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    Clinical Trial Results:
    A Randomized, Double-blind, Parallel, Placebo-controlled Study Assessing the Efficacy and Safety of Sarilumab Added to Non-biologic DMARD Therapy in Patients With Rheumatoid Arthritis Who Are Inadequate Responders to or Intolerant of TNF-α Antagonists

    Summary
    EudraCT number
    2011-003538-16
    Trial protocol
    LT   CZ   HU   ES   DE   PT   GR   AT   IT   SK   PL  
    Global end of trial date
    23 Mar 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    10 Sep 2017
    First version publication date
    07 Apr 2016
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of data entry to secondary endpoints

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC10832
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01709578
    WHO universal trial number (UTN)
    U1111-1115-8466
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette,, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    22 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that sarilumab added to non-biologic disease modifying anti-rheumatic drugs (DMARDs) was effective in reducing the signs and symptoms at Week 24 and improving physical function at Week 12 in subjects with active rheumatoid arthritis (RA) who were inadequate responders to or intolerant of tumor necrosis factor alpha (TNF-α) antagonists.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    Subjects continued to receive regular treatment with at least one of the permitted background therapies that included hydroxychloroquine, methotrexate, sulfasalazine, leflunomide which were dispensed according to the local practice.
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    Colombia: 19
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    Ecuador: 11
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Guatemala: 13
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Mexico: 62
    Country: Number of subjects enrolled
    New Zealand: 10
    Country: Number of subjects enrolled
    Peru: 49
    Country: Number of subjects enrolled
    Poland: 59
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    United States: 147
    Country: Number of subjects enrolled
    Argentina: 52
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Brazil: 13
    Worldwide total number of subjects
    546
    EEA total number of subjects
    131
    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)
    456
    From 65 to 84 years
    88
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 240 centres in 27 countries. A total of 1224 subjects were screened between 29 October 2012 and 7 August 2014, of whom 546 subjects were randomized and 678 were screen failures. Screen failures were mainly due to failure to meet inclusion criteria.

    Pre-assignment
    Screening details
    Subjects were randomized 1:1:1 (placebo q2w: sarilumab 150 mg q2w: sarilumab 200 mg q2w) via a centralized randomization system using an interactive voice response system stratified by region and number of previous anti-tumor necrosis factor therapy (1 versus >1).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo q2w
    Arm description
    Placebo matched to sarilumab once every 2 weeks (q2w) was added to one or a combination of the non-biologic DMARD for 24 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to sarilumab administered subcutaneously in abdomen, thigh or upper arm.

    Arm title
    Sarilumab 150 mg q2w
    Arm description
    Sarilumab 150 mg q2w was added to one or a combination of the non-biologic DMARD for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sarilumab 150 mg administered subcutaneously in abdomen, thigh or upper arm.

    Arm title
    Sarilumab 200 mg q2w
    Arm description
    Sarilumab 200 mg q2w was added to one or a combination of the non-biologic DMARD for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191
    Other name
    REGN88
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sarilumab 200 mg administered subcutaneously in abdomen, thigh or upper arm.

    Number of subjects in period 1
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Started
    181
    181
    184
    Completed
    101
    125
    133
    Not completed
    80
    56
    51
         Other, not related to safety or efficacy
             2
             7
             5
         Rescued and entered in long term safety
             63
             25
             26
         Lack of efficacy
             5
             4
             2
         Poor compliance to protocol
             1
             2
             1
         Adverse Event
             9
             18
             17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo q2w
    Reporting group description
    Placebo matched to sarilumab once every 2 weeks (q2w) was added to one or a combination of the non-biologic DMARD for 24 weeks.

    Reporting group title
    Sarilumab 150 mg q2w
    Reporting group description
    Sarilumab 150 mg q2w was added to one or a combination of the non-biologic DMARD for 24 weeks.

    Reporting group title
    Sarilumab 200 mg q2w
    Reporting group description
    Sarilumab 200 mg q2w was added to one or a combination of the non-biologic DMARD for 24 weeks.

    Reporting group values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w Total
    Number of subjects
    181 181 184 546
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.9 ± 12.4 54 ± 11.7 52.9 ± 12.9 -
    Gender categorical
    Units: Subjects
        Female
    154 142 151 447
        Male
    27 39 33 99

    End points

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    End points reporting groups
    Reporting group title
    Placebo q2w
    Reporting group description
    Placebo matched to sarilumab once every 2 weeks (q2w) was added to one or a combination of the non-biologic DMARD for 24 weeks.

