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    Clinical Trial Results:
    Multicenter, randomized, double-blind study to evaluate the safety and efficacy of tocilizumab (TCZ) in combination with methotrexate (MTX) versus switching to TCZ (placebo-controlled) in patients with active rheumatoid arthritis (RA) who have inadequately responded to prior MTX treatment and have achieved a low disease activity (DAS28 < 3.2) with TCZ in combination with MTX.

    Summary
    EudraCT number
    		 2011-001626-15
    Trial protocol
    		 ES  
    Global end of trial date
    14 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jul 2016
    First version publication date
    07 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML27828
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01399697
    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 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
    14 Mar 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Assess the maintenance of response in patients after switching to managed TCZ monotherapy compared with combination therapy continued TCZ and MTX.
    Protection of trial subjects
    The investigator ensured that this study was conducted in full conformance with the principles of the "Declaration of Helsinki" or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study fully adhered to the principles outlined in "Guideline for Good Clinical Practice" ICH Tripartite Guideline or with local law if it afforded greater protection to the participant. For studies conducted in the EU/EEA countries, the investigator ensured compliance with the EU Clinical Trial Directive (2001/20/EC). For studies conducted in the USA or under US IND, the investigator additionally ensured adherence to the basic principles of "Good Clinical Practice" as outlined in the current version of 21 CRF, subchapter D, part 312, "Responsibilities of Sponsors and Investigators", part 50, "Protection of Human Subjects", and part 56, "Institutional Review Boards."
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 261
    Worldwide total number of subjects
    261
    EEA total number of subjects
    261
    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)
    221
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 44 centers in Spain between 31 August 2011 and 14 March 2014.

    Pre-assignment
    Screening details
    		 A total of 264 subjects were screened of whom 1 was screen failure and 263 subjects were included. Two subjects were included but did not receive any treatment, hence they were excluded from all analysis.

    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, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TCZ plus (+) MTX (Non Randomized)
    Arm description
    		 Participants received tocilizumab (TCZ) 8 milligrams per kilogram (mg/kg; maximum 800 mg) via intravenous (IV) infusion every 4 weeks (q4w) through Week 24 (total of 7 infusions). Participants also received MTX capsules orally, at a stable dose (10, 15, 17.5, or 20 mg, no maximum dose was defined) weekly from Week 1 through 16.
    Arm type
    		 Non-Randomized Arm

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TCZ 8 mg/kg (maximum 800 mg) IV infusion q4w from Weeks 1 thorough 16 (total of 4 infusions).

    Investigational medicinal product name
    Methorexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate 10, 15, 17.5, or 20 mg capsules, administered orally once per week from Weeks 1 through 16.

    Arm title
    		 TCZ + MTX (Randomized)
    Arm description
    		 Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules, orally, at a stable dose (10, 15, 17.5, or 20 mg/week, but no maximum dose was defined), weekly, from Weeks 1 through 24.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TCZ 8 mg/Kg (maximum 800 mg) IV infusion q4w from Weeks 1 thorough 16 (total of 4 infusions).

    Investigational medicinal product name
    Methorexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate 10, 15, 17.5, or 20 mg capsules, administered orally once per week from Weeks 1 through 16

    Arm title
    		 Tocilizumab + Placebo (Randomized)
    Arm description
    		 Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules, orally, at stable dose (10, 15, 17.5, or 20 mg per week, but no maximum dose was defined) weekly, from Weeks 1 through 16 followed by matching placebo capsules, orally, weekly through Week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TCZ 8 mg/Kg (maximum 800 mg) IV infusion q4w from Weeks 1 thorough 16 (total of 4 infusions).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Methotrexate 10, 15, 17.5, or 20 mg capsules, administered orally once per week from Weeks 1 through 16.

