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    Clinical Trial Results:
    Prospective, multicentre, placebo controlled, double-blind study to compare the efficacy of maintenance treatment with Tocilizumab with or without glucocorticoid discontinuation in rheumatoid arthritis patients

    Summary
    EudraCT number
    		 2014-004673-16
    Trial protocol
    		 DE   FR   IT  
    Global end of trial date
    09 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Feb 2019
    First version publication date
    23 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MA29585
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann- LaRoche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG., +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG., +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the change in disease activity as assessed by Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28 ESR) from randomization to Week 24 post-randomization, in subjects with stable low disease activity (LDA, DAS28 ESR score ≤ 3.2) who have been randomized to either continue or taper prednisone in a double-blinded fashion.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the "Declaration of Helsinki" and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol. All the investigators were trained according to the applicable Sponsor standard operating procedures, and strictly adhered to the stated provisions. This was documented by investigator's signature on the protocol agreeing to carry out all of its terms in accordance with the applicable regulations and to follow International Conference on Harmonization (ICH) GCP guidelines. Approval from Institutional Review Boards (IRBs) and Ethics Committee (EC) was obtained before study start and was documented in a letter to investigator specifying the date the committee met, and granted approval. Approval from relevant competent authority was also obtained prior to starting the study. Protocol amendments were prepared by the Sponsor, and were submitted to IRB/EC and to Regulatory Authorities in accordance with the local regulatory requirements. Audits were performed by the Sponsor Quality Assurance group in compliance with GCP. An independent Data Monitoring Committee (iDMC) shared responsibility for evaluating the safety of the subjects participating in the trial at regular intervals throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Mar 2016
    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
    France: 13
    Country: Number of subjects enrolled
    Germany: 129
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Russian Federation: 52
    Country: Number of subjects enrolled
    Serbia: 44
    Country: Number of subjects enrolled
    Tunisia: 6
    Worldwide total number of subjects
    259
    EEA total number of subjects
    157
    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)
    198
    From 65 to 84 years
    60
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Overall, 314 patients were enrolled into the study. 246 subjects were Track TCZ-naive subjects and 68 subjects were Track TCZ-experienced subjects. A total of 9 TCZ-naive subjects failed to complete 4 weeks’ treatment with SPOL prednisone 5 mg/day and were withdrawn from the study prior to randomization.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tocilizumab+prednisone (tapering dose)
    Arm description
    		 Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously or 8 mg/kg intravenously every 4 weeks; and prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Infusion
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously or 8 mg/kg intravenously every 4 weeks

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks.

    Investigational medicinal product name
    Placebo matched to prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.

    Arm title
    		 Tocilizumab+prednisone (constant dose)
    Arm description
    		 Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously or 8 mg/kg intravenously every 4 weeks; and prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Infusion
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously or 8 mg/kg intravenously every 4 weeks

    Investigational medicinal product name
    Placebo matched to prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.

    Number of subjects in period 1
    		Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Started
    131
    128
    Completed
    116
    113
    Not completed
    15
    15
         Consent withdrawn by subject
    2
    2
         Physician decision
    1
    2
         Adverse event, non-fatal
    5
    5
         Non-compliance
    1
    2
         Study terminated by sponsor
    1
    -
         Lack of efficacy
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tocilizumab+prednisone (tapering dose)
    Reporting group description
    		 Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously or 8 mg/kg intravenously every 4 weeks; and prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.

    Reporting group title
    Tocilizumab+prednisone (constant dose)
    Reporting group description
    		 Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously or 8 mg/kg intravenously every 4 weeks; and prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks.

    Reporting group values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose) Total
    Number of subjects
    		 131 128 259
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.8 ( 14.0 ) 54.0 ( 12.8 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 103 97 200
        Male
    		 28 31 59
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 1 2 3
        Native Hawaiian or Other Pacific Islander
    		 0 3 3
        Black or African American
    		 0 0 0
        White
    		 129 123 252
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 120 114 234
        Unknown or Not Reported
    		 10 14 24

    End points

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    End points reporting groups
    Reporting group title
    Tocilizumab+prednisone (tapering dose)
    Reporting group description
    		 Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously or 8 mg/kg intravenously every 4 weeks; and prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.

    Reporting group title
    Tocilizumab+prednisone (constant dose)
    Reporting group description
    		 Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously or 8 mg/kg intravenously every 4 weeks; and prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks.

