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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy and Safety of Tocilizumab Versus Placebo in Patients With Systemic Sclerosis

    Summary
    EudraCT number
    2015-000424-28
    Trial protocol
    DK   DE   BE   LT   PT   ES   HU   NL   GR   HR   IE  
    Global end of trial date
    04 Feb 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Feb 2020
    First version publication date
    19 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WA29767
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02453256
    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
    04 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of tocilizumab compared with placebo in subjects with systemic sclerosis (SSc).
    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
    20 Nov 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    11 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Bulgaria: 26
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Japan: 20
    Country: Number of subjects enrolled
    Lithuania: 8
    Country: Number of subjects enrolled
    Mexico: 21
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    United States: 39
    Worldwide total number of subjects
    210
    EEA total number of subjects
    116
    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)
    193
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Overall 212 participants were randomized on to the study, 107 to the placebo arm and 105 to the Tocilizumab arm. One participant in placebo arm withdrew consent prior to receiving any treatment and one participant in the tocilizumab arm was withdrawn due to randomization error prior to receiving any treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Double-Blind Placebo, then Open Label Tocilizumab
    Arm description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered a subcutaneous (SC) injection of matching placebo once weekly (QW) for 48 weeks during the double-blind period.

    Arm title
    Double-Blind Tocilizumab, then Open Label Tocilizumab
    Arm description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.
    Arm type
    Experimental

    Investigational medicinal product name
    tocilizumab
    Investigational medicinal product code
    Other name
    Actemra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered a subcutaneous (SC) injection of tocilizumab 162 mg once weekly (QW) for 48 weeks during the double-blind treatment period.

    Number of subjects in period 1
    Double-Blind Placebo, then Open Label Tocilizumab Double-Blind Tocilizumab, then Open Label Tocilizumab
    Started
    106
    104
    Completed
    93
    95
    Not completed
    13
    9
         Adverse event, serious fatal
    1
    1
         Adverse event, non-fatal
    3
    2
         Consent withdrawn by subject
    9
    5
         Not Specified
    -
    1
    Period 2
    Period 2 title
    Open Label Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Double-Blind Placebo, then Open Label Tocilizumab
    Arm description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.
    Arm type
    Active comparator

    Investigational medicinal product name
    tocilizumab
    Investigational medicinal product code
    Other name
    Actemra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered a subcutaneous (SC) injection of tocilizumab (TCZ) 162 mg once weekly (QW) during the open label period for up to 48 weeks. First dose of open-label TCZ was at Week 48.

    Arm title
    Double-Blind Tocilizumab, then Open Label Tocilizumab
    Arm description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.
    Arm type
    Experimental

    Investigational medicinal product name
    tocilizumab
    Investigational medicinal product code
    Other name
    Actemra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered a subcutaneous (SC) injection of tocilizumab (TCZ) 162 mg once weekly (QW) for 48 weeks during the open label period. First dose of open-label TCZ was at Week 48.

    Number of subjects in period 2 [1]
    Double-Blind Placebo, then Open Label Tocilizumab Double-Blind Tocilizumab, then Open Label Tocilizumab
    Started
    89
    92
    Completed
    82
    85
    Not completed
    7
    7
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    1
    3
         Consent withdrawn by subject
    5
    1
         Not Specified
    -
    2
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some participants who completed the double-blind period did not start the open-label period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-Blind Placebo, then Open Label Tocilizumab
    Reporting group description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.

    Reporting group title
    Double-Blind Tocilizumab, then Open Label Tocilizumab
    Reporting group description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.

    Reporting group values
    Double-Blind Placebo, then Open Label Tocilizumab Double-Blind Tocilizumab, then Open Label Tocilizumab Total
    Number of subjects
    106 104
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    49.3 ± 12.6 47.0 ± 12.2 -
    Sex: Female, Male
    Units: Participants
        Female
    90 81 171
        Male
    16 23 39

    End points

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    End points reporting groups
    Reporting group title
    Double-Blind Placebo, then Open Label Tocilizumab
    Reporting group description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.

    Reporting group title
    Double-Blind Tocilizumab, then Open Label Tocilizumab
    Reporting group description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.
    Reporting group title
    Double-Blind Placebo, then Open Label Tocilizumab
    Reporting group description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.

    Reporting group title
    Double-Blind Tocilizumab, then Open Label Tocilizumab
    Reporting group description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Placebo, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Tocilizumab, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants then received open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Tocilizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Tocilizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Tocilizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Tocilizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Placebo, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Subject analysis set title
    Tocilizumab, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Subject analysis set title
    Double-Blind Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Double-Blind Tocilizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Placebo, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Subject analysis set title
    Tocilizumab, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Subject analysis set title
    Placebo, then Tocilizumab Open Labe
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Subject analysis set title
    Tocilizumab, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Subject analysis set title
    Double-Blind Tocilizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Subject analysis set title
    Placebo, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Subject analysis set title
    Tocilizumab, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Subject analysis set title
    Placebo, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Subject analysis set title
    Tocilizumab, then Tocilizumab Open Label
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Primary: Change in Modified Rodnan Skin Score (mRSS) During Double-blind Period

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    End point title
    Change in Modified Rodnan Skin Score (mRSS) During Double-blind Period
    End point description
    The efficacy of TCZ vs placebo is evaluated in terms of in mean change in mRSS. Skin thickness will be assessed by palpation and rated using an mRSS that ranges from 0 (normal) to 3 (severe skin thickening) across 17 different body sites. The total score is the sum of the individual skin scores from all of these sites and ranges from 0 to 51 units. The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all participants who were randomized and received any study drug.
    End point type
    Primary
    End point timeframe
    From baseline to week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    104
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    -4.41 (-5.96 to -2.86)
    -6.14 (-7.71 to -4.57)
    Statistical analysis title
    Placebo versus Tocilizumab
    Statistical analysis description
    Difference in least square means between the TCZ group and the Placebo group at week 48. Null hypothesis: There is no difference between the TCZ group and the placebo group in mean change in mRSS from baseline to Week 48.
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0983
    Method
    Repeated Measure
    Parameter type
    Difference in least square means
    Point estimate
    -1.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.78
         upper limit
    0.32