    Number of subjects in period 1
    		TCZ plus (+) MTX (Non Randomized) TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Started
    96
    83
    82
    Completed
    55
    80
    78
    Not completed
    41
    3
    4
         Consent withdrawn by subject
    8
    -
    -
         Inclusion error
    2
    -
    -
         Clinical RA remission
    1
    -
    -
         Physician decision
    -
    -
    2
         Sponsor decisión
    1
    -
    -
         Non-compliant
    1
    -
    -
         Positive result for hepatitis B
    1
    -
    -
         Adverse event
    13
    3
    1
         Sponsor decision
    1
    -
    -
         Lost to follow-up
    2
    -
    -
         Protocol deviation
    2
    -
    -
         Lack of efficacy
    9
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TCZ plus (+) MTX (Non Randomized)
    Reporting group description
    		 Participants received tocilizumab (TCZ) 8 milligrams per kilogram (mg/kg; maximum 800 mg) via intravenous (IV) infusion every 4 weeks (q4w) through Week 24 (total of 7 infusions). Participants also received MTX capsules orally, at a stable dose (10, 15, 17.5, or 20 mg, no maximum dose was defined) weekly from Week 1 through 16.

    Reporting group title
    TCZ + MTX (Randomized)
    Reporting group description
    		 Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules, orally, at a stable dose (10, 15, 17.5, or 20 mg/week, but no maximum dose was defined), weekly, from Weeks 1 through 24.

    Reporting group title
    Tocilizumab + Placebo (Randomized)
    Reporting group description
    		 Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules, orally, at stable dose (10, 15, 17.5, or 20 mg per week, but no maximum dose was defined) weekly, from Weeks 1 through 16 followed by matching placebo capsules, orally, weekly through Week 24.

    Reporting group values
    		 TCZ plus (+) MTX (Non Randomized) TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized) Total
    Number of subjects
    		 96 83 82 261
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 81 71 69 221
        From 65-84 years
    		 15 12 13 40
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.3 ( 13.2 ) 50.2 ( 12.5 ) 51 ( 12.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 76 62 65 203
        Male
    		 20 21 17 58

    End points

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    End points reporting groups
    Reporting group title
    TCZ plus (+) MTX (Non Randomized)
    Reporting group description
    		 Participants received tocilizumab (TCZ) 8 milligrams per kilogram (mg/kg; maximum 800 mg) via intravenous (IV) infusion every 4 weeks (q4w) through Week 24 (total of 7 infusions). Participants also received MTX capsules orally, at a stable dose (10, 15, 17.5, or 20 mg, no maximum dose was defined) weekly from Week 1 through 16.

    Reporting group title
    TCZ + MTX (Randomized)
    Reporting group description
    		 Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules, orally, at a stable dose (10, 15, 17.5, or 20 mg/week, but no maximum dose was defined), weekly, from Weeks 1 through 24.

    Reporting group title
    Tocilizumab + Placebo (Randomized)
    Reporting group description
    		 Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules, orally, at stable dose (10, 15, 17.5, or 20 mg per week, but no maximum dose was defined) weekly, from Weeks 1 through 16 followed by matching placebo capsules, orally, weekly through Week 24.

    Primary: Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28

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    End point title
    		 Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28 [1]
    End point description
    The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (erythrocyte sedimentation rate [ESR] in millimeters per hour [mm/hr]), and general health status (participant global assessment of disease activity using visual analog scale [VAS], range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. Intent-to-treat (ITT) population: all randomized participants who received at least one dose of study medication and who had at least one efficacy measurement performed.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16, and Week 28
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were planned to be analyzed only for those participants who were randomized as per protocol.
    End point values
    		 TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Number of subjects analysed
    82 [2]
    82 [3]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n = 82, 81)
    5.42 ( 1.01 )
    5.29 ( 1.01 )
        Week 16 (n = 81, 82)
    1.77 ( 0.77 )
    1.96 ( 0.76 )
        Week 28 (n = 79, 79)
    1.82 ( 1.18 )
    1.98 ( 1.13 )
    Notes
    [2] - n (number) = number of participants assessed for the given parameter at the specified visit.
    [3] - n (number) = number of participants assessed for the given parameter at the specified visit.
    Statistical analysis title
    		 TCZ+MTX vs. TCZ+Placebo
    Comparison groups
    Tocilizumab + Placebo (Randomized) v TCZ + MTX (Randomized)
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Percentage of Participants With DAS28 Score Less Than (<) 2.6 at Week 28

