A good response could not be achieved for post-baseline scores > 3.2.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    374 [22]
    138 [23]
    Units: Percentage of patients
    number (not applicable)
        Good Response
    41.7
    13.8
        Moderate Response
    44.9
    54.3
        No Response
    13.4
    31.9
    Notes
    [22] - Only patients with available data were included in the analysis.
    [23] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in the van der Heijde modified Sharp radiographic score at Week 24

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    End point title
    		 Change from baseline in the van der Heijde modified Sharp radiographic score at Week 24
    End point description
    The degree of joint damage was assessed using the van der Heijde modified total Sharp score (mTSS). The methodology quantifies the extent of bone erosions for 44 joints and joint space narrowing (JSN) for 42 joints, with higher scores representing greater damage. The independent read of X-ray images was performed by 2 primary readers. In case of discrepancy between the 2 primary readers, an adjudicator was involved. The mTSS can range from 0 to 448 with a higher score indicating more joint damage. A negative change score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    391 [24]
    186 [25]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    0.62 ( 2.692 )
    1.23 ( 2.816 )
    Notes
    [24] - Only patients with available data were included in the analysis.
    [25] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in the Physical and Mental Component Scores of the Short Form 36 (SF-36) Health Survey at Week 24

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    End point title
    		 Change from baseline in the Physical and Mental Component Scores of the Short Form 36 (SF-36) Health Survey at Week 24
    End point description
    The SF-36 Health Survey uses patient-reported symptoms on 8 subscales to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role−Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role−Emotional, and Mental Health. Each score was scaled from 0 to 100 with a higher score indicating better HRQoL. A positive change score indicates an improvement in HRQoL.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    347 [26]
    123 [27]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Physical Component
    7.2 ( 8 )
    4.3 ( 5.9 )
        Mental Component
    6.1 ( 10.8 )
    3 ( 9.7 )
    Notes
    [26] - Only patients with available data were included in the analysis.
    [27] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in haemoglobin at Week 24

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    End point title
    		 Change from baseline in haemoglobin at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab 162 mg sc Placebo sc
    Number of subjects analysed
    343 [28]
    123 [29]
    Units: g/L
        arithmetic mean (standard deviation)
    11 ( 12.6 )
    0 ( 7.1 )
    Notes
    [28] - Only patients with available data were included in the analysis.
    [29] - Only patients with available data were included in the analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time of each patient’s randomization into the study until their last visit (up to 96 weeks).
    Adverse event reporting additional description
    Safety population: All patients who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. One patient who received tocilizumab had no post-baseline safety data and was excluded from the safety population. Due to the study design, some participants received tocilizumab throughout the study, others not.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Tocilizumab pre-filled syringe
    Reporting group description
    		 Patients received tocilizumab 162 mg sc via a pre-filled syringe every 2 weeks for 24 weeks. In addition, this reporting group includes participants rerandomised at Week 24 to tocilizumab 162 mg sc via a pre-filled syringe every 2 weeks for 72 weeks (Weeks 25-96).

    Reporting group title
    Placebo pre-filled syringe
    Reporting group description
    		 Patients received placebo subcutaneously (sc) via a pre-filled syringe every 2 weeks for 24 weeks.

    Reporting group title
    Tocilizumab pre-filled syringe to tocilizumab auto-injector
    Reporting group description
    		 Patients received tocilizumab 162 mg sc via a pre-filled syringe every 2 weeks for 24 weeks followed by tocilizumab162 mg sc via an autoinjector every 2 weeks for 72 weeks.

    Reporting group title
    Placebo pre-filled syringe to tocilizumab pre-filled syringe
    Reporting group description
    		 Patients received placebo sc via a pre-filled syringe every 2 weeks for 24 weeks followed by tocilizumab162 mg sc via a pre-filled syringe every 2 weeks for 72 weeks.

    Reporting group title
    Placebo pre-filled syringe to tocilizumab autoinjector
    Reporting group description
    		 Patients received placebo sc via a pre-filled syringe every 2 weeks for 24 weeks followed by tocilizumab162 mg sc via an autoinjector every 2 weeks for 72 weeks.