    Secondary: Percentage of Participants with Greater Than or Equal to (>/=) 20%, 40%, or 60% Improvement in mRSS During Double-blind Period

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    End point title
    Percentage of Participants with Greater Than or Equal to (>/=) 20%, 40%, or 60% Improvement in mRSS During Double-blind Period
    End point description
    The proportion of participants with threshold improvements in mRSS at Week 48 relative to baseline. The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all participants who were randomized and received any study drug.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    104
    Units: Percentage of Participants
    number (confidence interval 95%)
        ≥ 20%
    50.0 (40.01 to 59.99)
    72.1 (63.02 to 81.21)
        ≥ 40%
    37.7 (28.04 to 47.44)
    42.3 (32.33 to 52.28)
        ≥ 60%
    22.6 (14.20 to 31.08)
    17.3 (9.56 to 25.06)
    Statistical analysis title
    Placebo versus Tocilizumab
    Statistical analysis description
    This statistical analysis applies to participants with ≥ 20% improvement in mRSS.
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    21.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.2
         upper limit
    34.6
    Statistical analysis title
    Placebo versus Tocilizumab
    Statistical analysis description
    This statistical analysis applies to participants with ≥ 40% improvement in mRSS.
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5139
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    4.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.7
         upper limit
    17.3
    Statistical analysis title
    Placebo versus Tocilizumab
    Statistical analysis description
    This statistical analysis applies to participants with ≥ 60% improvement in mRSS.
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3276
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted difference
    Point estimate
    -5.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.2
         upper limit
    5.4

    Secondary: Change from baseline in percent predicted FVC (ppFVC) During Double-blind Period

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    End point title
    Change from baseline in percent predicted FVC (ppFVC) During Double-blind Period
    End point description
    FVC is pulmonary function test and will be conducted as per the study Pulmonary Function Manual, which is based on the American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement. FVC is the maximum amount of air exhaled from the lungs after taking the deepest breath possible. Patients perform three to eight exhalations into a spirometer with the highest value recorded. The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all participants who were randomized and received any study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    104
    Units: Percent Predicted FVC
        median (confidence interval 95%)
    -3.910 (-4.820 to -1.620)
    -0.600 (-2.380 to 0.880)
    Statistical analysis title
    Placebo versus Tocilizumab
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0015 [1]
    Method
    Van Elteren
    Confidence interval
    Notes
    [1] - P-value from Van Elteren analysis stratified by IL-6 level (<10; >=10 pg/mL) at screening.

    Secondary: Change in Forced Vital Capacity (FVC) During Double-blind Period

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    End point title
    Change in Forced Vital Capacity (FVC) During Double-blind Period
    End point description
    FVC is pulmonary function test and will be conducted as per the study Pulmonary Function Manual, which is based on the American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement. FVC is the maximum amount of air exhaled from the lungs after taking the deepest breath possible. Patients perform three to eight exhalations into a spirometer with the highest value recorded. The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all participants who were randomized and received any study drug.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    104
    Units: Liters of air
        least squares mean (confidence interval 95%)
    -0.19 (-0.25 to -0.13)
    -0.02 (-0.09 to 0.04)
    Statistical analysis title
    Placebo versus Tocilizumab
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Repeated Measure
    Parameter type
    Difference in least square means
    Point estimate
    0.167
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.083
         upper limit
    0.25

    Secondary: Change in Health Assessment Questionnaire Disability Index (HAQ-DI) Score During Double-blind Period

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    End point title
    Change in Health Assessment Questionnaire Disability Index (HAQ-DI) Score During Double-blind Period
    End point description
    The Health Assessment Questionnaire Disability Index (HAQ-DI) consists of 20 questions referring to eight component sets consisting of dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each item is scored on a 4-point scale from 0 to 3: 0 = Without any difficulty; 1 = With some difficulty; 2 = With much difficulty; 3 = Unable to do. Overall score was computed as the sum of component set scores and divided by the number of component sets answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. The total score indicates the patient’s self-assessed level of disability. This outcome measure represents the change in mean score from baseline. A negative change from baseline indicates improvement. The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all participants who were randomized and received any study drug.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    104
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    -0.06 (-0.16 to 0.05)
    -0.11 (-0.22 to -0.01)
    Statistical analysis title
    Placebo versus Tocilizumab
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4489
    Method
    Repeated Measure
    Parameter type
    Difference in least square means
    Point estimate
    -0.053
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.192
         upper limit
    0.085

    Secondary: Change in Patient Global Assessment Score During Double-blind Period

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    End point title
    Change in Patient Global Assessment Score During Double-blind Period
    End point description
    The Patient's Global Assessment represents the patient’s overall assessment of current SSc status on a 100-mm horizontal visual analogue scale (VAS), ranging from 0 on the extreme left end of the scale indicating “has no effect at all” (symptom free), and 100 on the extreme right end indicating “worst possible effect”. The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all participants who were randomized and received any study drug.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    104
    Units: mm
        least squares mean (confidence interval 95%)
    -7.66 (-12.31 to -3.02)
    -10.10 (-14.79 to -5.41)
    Statistical analysis title
    Placebo versus Tocilizumab
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4339
    Method
    Repeated Measure
    Parameter type
    Difference in least square means
    Point estimate
    -2.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.57
         upper limit
    3.7