    Reporting group title
    Sarilumab 150 mg q2w
    Reporting group description
    Sarilumab 150 mg q2w was added to one or a combination of the non-biologic DMARD for 24 weeks.

    Reporting group title
    Sarilumab 200 mg q2w
    Reporting group description
    Sarilumab 200 mg q2w was added to one or a combination of the non-biologic DMARD for 24 weeks.

    Primary: Percentage of Subjects Who Achieved at Least 20% Improvement in the American College of Rheumatology (ACR20) Criteria at Week 24

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    End point title
    Percentage of Subjects Who Achieved at Least 20% Improvement in the American College of Rheumatology (ACR20) Criteria at Week 24
    End point description
    ACR responses were assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: tender joint count (TJC); swollen joint count (SJC); levels of an acute phase reactant (C-reactive Protein levels [CRP]); subject's assessment of pain; subject's global assessment of disease activity; physician's global assessment of disease activity; subject's assessment of physical function (HAQ-DI). ACR20 is defined as achieving at least 20% improvement in both TJC and SJC, and at least 20% improvement in at least 3 of the 5 other assessments of the ACR. Analysis was performed on intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: percentage of subjects
        number (not applicable)
    33.7
    55.8
    60.9
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error rate at 0.05 and handle multiple endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level.
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.711
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.73
         upper limit
    4.247
    Notes
    [1] - Threshold for significance at 0.025 level
    Statistical analysis title
    Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.284
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.108
         upper limit
    5.115
    Notes
    [2] - Threshold for significance at 0.025 level

    Primary: Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12

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    End point title
    Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12
    End point description
    Physical function was assessed by HAQ-DI. It consisted of at least 2 questions per category, subject reported ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week rated on a 4-point scale where 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was the sum of category scores and divided by the number of categories answered, ranging from 0 to 3, where 0 = no disability and 3 = unable to do, high-dependency disability. Least-squares (LS) means and standard errors (SE) at Week 12 were obtained from a mixed-effect model with repeated measures (MMRM) with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline HAQ-DI as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = number of subjects with HAQ-DI assessment at both baseline and Week 12.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    170
    165
    171
    Units: units on a scale
        least squares mean (standard error)
    -0.26 ± 0.043
    -0.46 ± 0.044
    -0.47 ± 0.043
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007 [3]
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.202
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.318
         upper limit
    -0.086
    Notes
    [3] - Threshold for significance at 0.025 level
    Statistical analysis title
    Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [4]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.325
         upper limit
    -0.095
    Notes
    [4] - Threshold for significance at 0.025 level

    Secondary: Change From Baseline in Disease Activity Score for 28 Joints -C-Reactive Protein (DAS28-CRP) Score at Week 24

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    End point title
    Change From Baseline in Disease Activity Score for 28 Joints -C-Reactive Protein (DAS28-CRP) Score at Week 24
    End point description
    DAS28 is a composite score of 4 variables:TJC (28 joints);SJC (28 joints);General health (GH) assessment by the subject assessed from the ACR (RA) core set questionnaire (subject global assessment) in 100 mm visual analog scale(VAS). Marker of inflammation assessed by the high sensitivity C-reactive protein (hs-CRP) in mg/L. The DAS28 score indicate the current disease activity of the RA. DAS28 total score ranges from 2-10. A DAS28 score above 5.1 means high disease activity, score below 3.2 indicates low disease activity and a score below 2.6 means disease remission. LS means and SE at Week 24 by MMRM with treatment, region, number of previous anti-TNFs,visit,and treatment-by-visit interaction as fixed effects and baseline DAS28-CRP score as a covariate. Analysis was performed on ITT population. Number of subjects analyzed=number of subjects with DAS28-CRP Score at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    99
    126
    136
    Units: units on a scale
        least squares mean (standard error)
    -1.38 ± 0.119
    -2.35 ± 0.111
    -2.82 ± 0.108
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.971
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.283
         upper limit
    -0.658
    Notes
    [5] - Threshold for significance at 0.025 level
    Statistical analysis title
    Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -1.444
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.752
         upper limit
    -1.135
    Notes
    [6] - Threshold for significance at 0.025 level

