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    Clinical Trial Results:
    Randomized, Phase IV, Placebo-controlled, Comparative Study to Evaluate the Efficacy and Safety of Tapering Methotrexate (MTX) Dosage Versus Maintaining the Dosage in Patients with Severe Active Rheumatoid Arthritis (RA) Who Have Demonstrated an Inadequate Response (IR) to Prior Disease-modifying Anti-rheumatic Drugs (DMARDs) Treatment and Have Initiated RoActemra (RoActemra, TCZ) in Combination with MTX

    Summary
    EudraCT number
    2011-005260-20
    Trial protocol
    GB  
    Global end of trial date
    05 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Sep 2016
    First version publication date
    04 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML28096
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01661140
    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
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, 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
    05 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the percentage of subjects who maintain good/moderate European League Against Rheumatism (EULAR) response between subjects receiving RoActemra in combination with a tapering dose of MTX and subjects receiving RoActemra in combination with a stable dose of MTX from Week 24 to Week 60.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Sep 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 427
    Worldwide total number of subjects
    427
    EEA total number of subjects
    427
    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)
    335
    From 65 to 84 years
    90
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The initial open label phase of the study consisted of one group of 427 subjects. After completion of the open label phase only subjects, who achieved a good/moderate disease response, were randomised into the double blind phase of the study. 272 subjects were randomised into the two groups entering the main phase of the study.

    Period 1
    Period 1 title
    Open-Label Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Initial Phase
    Arm description
    At Week 0 subjects started open-label tocilizumab and open-label methotrexate (MTX) for 24 weeks, which was the initial phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 milligrams per kilogram (mg/kg) intravenously every 4 weeks, 24 weeks

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate (MTX) was administered weekly according to the subject's pre-study MTX dose.

    Number of subjects in period 1
    Initial Phase
    Started
    427
    Completed
    351
    Not completed
    76
         Investigator decision
    3
         Death
    1
         Protocol violation
    3
         Did not meet EULAR criteria
    1
         Sponsor termination
    16
         Withdrew consent
    5
         Adverse event, non-fatal
    44
         Administrative/other
    1
         Lost to follow-up
    2
    Period 2
    Period 2 title
    Double-Blind Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Methotrexate (MTX) Tapering Group
    Arm description
    After the open-label period ended at Week 24, subjects achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomised to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group subjects received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, subjects continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 subjects received tocilizumab monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 milligrams per kilogram (mg/kg) intravenously every 4 weeks, 72 weeks.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tapering doses of methotrexate (MTX) were administered weekly from Week 24 to Week 56. Tapering doses depended on dose administered to the subject during the open label period. First tapering occured at randomisation (Week 24), second tapering at Week 32, third tapering at Week 40 and final tapering at Week 48.

    Arm title
    Methotrexate (MTX) Maintenance Group
    Arm description
    After the open-label period ended at Week 24, subjects achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomised to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group subjects continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, subjects continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 subjects received tocilizumab monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 milligrams per kilogram (mg/kg) intravenously every 4 weeks, 72 weeks

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Stable doses of methotrexate (MTX) were administered weekly from Week 24 to Week 56. MTX was dosed according to the subject's open-label MTX dose.

    Number of subjects in period 2 [1]
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Started
    136
    136
    Completed
    95
    86
    Not completed
    41
    50
         Investigator decision
    1
    2
         Refused treatment
    -
    1
         Protocol violation
    2
    3
         Sponsor termination
    14
    17
         Administrative/other
    7
    6
         Withdrew consent
    1
    3
         Adverse event, non-fatal
    16
    18
    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: Of the 351 subjects who completed the open-label period, 79 did not continue to the double-blind period. The remaining 272 subjects were randomised to double blind treatment groups.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Initial Phase
    Reporting group description
    At Week 0 subjects started open-label tocilizumab and open-label methotrexate (MTX) for 24 weeks, which was the initial phase of the study.