    Secondary: Change in Physician Global Assessment Score During Double-blind Period

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    End point title
    Change in Physician Global Assessment Score During Double-blind Period
    End point description
    The Physician's Global Assessment is to be completed on the basis of examination and overall assessment of the patient. The physician’s assessment of the patient’s SSc status will be scored on a 100-mm horizontal visual analogue scale (VAS), ranging from 0 on the extreme left end of the scale indicating “has no effect at all” (symptom free), and 100 on the extreme right end indicating “worst possible effect”. The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all participants who were randomized and received any study drug.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    104
    Units: mm
        least squares mean (confidence interval 95%)
    -19.99 (-24.76 to -15.22)
    -22.45 (-27.33 to -17.57)
    Statistical analysis title
    Placebo versus Tocilizumab
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4378
    Method
    Repeated Measure
    Parameter type
    Difference in least square means
    Point estimate
    -2.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.72
         upper limit
    3.79

    Secondary: Time to Treatment Failure According to mRSS, FVC, or Protocol-Specified Event During Double-blind Period

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    End point title
    Time to Treatment Failure According to mRSS, FVC, or Protocol-Specified Event During Double-blind Period
    End point description
    Time to treatment failure is defined as the time from randomization to the time of death, decline in percent-predicted FVC > 10% relative to baseline, > 20% increase in mRSS and an increase in mRSS of equal to or more than 5 points, or occurrence of a predefined SSc-related complication as adjudicated by the Clinical Adjudication Committee (whichever occurs first) during the 48-week double-blind treatment period. The median TTF was not estimable and is not presented for either treatment arm because of the low number of patients with events at Week 48. The analysis was conducted in the Intent-to-treat (ITT) population, i.e. all participants who were randomized and received any study drug. 99999 = not evaluable.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    104
    Units: months
        median (confidence interval 95%)
    99999 (48.7 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Placebo versus Tocilizumab
    Comparison groups
    Double-Blind Placebo v Double-Blind Tocilizumab
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0821
    Method
    Cox-proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    1.06

    Secondary: Frequency of Serious Systemic Sclerosis (SSC) Related Complications During Double-blind Period

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    End point title
    Frequency of Serious Systemic Sclerosis (SSC) Related Complications During Double-blind Period
    End point description
    Adverse event terms coded using MedDRA 20.1. Includes only those serious events adjudicated as SSC-related complications by an independent external committee.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    104
    Units: Number of Participants
        CARDIAC FAILURE
    0
    1
        CARDIAC FAILURE CHRONIC
    1
    0
        MICROVASCULAR CORONARY ARTERY DISEASE
    1
    0
        MYOCARDITIS
    1
    0
        INFECTED SKIN ULCER
    1
    0
        OSTEOMYELITIS
    0
    1
        WOUND INFECTION
    0
    1
        ILEUS PARALYTIC
    1
    0
        PAIN
    1
    0
        WEIGHT DECREASED
    0
    1
        SCLERODERMA
    1
    0
        HYPOKINESIA
    0
    1
        ADJUSTMENT DISORDER
    1
    0
        SCLERODERMA RENAL CRISIS
    0
    1
        DIGITAL PITTING SCAR
    1
    0
    No statistical analyses for this end point

    Secondary: Correlation Between Anti-Tocilizumab Antibody Status and Outcome Measures Pertaining to the Efficacy, Safety, and Pharmacokinetics of Tocilizumab

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    End point title
    Correlation Between Anti-Tocilizumab Antibody Status and Outcome Measures Pertaining to the Efficacy, Safety, and Pharmacokinetics of Tocilizumab
    End point description
    Pre-specified analysis of the relationship between Anti-Tocilizumab Antibody status and safety, efficacy, and PK endpoints were not analyzed via subgroup analyses as there was only 1 participant with anti-tocilizumab antibody-positive status.
    End point type
    Secondary
    End point timeframe
    Baseline; during Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Units on a scale
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [2] - Correlation not analyzed as there was only one anti-TCZ antibody positive participant in the study.
    [3] - Correlation not analyzed as there was only one anti-TCZ antibody positive participant in the study.
    No statistical analyses for this end point

    Secondary: Correlation Between Low Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

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    End point title
    Correlation Between Low Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    30
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    20.4 ± 6.95
    20.3 ± 5.56
        Week 8
    18.6 ± 7.78
    17.9 ± 5.84
        Week 16
    17.9 ± 8.71
    16.2 ± 5.58
        Week 24
    16.9 ± 9.38
    14.7 ± 5.61
        Week 36
    16.2 ± 10.24
    13.2 ± 4.97
        Week 48
    14.8 ± 9.89
    12.2 ± 6.03
    No statistical analyses for this end point

    Secondary: Correlation Between Low Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

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    End point title
    Correlation Between Low Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    30
    Units: Units on a scale
    median (full range (min-max))
        Baseline
    19.0 (10 to 40)
    20.0 (11 to 31)
        Week 8
    18.0 (4 to 43)
    16.0 (9 to 34)
        Week 16
    17.0 (0 to 38)
    15.0 (8 to 30)
        Week 24
    16.0 (0 to 42)
    14.0 (6 to 29)
        Week 36
    14.0 (0 to 47)
    13.5 (5 to 27)
        Week 48
    14.0 (0 to 43)
    12.5 (2 to 30)
    No statistical analyses for this end point

    Secondary: Correlation Between Medium Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

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    End point title
    Correlation Between Medium Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    29
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    20.4 ± 6.95
    19.1 ± 6.24
        Week 8
    18.6 ± 7.78
    17.2 ± 6.17
        Week 16
    17.9 ± 8.71
    16.2 ± 6.10
        Week 24
    16.9 ± 9.38
    14.6 ± 6.66
        Week 36
    16.2 ± 10.24
    13.4 ± 6.20
        Week 48
    14.8 ± 9.89
    11.6 ± 5.72
    No statistical analyses for this end point