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    End point title
    		 Percentage of Participants With DAS28 Score Less Than (<) 2.6 at Week 28 [4]
    End point description
    The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (ESR in mm/hr), and general health status (participant global assessment of disease activity using VAS, range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores indicate worsening. DAS28 <2.6 equals (=) remission. ITT Population; only participants with Week 28 DAS28 values were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 28
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were planned to be analyzed only for those participants who were randomized as per protocol.
    End point values
    		 TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Number of subjects analysed
    79
    79
    Units: percentage of participants
        number (not applicable)
    82.3
    75.9
    Statistical analysis title
    		 TCZ+MTX vs. TCZ+Placebo
    Comparison groups
    Tocilizumab + Placebo (Randomized) v TCZ + MTX (Randomized)
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.328
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Percentage of Participants with Clinical Disease Activity Index (CDAI) <2.8 at Week 28

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    End point title
    		 Percentage of Participants with Clinical Disease Activity Index (CDAI) <2.8 at Week 28 [5]
    End point description
    CDAI is the sum of tender and swollen joint count based on 28 joints and the participant and physician global disease assessment (VAS 0-10 centimeters [cm]). CDAI total score 0-76; higher scores = greater affect due to disease activity. CDAI <2.8 = clinical remission. ITT Population; only participants with CDAI scores at Weeks 28 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 28
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were planned to be analyzed only for those participants who were randomized as per protocol.
    End point values
    		 TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Number of subjects analysed
    81
    81
    Units: percentage of participants
        number (not applicable)
    40.7
    35.8
    Statistical analysis title
    		 TCZ+MTX vs. TCZ+Placebo
    Comparison groups
    TCZ + MTX (Randomized) v Tocilizumab + Placebo (Randomized)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.518
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Percentage of Participants With Simplified Disease Activity Index (SDAI) <3.3 at Week 28

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    End point title
    		 Percentage of Participants With Simplified Disease Activity Index (SDAI) <3.3 at Week 28 [6]
    End point description
    SDAI is calculated by a simple numerical sum of tender and swollen joint count (based on a 28-joint assessment), participant and physician global assessment of disease activity (VAS 0-10 cm), and level of C-reactive protein in milligram per deciliter (mg/dL). SDAI total score 0-86; higher scores = greater affect due to disease activity. SDAI <3.3 = clinical remission. ITT Population; only participants with SDAI scores at Week 28 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    28 weeks
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were planned to be analyzed only for those participants who were randomized as per protocol.
    End point values
    		 TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Number of subjects analysed
    77
    78
    Units: percentage of participant
        number (not applicable)
    35.1
    28.2
    Statistical analysis title
    		 TCZ+MTX vs. TCZ+Placebo
    Comparison groups
    TCZ + MTX (Randomized) v Tocilizumab + Placebo (Randomized)
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.358
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) From Week 16 to Week 28

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    End point title
    		 Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) From Week 16 to Week 28 [7]
    End point description
    HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. ITT Population; only participants with nonmissing values were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 16 and Week 28
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were planned to be analyzed only for those participants who were randomized as per protocol.
    End point values
    		 TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Number of subjects analysed
    80
    82
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.08 ( 0.47 )
    0 ( 0.52 )
    Statistical analysis title
    		 TCZ+MTX vs. TCZ+Placebo
    Comparison groups
    TCZ + MTX (Randomized) v Tocilizumab + Placebo (Randomized)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.674
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Square (LS) Mean
    Point estimate
    0.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.119
         upper limit
    		 0.184

    Secondary: Change in the Quality of Life Questionnaire (Short Form-12 [SF-12]) From Week 16 to Week 28 in Mental Health

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    End point title
    		 Change in the Quality of Life Questionnaire (Short Form-12 [SF-12]) From Week 16 to Week 28 in Mental Health [8]
    End point description
    Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated decline in health and higher scores indicated improvement in health. ITT Population; only participants with nonmissing values were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 16 and Week 28
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were planned to be analyzed only for those participants who were randomized as per protocol.
    End point values
    		 TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Number of subjects analysed
    79
    79
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.36 ( 10.22 )
    -0.38 ( 9.25 )
    Statistical analysis title
    		 TCZ+MTX vs. TCZ+Placebo
    Comparison groups
    TCZ + MTX (Randomized) v Tocilizumab + Placebo (Randomized)
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.204
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -1.873
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.775
         upper limit
    		 1.03