    Reporting group values
    Initial Phase Total
    Number of subjects
    427 427
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55 ± 12.03 -
    Gender categorical
    Units: Subjects
        Female
    326 326
        Male
    101 101

    End points

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    End points reporting groups
    Reporting group title
    Initial Phase
    Reporting group description
    At Week 0 subjects started open-label tocilizumab and open-label methotrexate (MTX) for 24 weeks, which was the initial phase of the study.
    Reporting group title
    Methotrexate (MTX) Tapering Group
    Reporting group description
    After the open-label period ended at Week 24, subjects achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomised to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group subjects received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, subjects continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 subjects received tocilizumab monotherapy.

    Reporting group title
    Methotrexate (MTX) Maintenance Group
    Reporting group description
    After the open-label period ended at Week 24, subjects achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomised to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group subjects continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, subjects continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 subjects received tocilizumab monotherapy.

    Primary: Percentage of Subjects Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomisation) to Week 60

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    End point title
    Percentage of Subjects Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomisation) to Week 60
    End point description
    Response was determined using EULAR criteria based upon (Disease Activity Score In 28 Joints) DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Subjects with a score lesser than or equal to (<=) 3.2 and reduction of greater than (>) 1.2 points were assessed as having a 'good' response. Subjects with a score >3.2 with reduction of >1.2 points, or a score <=5.1 with reduction of >0.6 to <=1.2 points, were assessed as having a 'moderate' response. Subjects with a score >5.1 with reduction of >0.6 to <=1.2 points, or any score with reduction <=0.6 points, were assessed as non-responders with response recorded as 'none.' Intention to treat (ITT) population included all randomised participants.
    End point type
    Primary
    End point timeframe
    From randomisation (Week 24) to Week 60
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
        number (not applicable)
    76.5
    65.4
    Statistical analysis title
    Difference in percentage
    Statistical analysis description
    Comparison was Tapering MTX : MTX maintenance. Last post-baseline EULAR response recorded used for subjects with a missing result at Week 60.
    Comparison groups
    Methotrexate (MTX) Tapering Group v Methotrexate (MTX) Maintenance Group
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.036
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.803
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.037
         upper limit
    3.133
    Notes
    [1] - Non-inferiority if the difference between treatments is statistically significant and the lower limit of the 95% confidence interval (CI) is greater than 0.9.

    Secondary: Change From Week 24 in Disease Activity Score In 28 Joints (DAS28) Score at Week 60

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    End point title
    Change From Week 24 in Disease Activity Score In 28 Joints (DAS28) Score at Week 60
    End point description
    The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. ITT population included all randomised subjects. Here, number of subjects analysed signifies those subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    From randomisation (Week 24) to Week 60
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 135, 136)
    2.572 ± 1.3218
    2.573 ± 1.3017
        Change at Week 60 (n= 134, 135)
    -0.179 ± 1.1702
    -0.233 ± 1.5156
    No statistical analyses for this end point

    Secondary: Change From Week 24 in Disease Activity Score In 28 Joints (DAS28) Score at Week 72

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    End point title
    Change From Week 24 in Disease Activity Score In 28 Joints (DAS28) Score at Week 72
    End point description
    The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. ITT population included all randomised subjects. Here, number of subjects analysed signifies those subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    From randomisation (Week 24) to Week 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    134
    135
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.105 ± 1.2262
    -0.224 ± 1.4961
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72

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    End point title
    Percentage of Subjects Who Achieved Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72
    End point description
    Percentage of subjects who achieve score of <=1 in TJC and SJC at week 60 and 72 were reported. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
    number (not applicable)
        TJC <=1, Week 60
    39
    39
        SJC <=1, Week 60
    44.1
    58.1
        TJC <=1, Week 72
    37.5
    40.4
        SJC <=1, Week 72
    55.9
    60.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved a Disease Activity Score In 28 Joints (DAS28) <= 3.2

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    End point title
    Percentage of Subjects Who Achieved a Disease Activity Score In 28 Joints (DAS28) <= 3.2
    End point description
    The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Subjects who achieved score <=3.2 at weeks 60 and 72 were reported. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
    number (not applicable)
        Week 60
    59.6
    62.5
        Week 72
    61
    60.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved DAS28 Remission (DAS28 < 2.6)

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    End point title
    Percentage of Subjects Who Achieved DAS28 Remission (DAS28 < 2.6)
    End point description
    The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve DAS28 remission score <2.6 at weeks 60 and 72 were reported. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
    number (not applicable)
        Week 60
    51.5
    47.1
        Week 72
    50
    51.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Change in Disease Activity Score (cDAS) >=1.2