    Secondary: Percentage of Subjects Achieving ACR50 Criteria at Week 24

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    End point title
    Percentage of Subjects Achieving ACR50 Criteria at Week 24
    End point description
    ACR responses were assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: TJC; SJC; levels of an acute phase reactant (CRP level); subject’s assessment of pain; subject’s global assessment of disease activity; physician’s global assessment of disease activity; subject’s assessment of physical function (HAQ-DI). ACR50 is defined as achieving at least 50% improvement in both TJC and SJC, and at least 50% improvement in at least 3 of the 5 other assessments of the ACR. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: percentage of subjects
        number (not applicable)
    18.2
    37
    40.8
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.958
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.764
         upper limit
    4.959
    Notes
    [7] - Threshold for significance at 0.025 level
    Statistical analysis title
    Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.374
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.045
         upper limit
    5.566
    Notes
    [8] - Threshold for significance was 0.025 level

    Secondary: Percentage of Subjects Achieving ACR70 Criteria at Week 24

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    End point title
    Percentage of Subjects Achieving ACR70 Criteria at Week 24
    End point description
    ACR responses were assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: TJC; SJC; levels of an acute phase reactant (CRP level); subject’s assessment of pain; subject’s global assessment of disease activity; physician’s global assessment of disease activity; subject’s assessment of physical function (HAQ-DI). ACR70 is defined as achieving at least 70% improvement in both TJC and SJC, and at least 70% improvement in at least 3 of the 5 other assessments of the ACR. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: Percentage of subjects
        number (not applicable)
    7.2
    19.9
    16.3
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [9]
    Method
    Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.607
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.774
         upper limit
    7.332
    Notes
    [9] - Threshold for significance at 0.025 level
    Statistical analysis title
    Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0056 [10]
    Method
    Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.653
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.308
         upper limit
    5.383
    Notes
    [10] - Threshold for significance at 0.025 level

    Secondary: Percentage of Subjects Achieving Clinical Remission Score (DAS28-CRP) <2.6 at Week 24

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    End point title
    Percentage of Subjects Achieving Clinical Remission Score (DAS28-CRP) <2.6 at Week 24
    End point description
    DAS28 is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH by the subject assessed from the ACR rheumatoid arthritis core set questionnaire (subject global assessment) in 100 mm VAS; marker of inflammation assessed by hs-CRP in mg/L. The DAS28 provides a number indicating the current activity of the RA. DAS28 total score ranges from 2-10. A DAS28 score above 5.1 means high disease activity, whereas a DAS28 score below 3.2 indicates low disease activity and a DAS28 score below 2.6 means disease remission. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: percentage of subjects
        number (not applicable)
    7.2
    24.9
    28.8
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [11]
    Method
    Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.622
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.339
         upper limit
    9.132
    Notes
    [11] - Threshold for significance at 0.025 level
    Statistical analysis title
    Copy of Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    5.801
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.948
         upper limit
    11.413
    Notes
    [12] - Threshold for significance at 0.025 level

    Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24

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    End point title
    Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24
    End point description
    CDAI is a composite index constructed to measure clinical remission in RA that does not include a laboratory test, and is a numerical summation of 4 components: TJC (28 joints), SJC (28 joints), Subject’s Global Assessment of Disease Activity VAS (in cm), and Physician’s Global Assessment of Disease VAS (in cm). Total scores ranges from 0 to 76 with a negative change in CDAI score indicating an improvement in disease activity and a positive change in score indicating a worsening of disease activity. LS means and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline CDAI as a covariate. Analysis was performed on ITT population. Number of subjects analyzed=number of subjects with CDAI assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    100
    127
    136
    Units: units on a scale
        least squares mean (standard error)
    -16.35 ± 1.195
    -23.65 ± 1.136
    -26.08 ± 1.109
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -7.306
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.444
         upper limit
    -4.167
    Notes
    [13] - Threshold for significance at 0.025 level
    Statistical analysis title
    Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -9.727
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.833
         upper limit
    -6.622
    Notes
    [14] - Threshold for significance at 0.025 level

    Secondary: Change From Baseline in HAQ-DI at Week 24

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    End point title
    Change From Baseline in HAQ-DI at Week 24
    End point description
    Physical function was assessed by HAQ-DI. It consisted of at least 2 questions per category, subject reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week rated on a 4-point scale where 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of category scores and divided by the number of categories answered, ranging from 0 to 3, where 0 = no disability and 3 = unable to do, high-dependency disability. LS means and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline HAQ-DI as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = number of subjects with HAQ-DI assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    101
    127
    136
    Units: units on a scale
        least squares mean (standard error)
    -0.34 ± 0.051
    -0.52 ± 0.049
    -0.58 ± 0.048
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0078 [15]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.183
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.318
         upper limit
    -0.048
    Notes
    [15] - Threshold for significance was 0.025 level
    Statistical analysis title
    Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [16]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.242
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.376
         upper limit
    -0.109
    Notes
    [16] - Threshold for significance was 0.025 level