    Secondary: Correlation Between Medium Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

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    End point title
    Correlation Between Medium Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    29
    Units: Units on a scale
    median (full range (min-max))
        Baseline
    19.0 (10 to 40)
    18.0 (10 to 35)
        Week 8
    18.0 (4 to 43)
    17.0 (5 to 31)
        Week 16
    17.0 (0 to 38)
    16.0 (5 to 27)
        Week 24
    16.0 (0 to 42)
    14.0 (3 to 28)
        Week 36
    14.0 (0 to 47)
    13.0 (2 to 25)
        Week 48
    14.0 (0 to 43)
    11.0 (0 to 24)
    No statistical analyses for this end point

    Secondary: Correlation Between High Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

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    End point title
    Correlation Between High Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    29
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    20.4 ± 6.95
    19.8 ± 6.82
        Week 8
    18.6 ± 7.78
    17.9 ± 7.35
        Week 16
    17.9 ± 8.71
    16.7 ± 7.31
        Week 24
    16.9 ± 9.38
    15.6 ± 7.50
        Week 36
    16.2 ± 10.24
    13.7 ± 7.07
        Week 48
    14.8 ± 9.89
    12.8 ± 7.20
    No statistical analyses for this end point

    Secondary: Correlation Between High Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48

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    End point title
    Correlation Between High Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab
    Number of subjects analysed
    106
    29
    Units: Units on a scale
    median (full range (min-max))
        Baseline
    19.0 (10 to 40)
    19.0 (11 to 33)
        Week 8
    18.0 (4 to 43)
    17.5 (5 to 32)
        Week 16
    17.0 (0 to 38)
    15.0 (6 to 33)
        Week 24
    16.0 (0 to 42)
    15.0 (2 to 31)
        Week 36
    14.0 (0 to 47)
    11.0 (4 to 30)
        Week 48
    14.0 (0 to 43)
    11.0 (4 to 34)
    No statistical analyses for this end point

    Secondary: Change in Mean Modified Rodnan Skin Score (mRSS) at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48

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    End point title
    Change in Mean Modified Rodnan Skin Score (mRSS) at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Tocilizumab Double-Blind Placebo
    Number of subjects analysed
    30
    92
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Low Exposure
    -8.0 ± 5.85
    -5.3 ± 7.77
        Medium Exposure
    -7.5 ± 5.06
    -5.3 ± 7.77
        High Exposure
    -7.0 ± 6.26
    -5.3 ± 7.77
    No statistical analyses for this end point

    Secondary: Change in Median Modified Rodnan Skin Score (mRSS), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48

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    End point title
    Change in Median Modified Rodnan Skin Score (mRSS), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Tocilizumab Double-Blind Placebo
    Number of subjects analysed
    30
    92
    Units: Units on a scale
    median (full range (min-max))
        Low Exposure
    -8.0 (-19 to 4)
    -5.5 (-25 to 22)
        Medium Exposure
    -7.0 (-18 to 2)
    -5.5 (-25 to 22)
        High Exposure
    -6.0 (-20 to 6)
    -5.5 (-25 to 22)
    No statistical analyses for this end point

    Secondary: Change in Mean Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48

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    End point title
    Change in Mean Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, ppFVC scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Tocilizumab Double-Blind Placebo
    Number of subjects analysed
    29
    91
    Units: Percent
    arithmetic mean (standard deviation)
        Low Exposure
    0.144 ± 6.474
    -4.264 ± 8.155
        Medium Exposure
    -0.161 ± 6.440
    -4.264 ± 8.155
        High Exposure
    -0.297 ± 7.895
    -4.264 ± 8.155
    No statistical analyses for this end point

    Secondary: Change in Median Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48

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    End point title
    Change in Median Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48
    End point description
    In order to characterize exposure-efficacy relationships, ppFVC scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-<41 ug/ml, Medium = 41-<=61.1 ug/ml, High = 61.1-<=145 ug/ml.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Double-Blind Tocilizumab Double-Blind Placebo
    Number of subjects analysed
    29
    91
    Units: Percent
    median (full range (min-max))
        Low Exposure
    0.525 (-14.25 to 11.38)
    -3.910 (-31.47 to 13.47)
        Medium Exposure
    -1.600 (-13.83 to 17.00)
    -3.910 (-31.47 to 13.47)
        High Exposure
    0.000 (-10.55 to 19.69)
    -3.910 (-31.47 to 13.47)
    No statistical analyses for this end point