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    End point title
    Percentage of Subjects Who Achieved Change in Disease Activity Score (cDAS) >=1.2
    End point description
    The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve cDAS28 >=1.2 score at weeks 60 and 72 were reported. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
    number (not applicable)
        Week 60
    9.6
    16.2
        Week 72
    9.6
    15.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72

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    End point title
    Percentage of Subjects Who Achieved Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72
    End point description
    Clinical Disease Activity Index (CDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + patient global assessment of disease (PGA) 10 centimeter [cm] Visual Analog Scale [VAS] + physician global assessment of disease (PhGA) 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Randomisation (Week 24), Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
    number (not applicable)
        Week 60
    2.9
    1.5
        Week 72
    1.5
    3.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72

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    End point title
    Percentage of Subjects Who Achieved Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72
    End point description
    Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Randomisation (Week 24), Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
    number (not applicable)
        Week 60
    2.9
    0.7
        Week 72
    2.9
    0.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72

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    End point title
    Percentage of Subjects With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72
    End point description
    The HAQ-disability index (DI) evaluates subject-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 to 3. The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in HAQ-DI score. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Randomisation (Week 24), Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
    number (not applicable)
        Improvement at Week 60
    27
    39.6
        Improvement at Week 72
    40.5
    50
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72

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    End point title
    Percentage of Subjects With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72
    End point description
    The FACIT-fatigue assessment was a 13-item questionnaire with subjects scoring each item on a 5-point scale (not at all; a little bit; somewhat; quite a bit and very much). The total score ranges from 0 to 65 and higher scores indicate more fatigue. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in total FACIT score. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Randomisation (Week 24), Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
    number (not applicable)
        Improvement at Week 60
    54
    50
        Improvement at Week 72
    45.2
    56.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72

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    End point title
    Percentage of Subjects With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72
    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. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in SF-12 score. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Randomisation (Week 24), Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
    number (not applicable)
        Improvement at Week 60
    22.2
    10.4
        Improvement at Week 72
    23.8
    15.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Anaemia

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    End point title
    Percentage of Subjects With Anaemia
    End point description
    Safety population included all the randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 0 up to Week 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: percentage of subjects
        number (not applicable)
    1.5
    0.7
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE was any adverse event that can be fatal, life threatening, requires long or prolonged hospitalisation, results in persistent or significant disability/incapacity, congenital anomaly or significant medical event in the investigator’s judgment. Safety population included all the randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 0 up to Week 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: subjects
    number (not applicable)
        AEs
    98
    98
        SAEs
    9
    3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Able to Discontinue Methotrexate

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    End point title
    Percentage of Subjects Able to Discontinue Methotrexate
    End point description
    End point type
    Secondary
    End point timeframe
    Week 0 up to Week 60
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [2] - Data were not collected for this end point.
    [3] - Data were not collected for this end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP)

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    End point title
    Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP)
    End point description
    The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: participants
        Week 60
    33
    17
        Week 72
    23
    14
    No statistical analyses for this end point

    Secondary: Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP

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    End point title
    Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP
    End point description
    The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Reported here are hours actually worked, work hours missed due to rheumatoid arthritis (RA), work hours missed due to other reasons and the change from Week 24 for each of these parameters reported at Week 60 and Week 72. Subjects in the ITT population with available data were analysed.
    End point type
    Secondary
    End point timeframe
    Randomisation (Week 24), Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: hours
    median (full range (min-max))
        Hours actually worked (HAW), Week 60 (n=33, 17)
    25 (0 to 58)
    28 (0 to 40)
        Change from Week 24 in HAW, Week 60 (n=29, 17)
    -1 (-47 to 40)
    2 (-43 to 38)
        Work hours missed (WHM) to RA, Week 60 (n=33, 17)
    0 (0 to 15)
    0 (0 to 35)
        Change from Week 24 in WHM RA, Week 60 (n=30, 16)
    0 (-30 to 15)
    0 (-7 to 21)
        WHM other, Week 60 (n=33, 17)
    0 (0 to 46)
    0 (0 to 35)
        Change from Week 24 WHM other, Week 60 (n=30, 16)
    0 (-56 to 46)
    0 (-38 to 35)
        HAW, Week 72 (n=23, 13)
    30 (0 to 48)
    16 (0 to 40)
        Change from Week 24 in HAW, Week 72, (n=20, 12)
    0 (-37 to 23)
    2.5 (-30 to 40)
        WHM to RA, Week 72 (n=23, 13)
    0 (0 to 37)
    0 (0 to 35)
        Change from Week 24 in WHM RA, Week 72 (n=21, 11)
    0 (-30 to 37)
    0 (-7 to 21)
        WHM other, Week 72 (n=23, 13)
    0 (0 to 30)
    0 (0 to 8)
        Change from Week 24 WHM other, Week 72 (n=21, 11)
    0 (-56 to 30)
    0 (-38 to 2)
    No statistical analyses for this end point