    Secondary: Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Physical Component Summary Scores (PCS) at Week 24

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    End point title
    Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Physical Component Summary Scores (PCS) at Week 24
    End point description
    SF-36 a 36-item questionnaire measuring health-related quality of life (HRQL) covering 2 summary measures: PCS and mental component summary (MCS). The SF-36 consists of 8 subscales. The PCS had 4 subscales: physical function, role limitations due to physical problems, pain, and general health perception. The MCS had 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Reporting on subscale that have between 2-6 choices per item using Likert-type responses. Summations of item scores give the subscale scores, which range from 0 to 100; zero= worst HRQL, 100=best HRQL. Higher scores indicate better health and well-being. LS mean and SE at Week 24 by MMRM with treatment,region,number of previous anti TNFs,visit,and treatment-by-visit interaction as fixed effects and baseline SF-36 PCS as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with SF-36 PCS assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    99
    123
    134
    Units: units on a scale
        least squares mean (standard error)
    4.4 ± 0.692
    7.65 ± 0.653
    8.48 ± 0.63
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [17]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    3.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.45
         upper limit
    5.049
    Notes
    [17] - Threshold for significance at 0.025 level
    Statistical analysis title
    Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    4.075
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.305
         upper limit
    5.846
    Notes
    [18] - Threshold for significance at 0.025 level

    Secondary: Change From Baseline in SF-36 MCS at Week 24

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    End point title
    Change From Baseline in SF-36 MCS at Week 24
    End point description
    SF-36 is 36-item questionnaire measuring HRQL covering PCS and MCS. The SF-36 is of 8 subscales. The PCS is represented by 4 subscales: physical function, role limitations due to physical problems, pain, and general health perception. The MCS is represented by 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Subjects self-report on items in a subscale that have between 2-6 choices per item using Likert-type responses. Summations of item scores of the same subscale give the subscale scores, which range from 0to100; zero= worst HRQL, 100=best HRQL. Higher scores indicate better health and well-being. LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs,visit and treatment-by-visit interaction as fixed effects and baseline SF-36 MCS as a covariate. Analysis was performed on ITT population. Number of subjects analyzed=subjects with SF-36 MCS assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    99
    123
    134
    Units: units on a scale
        least squares mean (standard error)
    4.74 ± 0.902
    6.26 ± 0.848
    6.76 ± 0.817
    Statistical analysis title
    Placebo q2w vs Sarilumab 150 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 150 mg q2w
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2026 [19]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    1.515
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.818
         upper limit
    3.848
    Notes
    [19] - Threshold for significance at 0.025 level
    Statistical analysis title
    Placebo q2w vs Sarilumab 200 mg q2w
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo q2w v Sarilumab 200 mg q2w
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0854 [20]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    2.013
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.282
         upper limit
    4.309
    Notes
    [20] - Threshold for significance at 0.025 level

    Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-fatigue) Score at Week 24

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    End point title
    Change From Baseline in the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-fatigue) Score at Week 24
    End point description
    The FACIT-Fatigue is a 13-item questionnaire assessing fatigue where subjects scored each item on a 5-point scale (0-4): 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much. A total score ranging from 0 to 52. A higher score corresponded to a lower level of fatigue. A positive change from baseline score indicates an improvement. LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline FACIT-fatigue as a covariate. Analysis was performed on ITT population. Number of Subjects analyzed = number of subjects with FACIT-fatigue score assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    98
    126
    136
    Units: units on a scale
        least squares mean (standard error)
    6.82 ± 0.863
    9.86 ± 0.802
    10.06 ± 0.778
    No statistical analyses for this end point

    Secondary: Change From Baseline in Morning Stiffness VAS at Week 24

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    End point title
    Change From Baseline in Morning Stiffness VAS at Week 24
    End point description
    RA is associated with stiffness of joints, especially in the morning after prolonged stationery state. The degree of stiffness can be an indicator of disease severity. The severity of morning stiffness was assessed on a VAS scale from 0 mm (no problem) to 100 mm (major problem). LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline Morning Stiffness as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = number of subjects with morning stiffness VAS assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    101
    127
    136
    Units: units on a scale
        least squares mean (standard error)
    -21.66 ± 2.39
    -32.3 ± 2.213
    -33.79 ± 2.148
    No statistical analyses for this end point