    Secondary: Summary of Adverse Events Up to Week 96

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    End point title
    Summary of Adverse Events Up to Week 96
    End point description
    Summary of key safety results including Adverse Events of Special Interest (AESI). All adverse events categorized according to MedDRA version 21.1. NMSC = Non-Melanoma Skin Cancer. The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Label Tocilizumab, then Tocilizumab Open Label
    Number of subjects analysed
    106
    104
    89
    92
    Units: Percentage of participants
    number (not applicable)
        At least one Adverse Event (AE)
    77.4
    85.6
    77.5
    71.7
        Withdrawn from study due to an AE
    12.3
    6.7
    1.1
    1.1
        Fatal AE
    2.8
    1.0
    1.1
    1.1
        Serious Adverse Events (SAEs)
    17.0
    12.5
    7.9
    10.9
        SAE leading to withdrawal from treatment
    5.7
    4.8
    1.1
    1.1
        SAE leading to dose modification/interruption
    5.7
    2.9
    4.5
    3.3
        SAE related to study drug
    6.6
    1.0
    3.4
    3.3
        AE leading to withdrawal from treatment
    12.3
    6.7
    1.1
    1.1
        AE leading to dose modification/interruption
    26.4
    19.2
    28.1
    22.8
        AE related to study drug
    34.0
    46.2
    33.7
    34.8
        Related AE leading to withdrawal from treatment
    1.9
    1.0
    1.1
    1.1
        Related AE with dose modification/interruption
    17.0
    11.5
    12.4
    14.1
        Serious Infections and Infestations AEs
    6.6
    1.9
    3.4
    1.1
        Infections and Infestations AEs
    50.0
    52.9
    46.1
    39.1
        Opportunistic Infections AEs
    0.9
    1.0
    0
    1.1
        Malignancy AEs
    0.9
    1.9
    0
    1.1
        Malignancy AEs (excluding NMSC)
    0.9
    1.9
    0
    1.1
        Serious Hepatic AEs
    0
    0
    0
    0
        Serious Stroke AEs
    0
    0
    0
    0
        Serious Myocardial Infarction AEs
    1.9
    0
    0
    0
        Anaphylactic Reaction AEs
    0
    0
    0
    0
        Anaphylactic Reaction AEs (Sampson's Criteria)
    0
    0
    0
    0
        Serious Gastrointestinal Perforation AEs
    0
    0
    0
    0
        Serious Bleeding AEs
    0.9
    0
    0
    0
        Serious Demyelinating AEs
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Incidence and Severity of Adverse Events Up to Week 96

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    End point title
    Incidence and Severity of Adverse Events Up to Week 96
    End point description
    Adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) severity grade: 1 = mild, 2 = moderate, 3 = severe and/or requiring medical intervention but not life-threatening, 4 = life-threatening consequences, and 5 = death. The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Label Tocilizumab, then Tocilizumab Open Label
    Number of subjects analysed
    106
    104
    89
    92
    Units: Number of participants
        Grade 1
    61
    78
    60
    53
        Grade 2
    63
    53
    41
    35
        Grade 3
    21
    18
    9
    8
        Grade 4
    7
    0
    4
    5
        Grade 5
    3
    1
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events Leading to Death Up to Week 96

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    End point title
    Number of Participants With Adverse Events Leading to Death Up to Week 96
    End point description
    The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Label Tocilizumab, then Tocilizumab Open Label
    Number of subjects analysed
    106
    104
    89
    92
    Units: Number of participants
        CARDIAC FAILURE CHRONIC
    1
    0
    0
    0
        MYOCARDITIS
    1
    0
    0
    0
        MYOCARDIAL INFARCTION
    1
    0
    0
    0
        DEATH
    0
    1
    0
    0
        BRAIN INJURY
    0
    0
    1
    0
        PULMONARY HYPERTENSION
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Change in Digital Ulcer Count at Week 96

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    End point title
    Percentage of Participants With Change in Digital Ulcer Count at Week 96
    End point description
    A digital ulcer is defined as an ulcer at or distal to the MCP joint on either the dorsal or volar surface, with loss of surface epithelialization. This does not include fissures, cracks, or calcium extrusions from calcinosis cutis. The number of fingers (0−10) with digital ulcers and the number of digital (or finger) ulcers will be counted and recorded by the investigator. The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 96
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Label Tocilizumab, then Tocilizumab Open Label
    Number of subjects analysed
    106
    104
    89
    92
    Units: Percentage of participants
    number (not applicable)
        No change
    0
    0
    91.1
    83.3
        Increase by 1
    0
    0
    0
    4.8
        Increase by 2
    0
    0
    0
    1.2
        Increase by 3
    0
    0
    0
    1.2
        Increase by 4
    0
    0
    0
    0
        Increase by >4
    0
    0
    0
    1.2
        Decrease by 1
    0
    0
    3.8
    4.8
        Decrease by 2
    0
    0
    2.5
    0
        Decrease by 3
    0
    0
    1.3
    1.2
        Decrease by 4
    0
    0
    1.3
    1.2
        Decrease by >4
    0
    0
    0
    0
        Baseline missing
    0
    0
    0
    1.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Positive Anti-Tocilizumab Assay Up to Week 96

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    End point title
    Percentage of Participants with Positive Anti-Tocilizumab Assay Up to Week 96
    End point description
    Reported were the percentage of participants with anti-TCZ antibodies. Positive samples underwent additional analyses: a neutralizing assay for the ability to inhibit the activity of TCZ and a test for anti -TCZ of the IgE isotype. Safety population: received at least one dose of study drug and provide data from at least one post dose safety assessment. 9999 = not evaluated
    End point type
    Secondary
    End point timeframe
    Baseline, double-blind period (up to Week 48), open label period (from Week 48 to Week 96)
    End point values
    Double-Blind Placebo, then Tocilizumab Open Label Double-Blind Tocilizumab, then Tocilizumab Open Label
    Number of subjects analysed
    101
    104
    Units: Percentage of Participants
    number (not applicable)
        Baseline
    5.9
    2.9
        Double-blind: Positive anti-TCZ assay
    0.0
    2.9
        Double-blind: Positive confirmation assay
    0.0
    1.0
        Double-blind: Positive neutralizing assay
    0.0
    1.0
        Double-blind: Positive IgE assay
    0.0
    0.0
        Open label: Positive anti-TCZ assay
    9999
    0.0
        Open label: Positive neutralizing assay
    9999
    0.0
        Open label: Positive IgE assay
    9999
    0.0
    No statistical analyses for this end point