    Primary: Change from baseline in Disease Activity Score in 28 joints - Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24 post-randomization

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    End point title
    		 Change from baseline in Disease Activity Score in 28 joints - Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24 post-randomization
    End point description
    Comparing the impact on disease activity of continued versus tapered prednisone in Rheumatoid Arthritis participants with stable low disease activity (LDA) (DAS28-ESR score ≤ 3.2). The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, ESR, and general health status.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Units on a Scale
        least squares mean (confidence interval 95%)
    0.538 (0.346 to 0.729)
    -0.075 (-0.271 to 0.121)
    Statistical analysis title
    		 ANCOVA
    Comparison groups
    Tocilizumab+prednisone (constant dose) v Tocilizumab+prednisone (tapering dose)
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Means
    Point estimate
    0.613
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.346
         upper limit
    		 0.879

    Secondary: Treatment Success

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    End point title
    		 Treatment Success
    End point description
    Comparing the proportion of participants who continued versus tapered prednisone with LDA (DAS28-ESR score ≤ 3.2) at Week 24 who did not suffer a flare due to RA and who showed no confirmed adrenal insufficiency requiring replacement therapy.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Percentage of Participants
        number (confidence interval 95%)
    64.9 (56.1 to 73.0)
    77.3 (69.1 to 84.3)
    Statistical analysis title
    		 Odds Ratio
    Comparison groups
    Tocilizumab+prednisone (constant dose) v Tocilizumab+prednisone (tapering dose)
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.018
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.285
         upper limit
    		 0.889
    Statistical analysis title
    		 Relative Risk
    Comparison groups
    Tocilizumab+prednisone (constant dose) v Tocilizumab+prednisone (tapering dose)
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.021
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk
    Point estimate
    0.833
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.714
         upper limit
    		 0.972

    Secondary: Change from baseline in clinical disease activity index (CDAI) at Week 24

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    End point title
    		 Change from baseline in clinical disease activity index (CDAI) at Week 24
    End point description
    Comparison between participants who continued versus tapered prednisone in Clinical Disease Activity Index (CDAI) score.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Units on a Scale
        least squares mean (confidence interval 95%)
    2.663 (1.454 to 3.872)
    0.321 (-0.914 to 1.556)
    Statistical analysis title
    		 Least Square Means
    Comparison groups
    Tocilizumab+prednisone (tapering dose) v Tocilizumab+prednisone (constant dose)
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.006
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Means
    Point estimate
    2.342
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.661
         upper limit
    		 4.023

    Secondary: Percentage of participants with >=1 flare

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    End point title
    		 Percentage of participants with >=1 flare
    End point description
    Percentage of participants with >=1 flare
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Percentage of Participants
        number (not applicable)
    26.0
    10.9
    No statistical analyses for this end point

    Secondary: Percentage of participants with >=1 administration of flare rescue medication

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    End point title
    		 Percentage of participants with >=1 administration of flare rescue medication
    End point description
    The proportion of participants with at least one administration of RA flare rescue medication.
    End point type
    Secondary
    End point timeframe
    Randomization to 24 weeks
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Percentage of Participants
        number (not applicable)
    20.6
    6.3
    No statistical analyses for this end point

    Secondary: Time to first administration of flare rescue medication

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    End point title
    		 Time to first administration of flare rescue medication
    End point description
    Time of onset of first administration of RA flare rescue medication since randomization date
    End point type
    Secondary
    End point timeframe
    Randomization to 24 weeks
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Weeks
        arithmetic mean (standard deviation)
    13.59 ( 6.77 )
    8.76 ( 5.26 )
    No statistical analyses for this end point

    Secondary: Number of administrations of flare rescue medication

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    End point title
    		 Number of administrations of flare rescue medication
    End point description
    Proportion of participants who received courses of RA flare rescue medication by number of courses received.
    End point type
    Secondary
    End point timeframe
    Randomization to 24 weeks
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Percentage of Participants
    number (not applicable)
        0 courses
    79.4
    93.8
        1 course
    15.3
    3.9
        2 courses
    4.6
    1.6
        3 courses
    0
    0.8
        >3 courses
    0.8
    0
    No statistical analyses for this end point

    Secondary: Cumulative prednisone exposure (dose)

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    End point title
    		 Cumulative prednisone exposure (dose)
    End point description
    In Post-randomization prednisone arm, Cumulative dose = (number of capsules taken during week 1 to 4 * 1 mg) + (3/4 * number of capsules taken during week 5 to 8 * 1 mg) + (1/2 * number of capsules taken during week 9 to 12 * 1 mg) + (1/4 * number of capsules taken during week 13 to 16 * 1 mg). In continued arm, cumulative dose = (1/4 * number of capsule taken * 5 mg). Cumulative prednisone dose is defined as cumulative blinded prednisone + cumulative flare rescue prednisone.
    End point type
    Secondary
    End point timeframe
    Randomization to 24 weeks
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: mg
    arithmetic mean (standard deviation)
        Cumulative blinded prednisone dose
    267.099 ( 40.048 )
    769.459 ( 175.882 )
        Cumulative flare rescue prednisone dose
    98.519 ( 51.921 )
    121.875 ( 54.898 )
        Cumulative prednisone dose
    287.405 ( 63.184 )
    777.136 ( 172.881 )
    No statistical analyses for this end point