    Secondary: Change From Baseline in Work Productivity Survey - Rheumatoid Arthritis (WPS-RA) at Week 24: Work Days Missed Due to RA

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    End point title
    Change From Baseline in Work Productivity Survey - Rheumatoid Arthritis (WPS-RA) at Week 24: Work Days Missed Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of work days missed in the last month by the subject was reported. LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    32
    43
    45
    Units: days
        least squares mean (standard error)
    -2.01 ± 0.458
    -2.87 ± 0.438
    -3.19 ± 0.447
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 24: Days With Work Productivity Reduced by ≥ 50% Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 24: Days With Work Productivity Reduced by ≥ 50% Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of work days with reduced productivity by ≥ 50% in the last month by the subject was reported. LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed=subjects with WPS-RA individual items assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    32
    43
    45
    Units: days
        least squares mean (standard error)
    -3.64 ± 0.589
    -4.26 ± 0.521
    -4.34 ± 0.535
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 24: RA Interference With Work Productivity

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    End point title
    Change From Baseline in WPS-RA at Week 24: RA Interference With Work Productivity
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Interference in the last month with work productivity is measured on a scale that ranges from 0 (no interference) to 10 (complete interference). LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    32
    42
    45
    Units: units on a scale
        least squares mean (standard error)
    -1.632 ± 0.4186
    -2.422 ± 0.3719
    -2.727 ± 0.37
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 24: House Work Days Missed Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 24: House Work Days Missed Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with no household work in the last month by the subject was reported. LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    101
    126
    133
    Units: days
        least squares mean (standard error)
    -3.5 ± 0.59
    -6.13 ± 0.551
    -6.18 ± 0.537
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 24: Days With Household Work Productivity Reduced by ≥ 50% Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 24: Days With Household Work Productivity Reduced by ≥ 50% Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with reduced household work productivity by ≥ 50% in the last month by the subject was reported. LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    101
    125
    133
    Units: days
        least squares mean (standard error)
    -3.36 ± 0.632
    -4.6 ± 0.591
    -4.88 ± 0.574
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 24: Days With Family/Social/Leisure Activities Missed Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 24: Days With Family/Social/Leisure Activities Missed Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days missed of family/social/leisure activities in the last month by the subject was reported. LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate.Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    101
    127
    133
    Units: days
        least squares mean (standard error)
    -1.97 ± 0.479
    -3.51 ± 0.446
    -4.12 ± 0.435
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 24: Days With Outside Help Hired Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 24: Days With Outside Help Hired Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with outside help hired in the last month by the subject was reported. LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate.Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    101
    126
    133
    Units: days
        least squares mean (standard error)
    -1.6 ± 0.567
    -3.87 ± 0.536
    -3.86 ± 0.523
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 24: RA Interference With Household Work Productivity

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    End point title
    Change From Baseline in WPS-RA at Week 24: RA Interference With Household Work Productivity
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). The RA interference in the last month with household work productivity was measured on a scale that ranges from 0 (no interference) to 10 (complete interference). LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    100
    126
    132
    Units: units on a scale
        least squares mean (standard error)
    -1.97 ± 0.2438
    -3.096 ± 0.2238
    -3.269 ± 0.2186
    No statistical analyses for this end point

    Secondary: Change From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) Scores at Week 24

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    End point title
    Change From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) Scores at Week 24
    End point description
    RAID is a composite measure of the impact of RA on subjects that takes into account 7 domains: pain, functional disability, fatigue, physical and emotional well being, quality of sleep, and coping. The RAID is calculated based on 7 numerical rating scales (NRS) questions. Range of the final RAID value is 0-10 where 0= not affected, very good and 10 = most affected weighted and calculated with a total score range of 0 (not affected, very good) to 10 (most affected). A higher RAID value indicate worse status and lower indicate not affected. LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline RAID as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = number of subjects with RAID score assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    99
    126
    136
    Units: units on a scale
        least squares mean (standard error)
    -1.8 ± 0.203
    -2.55 ± 0.189
    -2.8 ± 0.183
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life-5 Dimension 3 Level (EQ-5D-3L) VAS Scores at Week 24