    Secondary: Erythrocyte Sedimentation Rate (ESR) Up to Week 96

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    End point title
    Erythrocyte Sedimentation Rate (ESR) Up to Week 96
    End point description
    Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug. The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment. 9999 indicates that 0 participants were analyzed for the specific arm and time point. n indicates the number of participants analyzed for the specific time point per arm.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Label Tocilizumab, then Tocilizumab Open Label
    Number of subjects analysed
    103
    100
    82
    89
    Units: mm/hr
    arithmetic mean (standard deviation)
        Baseline: n=103,100,0,0
    34.72 ± 18.49
    34.83 ± 16.29
    9999 ± 9999
    9999 ± 9999
        Week 4: n=96,98,0,0
    31.38 ± 19.00
    14.29 ± 12.98
    9999 ± 9999
    9999 ± 9999
        Week 24: n=98,94,0,0
    28.49 ± 20.86
    8.46 ± 8.63
    9999 ± 9999
    9999 ± 9999
        Week 48: n=91,93,0,0
    26.23 ± 18.53
    10.89 ± 15.39
    9999 ± 9999
    9999 ± 9999
        Week 72: n=0,0,82,89
    9999 ± 9999
    9999 ± 9999
    9.54 ± 9.47
    8.29 ± 10.13
        Week 96: n=0,0,79,85
    9999 ± 9999
    9999 ± 9999
    9.67 ± 8.67
    8.06 ± 8.86
    No statistical analyses for this end point

    Secondary: Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 96

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    End point title
    Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 96
    End point description
    Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug. The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment. 9999 indicates that 0 participants were analyzed for the specific arm and time point. n indicates the number of participants analyzed for the specific time point per arm.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Labe Tocilizumab, then Tocilizumab Open Label
    Number of subjects analysed
    106
    104
    79
    79
    Units: pg/mL
    arithmetic mean (standard deviation)
        Baseline: n=106,104,0,0
    11.85 ± 19.73
    13.86 ± 43.78
    9999 ± 9999
    9999 ± 9999
        Week 4: n=95,98,0,0
    13.41 ± 29.98
    144.75 ± 429.14
    9999 ± 9999
    9999 ± 9999
        Week 8: n=95,94,0,0
    14.21 ± 26.82
    111.44 ± 280.34
    9999 ± 9999
    9999 ± 9999
        Week 16: n=93,88,0,0
    15.40 ± 24.26
    66.20 ± 70.50
    9999 ± 9999
    9999 ± 9999
        Week 24: n=85,85,0,0
    11.81 ± 24.05
    62.74 ± 53.40
    9999 ± 9999
    9999 ± 9999
        Week 36: n=73,83,0,0
    9.32 ± 15.23
    62.15 ± 68.08
    9999 ± 9999
    9999 ± 9999
        Week 48: n=81,82,0,0
    9.10 ± 14.88
    53.34 ± 56.80
    9999 ± 9999
    9999 ± 9999
        Week 96: n=0,0,79,79
    9999 ± 9999
    9999 ± 9999
    62.60 ± 57.21
    52.03 ± 46.51
    No statistical analyses for this end point

    Secondary: Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, Up to Week 96

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    End point title
    Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, Up to Week 96
    End point description
    Serum Soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug. The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment. 9999 indicates that 0 participants were analyzed for the specific arm and time point. n indicates the number of participants analyzed for the specific time point per arm.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Label Tocilizumab, then Tocilizumab Open Label
    Number of subjects analysed
    103
    102
    79
    85
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline: n=100,102,0,0
    42.23 ± 32.56
    42.15 ± 14.50
    9999 ± 9999
    9999 ± 9999
        Week 4: n=103,101,0,0
    46.07 ± 73.52
    487.70 ± 123.02
    9999 ± 9999
    9999 ± 9999
        Week 8: n=103,101,0,0
    45.71 ± 57.95
    546.59 ± 142.58
    9999 ± 9999
    9999 ± 9999
        Week 16: n=102,96,0,0
    47.81 ± 68.22
    583.87 ± 164.36
    9999 ± 9999
    9999 ± 9999
        Week 24: n=95,95,0,0
    41.35 ± 15.17
    587.28 ± 153.90
    9999 ± 9999
    9999 ± 9999
        Week 36: n=89,93,0,0
    38.13 ± 11.22
    589.59 ± 140.63
    9999 ± 9999
    9999 ± 9999
        Week 48: n=93,92,0,0
    49.51 ± 76.17
    566.49 ± 175.25
    9999 ± 9999
    9999 ± 9999
        Week 96: n=0,0,79,85
    9999 ± 9999
    9999 ± 9999
    558.38 ± 256.86
    565.31 ± 159.82
    No statistical analyses for this end point

    Secondary: Serum C-Reactive Protein (CRP) Level, Mean, Up to Week 96

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    End point title
    Serum C-Reactive Protein (CRP) Level, Mean, Up to Week 96
    End point description
    Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug. The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment. 9999 indicates that 0 participants were analyzed for the specific arm and time point. n indicates the number of participants analyzed for the specific time point per arm.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 96
    End point values
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Label Tocilizumab, then Tocilizumab Open Label
    Number of subjects analysed
    106
    104
    83
    90
    Units: mg/L
    arithmetic mean (standard deviation)
        Baseline: n=106,104,0,0
    7.42 ± 12.62
    8.99 ± 14.76
    9999 ± 9999
    9999 ± 9999
        Week 4: n=103,103,0,0
    10.05 ± 20.82
    0.85 ± 2.50
    9999 ± 9999
    9999 ± 9999
        Week 24: n=100,97,0,0
    9.89 ± 13.99
    0.56 ± 1.19
    9999 ± 9999
    9999 ± 9999
        Week 48: n=93,96,0,0
    7.40 ± 12.62
    1.75 ± 6.43
    9999 ± 9999
    9999 ± 9999
        Week 72: n=0,0,82,90
    9999 ± 9999
    9999 ± 9999
    0.57 ± 0.80
    0.92 ± 3.61
        Week 96: n=0,0,83,86
    9999 ± 9999
    9999 ± 9999
    0.90 ± 2.73
    0.97 ± 5.08
    No statistical analyses for this end point