    Secondary: Change in the Quality of Life Questionnaire (SF-12) From Week 16 to Week 28 in Physical Health

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    End point title
    		 Change in the Quality of Life Questionnaire (SF-12) From Week 16 to Week 28 in Physical Health [9]
    End point description
    Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated a worsening of quality of life. ITT Population; only participants with nonmissing data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 16 and Week 28
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were planned to be analyzed only for those participants who were randomized as per protocol.
    End point values
    		 TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Number of subjects analysed
    79
    79
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.48 ( 9.49 )
    -2.26 ( 8.82 )
    Statistical analysis title
    		 TCZ+MTX vs. TCZ+Placebo
    Comparison groups
    TCZ + MTX (Randomized) v Tocilizumab + Placebo (Randomized)
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 ANCOVA
    Parameter type
    		 difference in LS Mean
    Point estimate
    3.376
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.676
         upper limit
    		 6.076

    Secondary: Change From Week 16 to Week 28 in Global Assessment of Disease Activity as Assessed With the Visual Analogue Scale (VAS) Performed by Participant

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    End point title
    		 Change From Week 16 to Week 28 in Global Assessment of Disease Activity as Assessed With the Visual Analogue Scale (VAS) Performed by Participant [10]
    End point description
    Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity . The distance from the left edge was measured in mm. ITT Population; only participants with nonmissing values were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 16 and Week 28
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were planned to be analyzed only for those participants who were randomized as per protocol.
    End point values
    		 TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Number of subjects analysed
    82
    82
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.68 ( 23.8 )
    0.56 ( 20.42 )
    Statistical analysis title
    		 TCZ+MTX vs. TCZ+Placebo
    Comparison groups
    TCZ + MTX (Randomized) v Tocilizumab + Placebo (Randomized)
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.769
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    0.969
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.526
         upper limit
    		 7.464

    Secondary: Change From Week 16 to Week 28 in Global Assessment of Disease Activity Assessed Using the VAS Performed by the Investigator

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    End point title
    		 Change From Week 16 to Week 28 in Global Assessment of Disease Activity Assessed Using the VAS Performed by the Investigator [11]
    End point description
    Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity . The distance from the left edge was measured in mm. ITT Population; only participants with nonmissing values were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 16 and Week 28
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were planned to be analyzed only for those participants who were randomized as per protocol.
    End point values
    		 TCZ + MTX (Randomized) Tocilizumab + Placebo (Randomized)
    Number of subjects analysed
    82
    81
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.71 ( 16.96 )
    2.85 ( 18.48 )
    Statistical analysis title
    		 TCZ+MTX vs. TCZ+Placebo
    Comparison groups
    TCZ + MTX (Randomized) v Tocilizumab + Placebo (Randomized)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.655
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -1.216
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.573
         upper limit
    		 4.141

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 up to Week 36
    Adverse event reporting additional description
    The data were planned per the protocol to be reported separately for pre-randomization period and post-randomization period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    TCZ + MTX (Non Randomized)
    Reporting group description
    		 Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules orally, at a stable dose (10, 15, 17.5, or 20 mg, no maximum dose was defined) weekly from Week 1 through 16.

    Reporting group title
    TCZ + MTX (Pre-randomization)
    Reporting group description
    		 Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w up to Week 16 (total of 4 infusions). Participants also received MTX capsules, orally at a stable dose (10, 15, 17.5, or 20 mg/week but no maximum dose was set) weekly, up to Week 16. Participants with a response were randomized to receive TCZ and MTX in the second part of the study. Response was defined as participants having DAS28 score less than or equal to (<=)3.2.