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    End point title
    Change From Baseline in European Quality of Life-5 Dimension 3 Level (EQ-5D-3L) VAS Scores at Week 24
    End point description
    The EQ-5D-3L is a standardized, generic measure of health outcome. EQ-5D was designed for self-completion by subjects. The EQ-5D was specifically included to address concerns regarding the health economic impact of RA. The EQ-5D-3L comprises 5 questions on mobility, self-care, pain, usual activities, and psychological status with 3 possible answers for each item (1=no problem, 2=moderate problems, 3=severe problems) and a vertical VAS that allows the subjects to indicate their health state today that can range from 0 (worst imaginable) to 100 (best imaginable). LS mean and SE at Week 24 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline EQ-5D-3L Scores as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = number of subjects with EQ-5D-3L score assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    96
    126
    133
    Units: units on a scale
        least squares mean (standard error)
    14.85 ± 2.098
    20.06 ± 1.891
    18.4 ± 1.842
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving ACR20, ACR50 and ACR70 Criteria at Week 12

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    End point title
    Percentage of Subjects Achieving ACR20, ACR50 and ACR70 Criteria at Week 12
    End point description
    ACR responses were assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: TJC; SJC; levels of an acute phase reactant (CRP level); subject’s assessment of pain; subject’s global assessment of disease activity; physician’s global assessment of disease activity; subject’s assessment of physical function (HAQ-DI). ACR20 is defined as achieving at least 20% improvement in both TJC and SJC, and at least 20% improvement in at least 3 of the 5 other assessments of the ACR. ACR50 is defined as achieving at least 50% improvement in both TJC and SJC, and at least 50% improvement in at least 3 of the 5 other assessments of the ACR. ACR70 is defined as achieving at least 70% improvement in both TJC and SJC, and at least 70% improvement in at least 3 of the 5 other assessments of the ACR. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: percentage of subjects
    number (not applicable)
        ACR20
    37.6
    54.1
    62.5
        ACR50
    13.3
    30.4
    33.2
        ACR70
    2.2
    13.8
    14.7
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Disease Activity Score (DAS) 28 at Week 12

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    End point title
    Changes From Baseline in Disease Activity Score (DAS) 28 at Week 12
    End point description
    DAS28 is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH by the subject assessed from the ACR rheumatoid arthritis core set questionnaire (subject global assessment) in 100 mm VAS; marker of inflammation assessed by hs-CRP in mg/L. The DAS28 provides a number indicating the current activity of the RA. DAS28 total score ranges from 2-10. A DAS28 score above 5.1 means high disease activity, whereas a DAS28 score below 3.2 indicates low disease activity and a DAS28 score below 2.6 means disease remission. LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline DAS score as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = number of subjects with DAS28- Score assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    168
    163
    169
    Units: : units on a scale
        least squares mean (standard error)
    -0.97 ± 0.104
    -2.13 ± 0.105
    -2.45 ± 0.103
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Clinical Remission Score (DAS28-­CRP) <2.6 at Week 12

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    End point title
    Percentage of Subjects Achieving Clinical Remission Score (DAS28-­CRP) <2.6 at Week 12
    End point description
    DAS28 was a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH by the subject assessed from the ACR rheumatoid arthritis core set questionnaire (subject global assessment) in 100 mm VAS; marker of inflammation assessed by hs-CRP in mg/L. The DAS28 provides a number indicating the current activity of the RA. DAS28 total score ranges from 2-10. A DAS28 score above 5.1 means high disease activity, whereas a DAS28 score below 3.2 indicates low disease activity and a DAS28 score below 2.6 means disease remission. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: percentage of subjects
        number (not applicable)
    3.9
    17.1
    17.9
    No statistical analyses for this end point

    Secondary: Change From Baseline in SF-36 at Week 12

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    End point title
    Change From Baseline in SF-36 at Week 12
    End point description
    SF-36 a 36-item questionnaire measuring health-related quality of life (HRQL) covering 2 summary measures: PCS and mental component summary (MCS). The SF-36 consists of 8 subscales. The PCS had 4 subscales: physical function, role limitations due to physical problems, pain, and general health perception. The MCS had 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Reporting on subscale that have between 2-6 choices per item using Likert-type responses. Summations of item scores give the subscale scores, which range from 0 to 100; zero= worst HRQL, 100=best HRQL. Higher scores indicate better health and well-being. LS mean and SE at Week 12 by MMRM with treatment,region,number of previous anti TNFs,visit,and treatment-by-visit interaction as fixed effects and baseline SF-36 (PCS) as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with SF-36 PCS assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    169
    160
    165
    Units: units on a scale
    least squares mean (standard error)
        PCS Score at Week 12
    3.74 ± 0.582
    6.93 ± 0.596
    6.84 ± 0.584
        MCS Score at Week 12
    3.5 ± 0.738
    5.14 ± 0.758
    6.47 ± 0.741
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 12: Work Days Missed Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 12: Work Days Missed Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of work days missed in the last month by the subject was reported. LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    54
    54
    56
    Units: days
        least squares mean (standard error)
    -1.2 ± 0.581
    -1.97 ± 0.571
    -2.98 ± 0.585
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 12: Days With Work Productivity Reduced by ≥ 50% Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 12: Days With Work Productivity Reduced by ≥ 50% Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of work days with reduced productivity by ≥ 50% in the last month by the subject was reported. LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    54
    54
    56
    Units: days
        least squares mean (standard error)
    -1.69 ± 0.784
    -4.24 ± 0.773
    -3.2 ± 0.785
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 12: RA Interference With Work Productivity