    Secondary: Serum Tocilizumab Concentration, Mean, Up to Week 96

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    End point title
    Serum Tocilizumab Concentration, Mean, Up to Week 96 [4]
    End point description
    Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter. The PK population included all participants who received at least one TCZ injection and had at least one PK sample with detectable results. Only samples from the Double Blind TCZ, then Open Label TCZ were measured by the lab after week 48. Data for the Double Blind Period were reported at the time in separate endpoint up to Week 48. n indicates the number of participants analyzed for the specific time point per arm.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    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: Serum tocilizumab was only measured after Week 48 in participants treated with tocilizumab throughout the study.
    End point values
    Double-Blind Tocilizumab, then Open Label Tocilizumab
    Number of subjects analysed
    103
    Units: ug/mL
    arithmetic mean (standard deviation)
        Baseline: n=101
    0.00 ± 0.03
        Week 4: n=101
    30.76 ± 15.23
        Week 8: n=100
    41.82 ± 17.66
        Week 16: n=93
    50.98 ± 23.33
        Week 24: n=93
    54.34 ± 26.24
        Week 36: n=91
    53.55 ± 29.25
        Week 48: n=89
    54.87 ± 29.69
        Week 96: n=82
    49.99 ± 26.19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 96
    Adverse event reporting additional description
    The analysis was conducted in the safety population i.e. received at least one dose of study drug and provide data from at least one post dose safety assessment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Double-Blind Placebo
    Reporting group description
    Participants received double-blind matching placebo from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Reporting group title
    Double-Blind Tocilizumab
    Reporting group description
    Participants received double-blind tocilizumab from Baseline to Week 48. Participants may then receive open-label tocilizumab from Weeks 48 to 96.

    Reporting group title
    Placebo, then Tocilizumab Open Label
    Reporting group description
    Participants who received placebo during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Reporting group title
    Tocilizumab, then Tocilizumab Open Label
    Reporting group description
    Participants who received tocilizumab during the double blind period from Baseline to Week 48, received tocilizumab from Week 48 to Week 96.