    Secondary: Percentage of participants who maintain LDA (DAS28 ESR score <=3.2) or remission (DAS28 ESR score <2.6) and the percentage of participants who maintain the baseline disease activity level

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    End point title
    		 Percentage of participants who maintain LDA (DAS28 ESR score <=3.2) or remission (DAS28 ESR score <2.6) and the percentage of participants who maintain the baseline disease activity level
    End point description
    The proportion of participants who maintained LDA and the proportion of participants who maintained the baseline disease activity level at Week 24. LDA was defined as DAS28 ESR score <= 3.2. Remission was defined as DAS28 ESR score <= 2.6. Participants who maintained the baseline activity was defined as DAS28-ESR at Week 24 <= DAS28-ESR at baseline.
    End point type
    Secondary
    End point timeframe
    Randomization to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Percentage of Participants
    number (not applicable)
        LDA at baseline
    97.7
    96.9
        LDA at Week 24
    73.4
    83.1
        Baseline DAS28-ESR ≤ 2.6
    78.6
    76.6
        Remission at Week 24
    61.2
    81.6
        Maintained baseline activity at Week 24
    36.6
    54.7
    No statistical analyses for this end point

    Secondary: Percentage of participants who permanently discontinue study treatment due to insufficient flare control

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    End point title
    		 Percentage of participants who permanently discontinue study treatment due to insufficient flare control
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Percentage of Participants
        number (not applicable)
    0
    0.8
    No statistical analyses for this end point

    Secondary: Change from baseline in simplified disease activity index (SDAI) at Week 24

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    End point title
    		 Change from baseline in simplified disease activity index (SDAI) at Week 24
    End point description
    The SDAI is the numerical sum of five outcome parameters: tender and swollen joint count (based on a 28-joint assessment), patient and physician global assessment of disease activity [visual analogue scale (VAS) 0-10 cm] and level of C-reactive protein (mg/dl, normal <1 mg/dl).
    End point type
    Secondary
    End point timeframe
    Randomization to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: SDAI Score
        least squares mean (confidence interval 95%)
    2.511 (1.296 to 3.727)
    0.248 (-0.994 to 1.489)
    Statistical analysis title
    		 Least Square Means
    Comparison groups
    Tocilizumab+prednisone (tapering dose) v Tocilizumab+prednisone (constant dose)
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.009
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Means
    Point estimate
    2.264
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.574
         upper limit
    		 3.953

    Secondary: Time to first RA flare

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    End point title
    		 Time to first RA flare
    End point description
    The mean time of onset for the first RA flare since randomization.
    End point type
    Secondary
    End point timeframe
    Randomization to 24 weeks
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Weeks
        arithmetic mean (standard deviation)
    15.64 ( 7.13 )
    12.11 ( 7.96 )
    No statistical analyses for this end point

    Secondary: Number of RA flares

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    End point title
    		 Number of RA flares
    End point description
    Number of visits with RA flares reported.
    End point type
    Secondary
    End point timeframe
    Randomization to 24 weeks
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Percentage of Visits
    number (not applicable)
        1 Visit
    16.0
    7.0
        2 Visits
    6.9
    3.9
        3 Visits
    2.3
    0
        >3 Visits
    0.8
    0
    No statistical analyses for this end point

    Secondary: Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Swollen 66 Joint Counts

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    End point title
    		 Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Swollen 66 Joint Counts
    End point description
    Count of swollen joints based upon 66 assessed joints.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Number of swollen joints
        arithmetic mean (standard deviation)
    0.129 ( 6.687 )
    -0.107 ( 1.618 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Tender 68 Joint Counts

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    End point title
    		 Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Tender 68 Joint Counts
    End point description
    Count of tender joints based on 68 assessed joints.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Number of tender joints
        arithmetic mean (standard deviation)
    0.793 ( 7.764 )
    -0.330 ( 2.729 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Patient's Assessment of Pain

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    End point title
    		 Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Patient's Assessment of Pain
    End point description
    Scored on a Visual Analogue Scale (VAS) from 0 to 100 mm.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: mm
        arithmetic mean (standard deviation)
    4.648 ( 24.315 )
    -8.010 ( 25.980 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Patient’s global assessment of disease activity

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    End point title
    		 Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Patient’s global assessment of disease activity
    End point description
    Scored on a Visual Analogue Scale (VAS) from 0 to 10 cm.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: cm
        arithmetic mean (standard deviation)
    0.280 ( 2.000 )
    -0.153 ( 1.506 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Physician’s Global Assessment of Disease Activity

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    End point title
    		 Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Physician’s Global Assessment of Disease Activity
    End point description
    Scored on a Visual Analogue Scale (VAS) from 0 to 10 cm.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: cm
        arithmetic mean (standard deviation)
    0.345 ( 1.463 )
    -0.248 ( 1.167 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Health Assessment Questionnaire–Disability Index (HAQ-DI)