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    End point title
    Change From Baseline in WPS-RA at Week 12: RA Interference With Work Productivity
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Interference in the last month with work productivity was measured on a scale that ranges from 0 (no interference) to 10 (complete interference). LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    53
    54
    56
    Units: units on a scale
        least squares mean (standard error)
    -1.043 ± 0.3803
    -1.924 ± 0.3742
    -1.873 ± 0.3764
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 12: House Work Days Missed Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 12: House Work Days Missed Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with no household work in the last month by the subject was reported. LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    170
    164
    169
    Units: days
        least squares mean (standard error)
    -2.1 ± 0.551
    -5.52 ± 0.563
    -5.54 ± 0.553
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 12: Days With Household Work Productivity Reduced by ≥ 50% Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 12: Days With Household Work Productivity Reduced by ≥ 50% Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with reduced household work productivity by ≥ 50% in the last month by the subject was reported. LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    169
    163
    169
    Units: days
        least squares mean (standard error)
    -2.6 ± 0.576
    -3.97 ± 0.587
    -3.98 ± 0.575
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 12: Days With Family/Social/Leisure Activities Missed Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 12: Days With Family/Social/Leisure Activities Missed Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days missed of family/social/leisure activities in the last month in the last month by the subject was reported. LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    170
    164
    169
    Units: days
        least squares mean (standard error)
    -2.23 ± 0.433
    -2.53 ± 0.442
    -3.26 ± 0.434
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 12: Days With Outside Help Hired Due to RA

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    End point title
    Change From Baseline in WPS-RA at Week 12: Days With Outside Help Hired Due to RA
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with outside help hired in the last month by the subject was reported. LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    170
    164
    169
    Units: days
        least squares mean (standard error)
    -0.77 ± 0.558
    -3.07 ± 0.57
    -2.94 ± 0.56
    No statistical analyses for this end point

    Secondary: Change From Baseline in WPS-RA at Week 12: RA Interference With Household Work Productivity

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    End point title
    Change From Baseline in WPS-RA at Week 12: RA Interference With Household Work Productivity
    End point description
    The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). The RA interference in the last month with household work productivity was measured on a scale that ranges from 0 (no interference) to 10 (complete interference). LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline WPS-RA as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = subjects with WPS-RA individual items assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    169
    164
    167
    Units: units on a scale
        least squares mean (standard error)
    -1.21 ± 0.2428
    -2.772 ± 0.2474
    -2.404 ± 0.2443
    No statistical analyses for this end point

    Secondary: Change From Baseline in the FACIT-fatigue at Week 12

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    End point title
    Change From Baseline in the FACIT-fatigue at Week 12
    End point description
    The FACIT-Fatigue is a 13-item questionnaire assessing fatigue where subjects scored each item on a 5-point scale (0-4): 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much. A total score ranging from 0 to 52. A higher score corresponded to a lower level of fatigue. A positive change from baseline score indicates an improvement. LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline FACIT-fatigue as a covariate. Analysis was performed on ITT population. Number of Subjects analyzed = number of subjects with FACIT-fatigue score assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    169
    165
    172
    Units: units on a scale
        least squares mean (standard error)
    5.56 ± 0.721
    8.02 ± 0.729
    9.45 ± 0.714
    No statistical analyses for this end point

    Secondary: Change From Baseline in EQ-5D-3L VAS Scores at Week 12

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    End point title
    Change From Baseline in EQ-5D-3L VAS Scores at Week 12
    End point description
    The EQ-5D-3L is a standardized, generic measure of health outcome. EQ-5D was designed for self-completion by subjects. The EQ-5D was specifically included to address concerns regarding the health economic impact of RA. The EQ-5D-3L comprises 5 questions on mobility, self-care, pain, usual activities, and psychological status with 3 possible answers for each item (1=no problem, 2=moderate problems, 3=severe problems) and a vertical VAS that allows the subjects to indicate their health state today that can range from 0 (worst imaginable) to 100 (best imaginable). LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline EQ-5D-3L Scores as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = number of subjects with EQ-5D-3L score assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    167
    163
    171
    Units: units on a scale
        least squares mean (standard error)
    8.39 ± 1.699
    17.16 ± 1.72
    15.23 ± 1.68
    No statistical analyses for this end point