    Serious adverse events
    		 Tocilizumab pre-filled syringe Placebo pre-filled syringe Tocilizumab pre-filled syringe to tocilizumab auto-injector Placebo pre-filled syringe to tocilizumab pre-filled syringe Placebo pre-filled syringe to tocilizumab autoinjector
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 437 (8.24%)
    8 / 218 (3.67%)
    17 / 168 (10.12%)
    2 / 61 (3.28%)
    0 / 59 (0.00%)
         number of deaths (all causes)
    4
    0
    3
    1
    0
         number of deaths resulting from adverse events
    3
    0
    1
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial hypertrophy
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst torsion
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 218 (0.46%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Grand mal convulsion
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    2 / 168 (1.19%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 218 (0.46%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pyoderma gangrenosum
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 218 (0.46%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 218 (0.46%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 218 (0.46%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 218 (0.46%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 218 (0.46%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 437 (0.46%)
    2 / 218 (0.92%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 437 (0.46%)
    1 / 218 (0.46%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coccidioidomycosis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 218 (0.46%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ludwig angina
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    1 / 168 (0.60%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 218 (0.46%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 218 (0.00%)
    0 / 168 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tocilizumab pre-filled syringe Placebo pre-filled syringe Tocilizumab pre-filled syringe to tocilizumab auto-injector Placebo pre-filled syringe to tocilizumab pre-filled syringe Placebo pre-filled syringe to tocilizumab autoinjector
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    212 / 437 (48.51%)
    65 / 218 (29.82%)
    89 / 168 (52.98%)
    35 / 61 (57.38%)
    33 / 59 (55.93%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    67 / 437 (15.33%)
    13 / 218 (5.96%)
    24 / 168 (14.29%)
    6 / 61 (9.84%)
    10 / 59 (16.95%)
         occurrences all number
    85
    14
    29
    7
    13
    Aspartate aminotransferase increased
         subjects affected / exposed
    40 / 437 (9.15%)
    10 / 218 (4.59%)
    14 / 168 (8.33%)
    4 / 61 (6.56%)
    6 / 59 (10.17%)
         occurrences all number
    53
    10
    21
    5
    9
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 437 (5.95%)
    8 / 218 (3.67%)
    9 / 168 (5.36%)
    2 / 61 (3.28%)
    2 / 59 (3.39%)
         occurrences all number
    30
    9
    11
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 437 (6.41%)
    13 / 218 (5.96%)
    8 / 168 (4.76%)
    5 / 61 (8.20%)
    2 / 59 (3.39%)
         occurrences all number
    35
    15
    9
    5
    2
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    25 / 437 (5.72%)
    1 / 218 (0.46%)
    8 / 168 (4.76%)
    5 / 61 (8.20%)
    7 / 59 (11.86%)
         occurrences all number
    33
    1
    14
    5
    7
    Leukopenia
         subjects affected / exposed
    13 / 437 (2.97%)
    1 / 218 (0.46%)
    5 / 168 (2.98%)
    0 / 61 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    17
    1
    5
    0
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    21 / 437 (4.81%)
    3 / 218 (1.38%)
    6 / 168 (3.57%)
    3 / 61 (4.92%)
    5 / 59 (8.47%)
         occurrences all number
    23
    3
    6
    3
    6
    Gastritis
         subjects affected / exposed
    6 / 437 (1.37%)
    3 / 218 (1.38%)
    1 / 168 (0.60%)
    2 / 61 (3.28%)
    3 / 59 (5.08%)
         occurrences all number
    6
    3
    1
    2
    3
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    14 / 437 (3.20%)
    4 / 218 (1.83%)
    12 / 168 (7.14%)
    1 / 61 (1.64%)
    3 / 59 (5.08%)
         occurrences all number
    16
    4
    14
    1
    4
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    52 / 437 (11.90%)
    14 / 218 (6.42%)
    21 / 168 (12.50%)
    12 / 61 (19.67%)
    6 / 59 (10.17%)
         occurrences all number
    66
    14
    32
    20
    7
    Nasopharyngitis
         subjects affected / exposed
    35 / 437 (8.01%)
    5 / 218 (2.29%)
    16 / 168 (9.52%)
    5 / 61 (8.20%)
    4 / 59 (6.78%)
         occurrences all number
    40
    5
    19
    7
    4
    Urinary tract infection
         subjects affected / exposed
    26 / 437 (5.95%)
    7 / 218 (3.21%)
    15 / 168 (8.93%)
    2 / 61 (3.28%)
    4 / 59 (6.78%)
         occurrences all number
    30
    8
    19
    2
    5
    Sinusitis
         subjects affected / exposed
    13 / 437 (2.97%)
    1 / 218 (0.46%)
    8 / 168 (4.76%)
    5 / 61 (8.20%)
    1 / 59 (1.69%)
         occurrences all number
    16
    3
    12
    5
    1
    Bronchitis
         subjects affected / exposed
    13 / 437 (2.97%)
    2 / 218 (0.92%)
    4 / 168 (2.38%)
    1 / 61 (1.64%)
    3 / 59 (5.08%)
         occurrences all number
    15
    2
    4
    1
    3
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    13 / 437 (2.97%)
    2 / 218 (0.92%)
    5 / 168 (2.98%)
    2 / 61 (3.28%)
    4 / 59 (6.78%)
         occurrences all number
    15
    2
    5
    2
    5
    Dyslipidaemia
         subjects affected / exposed
    6 / 437 (1.37%)
    2 / 218 (0.92%)
    2 / 168 (1.19%)
    6 / 61 (9.84%)
    1 / 59 (1.69%)
         occurrences all number
    7
    2
    2
    6
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2011
    Amendment B • Tocilizumab autoinjector, as a new investigational product, was made available for use in the open−label portion of the study. • Additional details for the analyses of the radiographic endpoint were included. • The required tests for the liver profile were clarified, liver profile testing was added at Week 36, and vital sign measurements were added at Weeks 10 and 36. • The adjustment of the random element used to ensure a baseline randomization ratio of 2:1 was clarified. • To prevent any potential unblinding, a dual assessor approach was used until the completion of Week 48 data analysis. • The reporting period for adverse events, including non-serious adverse events to Roche Drug Safety was clarified (ie, within 24 hours of learning of the event). • The requirement for an X−ray image at the initiation of escape therapy was clarified.
    26 Apr 2011
    Amendment C • An optional ease-of-use substudy was added to the open-label period for the sites in Canada and the United States in order to evaluate the ability of patients, caregivers and healthcare professionals to handle and use the pre-filled syringe or autoinjector.
    12 Sep 2012
    Amendments D and E • In response to cases of fatal infections in patients participating in the trial, Protocol versions D (rest of world sites) and E (US sites) implemented an increase in the frequency of study visits for safety monitoring. Starting at Week 44, the frequency of study visits was changed from every 12 weeks to every 4 weeks. Vital signs, concomitant medications, and adverse events were required at these additional visits.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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