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    End point title
    		 Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Health Assessment Questionnaire–Disability Index (HAQ-DI)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Questionnaire score
        arithmetic mean (standard deviation)
    0.167 ( 0.486 )
    -0.087 ( 0.527 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: High Sensitivity C-Reactive Protein (hsCRP)

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    End point title
    		 Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: High Sensitivity C-Reactive Protein (hsCRP)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: mg/dL
        arithmetic mean (standard deviation)
    -0.135 ( 1.470 )
    -0.040 ( 0.277 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Erythrocyte Sedimentation Rate (ESR)

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    End point title
    		 Changes from baseline in American College of Rheumatology (ACR) core set components at Week 24: Erythrocyte Sedimentation Rate (ESR)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: mm/hr
        arithmetic mean (standard deviation)
    1.517 ( 7.892 )
    -0.679 ( 5.433 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in Rheumatoid Arthritis Impact of Disease (RAID) Final score

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    End point title
    		 Changes from baseline in Rheumatoid Arthritis Impact of Disease (RAID) Final score
    End point description
    The RAID is a participant-completed questionnaire specific for RA consisting of a 1-10 rating for pain, functional disability, fatigue, sleep, physical well-being, emotional well-being and coping. Scores are weighted to produce a final numerical result.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Questionnaire Score
        arithmetic mean (standard deviation)
    0.469 ( 2.109 )
    -0.220 ( 1.940 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) score

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    End point title
    		 Changes from baseline in Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) score
    End point description
    The WPAI:SHP is a 6-item questionnaire evaluating the effect of the underlying disease or condition on the participant’s ability to work and perform regular activities
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Tocilizumab+prednisone (tapering dose) Tocilizumab+prednisone (constant dose)
    Number of subjects analysed
    131
    128
    Units: Percent
    arithmetic mean (standard deviation)
        Percent work time missed due to problem
    4.535 ( 23.283 )
    0.572 ( 31.455 )
        Percent impairment while working due to problem
    -0.851 ( 24.920 )
    -5.584 ( 23.343 )
        Percent overall work impairment due to problem
    6.219 ( 29.223 )
    -6.191 ( 30.531 )
        Percent activity impairment due to problem
    3.398 ( 23.786 )
    -4.190 ( 21.608 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomization to Week 28
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Tocilizumab+prednisone (constant dose)
    Reporting group description
    		 Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks.

    Reporting group title
    Tocilizumab+prednisone (tapering dose)
    Reporting group description
    		 Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.

    Serious adverse events
    		 Tocilizumab+prednisone (constant dose) Tocilizumab+prednisone (tapering dose)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 128 (3.13%)
    7 / 131 (5.34%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    BLOOD GLUCOSE FLUCTUATION
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCIATICA
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    NEUTROPENIA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    PSYCHOTIC DISORDER
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    SPINAL COLUMN STENOSIS
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    PNEUMONIA
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS GANGRENOUS
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tocilizumab+prednisone (constant dose) Tocilizumab+prednisone (tapering dose)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 128 (16.41%)
    46 / 131 (35.11%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 128 (2.34%)
    9 / 131 (6.87%)
         occurrences all number
    3
    10
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 128 (1.56%)
    9 / 131 (6.87%)
         occurrences all number
    2
    10
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    5 / 128 (3.91%)
    7 / 131 (5.34%)
         occurrences all number
    5
    7
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    2 / 128 (1.56%)
    8 / 131 (6.11%)
         occurrences all number
    2
    12
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    9 / 128 (7.03%)
    13 / 131 (9.92%)
         occurrences all number
    12
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2015
    Open-label prednisone tablets were to be offered during the 4 weeks preceding randomization for patients in both tracks and provided for the treatment of any flare following randomization (during the 24-week Tapering Phase); To facilitate the conduct and analysis of NSAIDs use, NSAID average use was captured as mean daily intake by considering the number of days on which NSAIDs had been taken during a period of interest (at screening, Week 12, and Week 24);Increasing the dose of NSAIDs during a flare was discouraged to minimize any confounding effect of NSAID use; In order to minimize screen failures due to temporary ailments or abnormalities, patients could be re-screened or re-tested, depending on the inclusion/exclusion criteria they failed, if authorized by the Sponsor; Timing of assessments of immunogenicity was clarified so that immunogenicity sampling was event-driven and therefore only patients who experienced anaphylaxis or other hypersensitivity reaction were evaluated at the time of the event and 8 weeks after, as part of standard immunogenicity sampling protocol.
    22 Jun 2016
    Amendment based on requests from the iDMC, investigator feedback, updated internal guidance and definitions, newly identified errata and updates to the IB.

    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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