    Reporting group title
    TCZ + Placebo (Pre-randomization)
    Reporting group description
    		 Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w up to Week 16 (total of 4 infusions). Participants also received MTX capsules, orally at a stable dose (10, 15, 17.5, or 20 mg/week but no maximum dose was set) weekly, up to Week 16. Participants with a response were randomized to receive TCZ and matching MTX placebo in the second part of the study. Response was defined as participants having DAS28 score <=3.2.

    Reporting group title
    TCZ + MTX (Post-randomization)
    Reporting group description
    		 TCZ 8 mg/kg (maximum 800 mg) q4w via IV infusion up to Week 16 (total of 4 infusions). Participants also received MTX capsules, orally, at a stable dose (10, 15, 17.5, or 20 mg/week but no maximum dose was set) weekly, up to Week 16. Participants with a response were randomized to receive 3 additional IV infusions of TCZ 8 mg/kg between Week 16 and Week 24 and MTX capsules, orally, at a stable dose (10, 15, 17.5, or 20 mg per week, but no maximum dose was set), weekly through Week 24. Response was defined as participants having DAS28 score <=3.2.

    Reporting group title
    TCZ + Placebo (Post-randomization)
    Reporting group description
    		 TCZ 8 mg/kg (maximum 800 mg) q4w via IV infusion up to Week 16 (total of 4 infusions). Participants also received MTX capsules, orally, at a stable dose (10, 15, 17.5, or 20 mg/week but no maximum dose was set) weekly, up to Week 16. Participants with a response were randomized to receive 3 additional IV infusions of TCZ 8 mg/kg between Week 16 and Week 24 and matching placebo MTX capsules, orally, at a stable dose (10, 15, 17.5, or 20 mg per week, but no maximum dose was set), weekly through Week 24. Response was defined as participants having DAS28 score <=3.2.

    Serious adverse events
    		 TCZ + MTX (Non Randomized) TCZ + MTX (Pre-randomization) TCZ + Placebo (Pre-randomization) TCZ + MTX (Post-randomization) TCZ + Placebo (Post-randomization)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 96 (11.46%)
    0 / 83 (0.00%)
    1 / 82 (1.22%)
    1 / 83 (1.20%)
    4 / 82 (4.88%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (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
    Nervous system disorders
    Epilepsy
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (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
    Chest pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (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
    Ear and labyrinth disorders
    Vertigo
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 96 (3.13%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    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
    Lupus-like syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (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
    Infections and infestations
    Bursitis infective
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis bacterial
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    1 / 83 (1.20%)
    0 / 82 (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
    Pneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal skin infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (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
    Herpes zoster
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (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
    Pyelonephritis acute
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (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
    Salpingitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (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
    Respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 83 (0.00%)
    1 / 82 (1.22%)
    0 / 83 (0.00%)
    0 / 82 (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
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TCZ + MTX (Non Randomized) TCZ + MTX (Pre-randomization) TCZ + Placebo (Pre-randomization) TCZ + MTX (Post-randomization) TCZ + Placebo (Post-randomization)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 96 (29.17%)
    20 / 83 (24.10%)
    24 / 82 (29.27%)
    8 / 83 (9.64%)
    4 / 82 (4.88%)
    Blood and lymphatic system disorders
    Leukopenia
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 96 (7.29%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
         occurrences all number
    7
    0
    0
    0
    0
    Neutropenia
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 96 (7.29%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
         occurrences all number
    8
    0
    0
    0
    0
    Gastrointestinal disorders
    Aphthous stomatitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 96 (0.00%)
    3 / 83 (3.61%)
    6 / 82 (7.32%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
         occurrences all number
    0
    3
    8
    0
    0
    Hepatobiliary disorders
    Hypertransaminasaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    15 / 96 (15.63%)
    12 / 83 (14.46%)
    10 / 82 (12.20%)
    8 / 83 (9.64%)
    4 / 82 (4.88%)
         occurrences all number
    20
    13
    11
    9
    6
    Infections and infestations
    Respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 96 (0.00%)
    3 / 83 (3.61%)
    5 / 82 (6.10%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
         occurrences all number
    0
    3
    6
    0
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 96 (9.38%)
    2 / 83 (2.41%)
    6 / 82 (7.32%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
         occurrences all number
    10
    2
    6
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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