    Serious adverse events
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Label Tocilizumab, then Tocilizumab Open Label
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 106 (16.98%)
    13 / 104 (12.50%)
    7 / 89 (7.87%)
    10 / 92 (10.87%)
         number of deaths (all causes)
    3
    1
    1
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-CELL LYMPHOMA
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BENIGN BONE NEOPLASM
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG ADENOCARCINOMA
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    DEATH
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    ADJUSTMENT DISORDER
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    LIMB TRAUMATIC AMPUTATION
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL CORD INJURY
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CHRONIC
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    MICROVASCULAR CORONARY ARTERY DISEASE
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    MYOCARDITIS
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    ARRHYTHMIA
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC TAMPONADE
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONGESTIVE CARDIOMYOPATHY
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PLEURAL EFFUSION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY HYPERTENSION
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    ANAEMIA MEGALOBLASTIC
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYMPHADENOPATHY MEDIASTINAL
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    BRAIN INJURY
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    RETINAL VEIN THROMBOSIS
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ILEUS PARALYTIC
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS EROSIVE
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RECTAL PROLAPSE
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SCLERODERMA RENAL CRISIS
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DIGITAL PITTING SCAR
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ECCHYMOSIS
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SKIN ULCER
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    SCLERODERMA
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JOINT STIFFNESS
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TENDONITIS
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TENOSYNOVITIS
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRIGGER FINGER
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DIABETIC KETOACIDOSIS
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    PNEUMONIA
         subjects affected / exposed
    3 / 106 (2.83%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTED SKIN ULCER
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PELVIC INFLAMMATORY DISEASE
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS CHRONIC
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SOFT TISSUE INFECTION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 104 (0.96%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTIVE TENOSYNOVITIS
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OTITIS MEDIA
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 104 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Double-Blind Placebo Double-Blind Tocilizumab Placebo, then Tocilizumab Open Label Tocilizumab, then Tocilizumab Open Label
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 106 (55.66%)
    60 / 104 (57.69%)
    46 / 89 (51.69%)
    28 / 92 (30.43%)
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    6 / 106 (5.66%)
    2 / 104 (1.92%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
         occurrences all number
    6
    2
    1
    0
    Respiratory, thoracic and mediastinal disorders
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    8 / 106 (7.55%)
    2 / 104 (1.92%)
    1 / 89 (1.12%)
    1 / 92 (1.09%)
         occurrences all number
    8
    2
    1
    1
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    6 / 106 (5.66%)
    2 / 104 (1.92%)
    1 / 89 (1.12%)
    1 / 92 (1.09%)
         occurrences all number
    6
    2
    1
    1
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    6 / 106 (5.66%)
    3 / 104 (2.88%)
    1 / 89 (1.12%)
    1 / 92 (1.09%)
         occurrences all number
    6
    3
    1
    2
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    7 / 106 (6.60%)
    8 / 104 (7.69%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    8
    9
    0
    0
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    7 / 106 (6.60%)
    6 / 104 (5.77%)
    6 / 89 (6.74%)
    5 / 92 (5.43%)
         occurrences all number
    7
    7
    7
    5
    NAUSEA
         subjects affected / exposed
    6 / 106 (5.66%)
    3 / 104 (2.88%)
    2 / 89 (2.25%)
    1 / 92 (1.09%)
         occurrences all number
    6
    3
    2
    1
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    6 / 106 (5.66%)
    4 / 104 (3.85%)
    8 / 89 (8.99%)
    2 / 92 (2.17%)
         occurrences all number
    6
    4
    8
    2
    Skin and subcutaneous tissue disorders
    PRURITUS
         subjects affected / exposed
    4 / 106 (3.77%)
    6 / 104 (5.77%)
    2 / 89 (2.25%)
    1 / 92 (1.09%)
         occurrences all number
    5
    6
    3
    1
    RASH
         subjects affected / exposed
    7 / 106 (6.60%)
    2 / 104 (1.92%)
    3 / 89 (3.37%)
    2 / 92 (2.17%)
         occurrences all number
    8
    2
    3
    2
    SKIN ULCER
         subjects affected / exposed
    12 / 106 (11.32%)
    15 / 104 (14.42%)
    16 / 89 (17.98%)
    11 / 92 (11.96%)
         occurrences all number
    22
    28
    28
    22
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    13 / 106 (12.26%)
    12 / 104 (11.54%)
    6 / 89 (6.74%)
    5 / 92 (5.43%)
         occurrences all number
    14
    14
    6
    5
    Infections and infestations
    GASTROENTERITIS
         subjects affected / exposed
    2 / 106 (1.89%)
    7 / 104 (6.73%)
    0 / 89 (0.00%)
    3 / 92 (3.26%)
         occurrences all number
    2
    7
    0
    3
    NASOPHARYNGITIS
         subjects affected / exposed
    8 / 106 (7.55%)
    13 / 104 (12.50%)
    9 / 89 (10.11%)
    4 / 92 (4.35%)
         occurrences all number
    9
    14
    10
    4
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    11 / 106 (10.38%)
    12 / 104 (11.54%)
    10 / 89 (11.24%)
    4 / 92 (4.35%)
         occurrences all number
    15
    13
    16
    5
    URINARY TRACT INFECTION
         subjects affected / exposed
    10 / 106 (9.43%)
    5 / 104 (4.81%)
    7 / 89 (7.87%)
    1 / 92 (1.09%)
         occurrences all number
    14
    5
    8
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Apr 2015
    The screening high-resolution computed tomography (HRCT) assessment was moved to the Day 1 visit as it is required only for subjects who are randomized. For the digital ulcer count, the definition of a digital ulcer was amended to include an additional joint (the metacarpal phalangeal [MCP]) and to clarify that the volar and dorsal surfaces are included. For the pulmonary function tests, the testing methods for FVC and diffusion capacity of the lung for carbon monoxide were clarified. Also, the reference value for the diffusion capacity of the lung for carbon monoxide was added. Whole blood for RNA extraction was added.
    12 Jul 2015
    The options for female contraception were amended to state that the double-barrier method is an acceptable form of contraception. An addition was made to specify that, in participants who are inadequate responders to methotrexate or hydroxychloroquine, other disease-modifying anti-rheumatic drugs (such as mycophenolate mofetil) may be used after discussion with the Medical Monitor. The guidance on when to report adverse events of worsening systemic sclerosis was amended to remove references to “unexpected” and “unanticipated” worsening to remove ambiguity in determining if a participant's systemic sclerosis has worsened. Body weight was added as a Day 1 assessment.
    17 Dec 2015
    Reduction of the time period for baseline HRCT scans performed prior to screening from 12 months to 3 months; Introduction of the option for participants who discontinued study medication during the 48-week double-blind treatment period to participate in the 48-week open-label treatment period and receive TCZ if they met specified criteria; Addition of Health Assessment Questionnaire-Disability Index (HAQ-DI) assessments up to Week 48 for participants who discontinued the study drug; Stipulation that C-reactive protein (CRP) results were not to be reported in the electronic case report form (eCRF) to avoid potential unblinding of the Sponsor to treatment assignment; Modification of the methotrexate (MTX) dose to be used as escape therapy from 10 to </= 25 mg/week to accommodate country-specific requirements; Clarification that the interim (futility) analysis was no longer optional and addition of details on the timing and stopping criteria for the analysis.
    06 Sep 2016
    Clarification of the exclusion criterion for limited cutaneous SSc to also exclude patients with skin involvement of the face from the study; Clarification of the exclusion criterion for corticosteroids to exclude patients who were treated with all routes of corticosteroids prior to baseline; Addition of the acceptable use of immuno-modulating drugs beyond Week 24 to allow patients with other significant SSc complications to be treated appropriately without being required to discontinue study medication; Addition of further details on the timing of the interim (futility) analysis; Addition of a HAQ-DI assessment at Week 36 of the double-blind treatment period to align with the schedule of assessments for patients who discontinued the study drug.
    05 May 2017
    Clarification of the timing of follow-up assessments after study drug discontinuation; Addition of language permitting participants who were on escape therapy during the 48-week double-blind treatment period to continue to do so during the 48-week open-label treatment period. Participants were also allowed to initiate escape therapy during the open-label treatment period if they met the specified criteria; Deletion of the criterion on washout times to allow participants who discontinued the study drug during the double-blind treatment period to participate in the open-label treatment period without having to undergo washout of other SSc treatments. Participants who were started on other SSc medications after study drug discontinuation were allowed to continue these medications during the 48-week open-label treatment period; Clarification that participants who discontinued the study drug prior to Week 48 and did not continue to the open-label treatment period were to complete a reduced schedule of assessments; Clarification that participants who discontinued prior to Week 48 and were eligible to continue to the open-label treatment period were to complete all Week 48 assessments; Revisions were made to ensure consistency of the mRSS assessments, emphasizing that the same assessor was to conduct the evaluations for a given participant at all visits; A stipulation was made that specified pulmonary function tests were to be repeated within 4 weeks if rejected by the over-readers; Addition of details for tuberculosis screening and clarification of the testing requirements for CRP.

    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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