    Secondary: Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP

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    End point title
    Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP
    End point description
    The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Assessments were made using a visual analogue scale ranging from 0 to 10 where 0 = minimum impact and 10 = maximum impact. Subjects in the ITT population with available data at the respective time points were analysed.
    End point type
    Secondary
    End point timeframe
    Randomisation (Week 24), Week 60, 72
    End point values
    Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Number of subjects analysed
    136
    136
    Units: units on a scale
    median (full range (min-max))
        Productivity (P), Week 60 (n=34, 18)
    2 (0 to 8)
    2 (0 to 10)
        Change in P from Week 24 at Week 60 (n=30, 16)
    1 (-6 to 8)
    0 (-5 to 7)
        Regular Daily Activities (RDA), Week 60 (n=60, 45)
    3 (0 to 9)
    3 (0 to 9)
        Change in RDA from Week 24 at Week 60 (n=59, 44)
    0 (-5 to 7)
    0 (-6 to 6)
        Productivity (P), Week 72 (n=24, 12)
    3 (0 to 8)
    3 (0 to 9)
        Change in P from Week 24 at Week 72 (n=21, 11)
    0 (-3 to 4)
    0 (-5 to 7)
        Regular Daily Activities (RDA), Week 72 (n=42, 31)
    3 (0 to 10)
    3 (0 to 9)
        Change in RDA from Week 24 at Week 72 (n=41, 29)
    0 (-5 to 4)
    -1 (-5 to 7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment to unscheduled visit (up to Week 72)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Initial Phase
    Reporting group description
    At Week 0 participants started open-label tocilizumab and open-label MTX for 24 weeks, which was the initial phase of the study. Adverse events in this reporting group are those occurring in the open-label phase only.

    Reporting group title
    Methotrexate (MTX) Tapering Group
    Reporting group description
    After the open-label period ended at Week 24, subjects achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomised to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group subjects received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, subjects continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 subjects received tocilizumab monotherapy. Adverse events in this reporting group are those occurring in the double-blind phase only.

    Reporting group title
    Methotrexate (MTX) Maintenance Group
    Reporting group description
    After the open-label period ended at Week 24, subjects achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomised to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group subjects continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, subjects continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 subjects received tocilizumab monotherapy. Adverse events in this reporting group are those occurring in the double-blind phase only.

    Serious adverse events
    Initial Phase Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 427 (4.92%)
    9 / 136 (6.62%)
    3 / 136 (2.21%)
         number of deaths (all causes)
    1
    1
    0
         number of deaths resulting from adverse events
    0
    1
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 136 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 136 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    2 / 427 (0.47%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon neoplasm
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 136 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carcinoid tumour of the gastrointestinal tract
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 427 (0.47%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 427 (0.47%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery dissection
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 136 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterovesical fistula
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Telangiectasia
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 136 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 136 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 136 (1.47%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 427 (0.47%)
    2 / 136 (1.47%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 136 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 136 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 136 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 136 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 427 (0.47%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral labyrinthitis
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 136 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Initial Phase Methotrexate (MTX) Tapering Group Methotrexate (MTX) Maintenance Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    263 / 427 (61.59%)
    62 / 136 (45.59%)
    70 / 136 (51.47%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    16 / 427 (3.75%)
    7 / 136 (5.15%)
    6 / 136 (4.41%)
         occurrences all number
    20
    7
    7
    Fall
         subjects affected / exposed
    15 / 427 (3.51%)
    8 / 136 (5.88%)
    4 / 136 (2.94%)
         occurrences all number
    15
    10
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    51 / 427 (11.94%)
    6 / 136 (4.41%)
    7 / 136 (5.15%)
         occurrences all number
    59
    7
    8
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    23 / 427 (5.39%)
    9 / 136 (6.62%)
    8 / 136 (5.88%)
         occurrences all number
    26
    12
    9
    Cough
         subjects affected / exposed
    29 / 427 (6.79%)
    8 / 136 (5.88%)
    6 / 136 (4.41%)
         occurrences all number
    30
    9
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    38 / 427 (8.90%)
    8 / 136 (5.88%)
    6 / 136 (4.41%)
         occurrences all number
    58
    10
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    54 / 427 (12.65%)
    7 / 136 (5.15%)
    11 / 136 (8.09%)
         occurrences all number
    67
    14
    12
    Mouth ulceration
         subjects affected / exposed
    48 / 427 (11.24%)
    5 / 136 (3.68%)
    9 / 136 (6.62%)
         occurrences all number
    56
    6
    10
    Nausea
         subjects affected / exposed
    28 / 427 (6.56%)
    5 / 136 (3.68%)
    8 / 136 (5.88%)
         occurrences all number
    36
    7
    11
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    32 / 427 (7.49%)
    3 / 136 (2.21%)
    7 / 136 (5.15%)
         occurrences all number
    36
    3
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 427 (3.75%)
    8 / 136 (5.88%)
    9 / 136 (6.62%)
         occurrences all number
    21
    9
    10
    Musculoskeletal pain
         subjects affected / exposed
    13 / 427 (3.04%)
    7 / 136 (5.15%)
    6 / 136 (4.41%)
         occurrences all number
    15
    8
    6
    Back pain
         subjects affected / exposed
    16 / 427 (3.75%)
    2 / 136 (1.47%)
    7 / 136 (5.15%)
         occurrences all number
    18
    2
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    61 / 427 (14.29%)
    16 / 136 (11.76%)
    17 / 136 (12.50%)
         occurrences all number
    68
    17
    22
    Lower respiratory tract infection
         subjects affected / exposed
    41 / 427 (9.60%)
    11 / 136 (8.09%)
    12 / 136 (8.82%)
         occurrences all number
    46
    12
    13
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 427 (5.39%)
    12 / 136 (8.82%)
    7 / 136 (5.15%)
         occurrences all number
    25
    13
    8
    Urinary tract infection
         subjects affected / exposed
    19 / 427 (4.45%)
    9 / 136 (6.62%)
    6 / 136 (4.41%)
         occurrences all number
    21
    12
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2012
    - Information added to include pregnancy report and study drug compliance information. - Information removed for immunogenicity as it was confirmed that the sites would not receive results.
    09 Jul 2013
    - Modification of the time-point for the primary endpoint analysis changed from Week 56 to Week 60 in order to obtain data on 12 weeks monotherapy, versus 8 weeks, after completion of tapering, as this represents more clinically meaningful and robust data to support the expected success of the tapering strategy. - Total study treatment duration changed to 72 weeks to ensure patient access to the drug and to have data on 24 weeks after the completion of tapering. - Change in the definition of disease flare, as during the conduct of the study, it was identified that the previous disease flare definition (based on the increase in the combined number of tender and swollen joints from the previous study visit) could classify patients as having disease flare even if they were in remission. - Modification of inclusion criterion number 3 to further clarify that patients had to qualify for biologic therapy according to National Institute for Health and Clinical Excellence (NICE) in order to be eligible to participate in the study. - Modification of exclusion criterion number 2 to align with the current version of the summary of product characteristics (SmPC). Also addition of exclusion criterion number 40 for consistency in the clinical trial program. - Length of study changed to 42 months and recruitment period changed to 23 months to ensure sufficient time for completion of patient enrollment into the study.
    13 Sep 2013
    - Text added to permitted therapy to provide clarification of the use of DMARDs at Week 0. - Text rewritten on MTX/Placebo to avoid changing MTX dose to handle neutropenia, as it should be dealt with as per RoActemra (tocilizumab) SmPC.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    05 Feb 2015
    The study was terminated early due to difficulty with recruitment and a higher than expected withdrawal rate.
    -

    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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