    Secondary: Change From Baseline in RAID Scores at Week 12

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    End point title
    Change From Baseline in RAID Scores at Week 12
    End point description
    RAID is a composite measure of the impact of RA on subjects that takes into account 7 domains: pain, functional disability, fatigue, physical and emotional well being, quality of sleep, and coping. The RAID is calculated based on 7 NRS questions. Range of the final RAID value is 0-10 where 0= not affected, very good and 10 = most affected weighted and calculated with a total score range of 0 (not affected, very good) to 10 (most affected). A higher RAID value indicate worse status and lower indicate not affected. LS mean and SE at Week 12 were obtained from a MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline RAID as a covariate. Analysis was performed on ITT population. Number of subjects analyzed = number of subjects with RAID score assessment at both baseline and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    167
    162
    171
    Units: units on a scale
        least squares mean (standard error)
    -1.34 ± 0.163
    -2.27 ± 0.165
    -2.47 ± 0.161
    No statistical analyses for this end point

    Secondary: Change From Baseline in Individual ACR Components - TJC and SJC at Week 12 and Week 24

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    End point title
    Change From Baseline in Individual ACR Components - TJC and SJC at Week 12 and Week 24
    End point description
    ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS,HAQ-DI & CRP. 68 joints were assessed for tenderness (TJC scoring 0-68) and 66 joints for swelling (SJC scoring 0-66). The 66 SJC evaluated the following joints: temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, metacarpophalangeal, interphalangeal of thumb, distal interphalangeal, proximal interphalangeal, knee, ankle mortise, ankle tarsus, metatarsophalangeal, interphalangeal of great toe, and proximal/distal interphalangeal of the toes. The TJC examined hip joints, in addition to the joints assessed for SJC. Increase in number of tender joints/swollen joints indicated severity. LS mean and SE at Week 12 & 24 by MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline ACR components as a covariate. ITT population. Here ’n’ signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: joints
    least squares mean (standard error)
        TJC at Week 12 (n=172,165,172)
    -8.55 ± 0.959
    -13.74 ± 0.975
    -14.87 ± 0.954
        SJC at Week 12 (n=172,165,172)
    -6.75 ± 0.687
    -10.54 ± 0.698
    -10.59 ± 0.684
        TJC at Week 24 (n=101,127,137)
    -10.55 ± 1.06
    -14.44 ± 1.017
    -16.95 ± 0.992
        SJC at Week 24 (n=101,127,137)
    -8.19 ± 0.721
    -11.56 ± 0.691
    -11.94 ± 0.674
    No statistical analyses for this end point

    Secondary: Change From Baseline in Individual ACR Component - Physician Global VAS, Subject Global VAS and Pain VAS at Week 12 and Week 24

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    End point title
    Change From Baseline in Individual ACR Component - Physician Global VAS, Subject Global VAS and Pain VAS at Week 12 and Week 24
    End point description
    ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI & CRP. Physician global VAS & subject global VAS was done by 100 mm non-anchored VAS, from no arthritis (0) activity to maximal arthritis (100) activity. Pain VAS by 100 mm VAS ranging from 0 "no pain" to 100 "worst pain". LS mean and SE at Week 12 & 24 by MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline ACR components as a covariate. Analysis was performed on ITT population. Here ’n’ signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: mm
    least squares mean (standard error)
        Physician global VAS at Week 12 (n=172,165,171)
    -22.74 ± 1.744
    -33.64 ± 1.775
    -35.44 ± 1.74
        Subject global VAS at Week 12 (n=172,165,171)
    -13.75 ± 1.807
    -25.28 ± 1.836
    -27.38 ± 1.803
        Pain VAS at Week 12 (n=171,165,171)
    -15.13 ± 1.908
    -26.93 ± 1.933
    -30.56 ± 1.901
        Physician global VAS at Week 24 (n=101,127,137)
    -28.55 ± 1.806
    -40.65 ± 1.695
    -43.22 ± 1.646
        Subject global VAS at Week 24 (n=100,127,136)
    -19.76 ± 2.171
    -29.59 ± 2.046
    -31.28 ± 1.997
        Pain VAS at Week 24 (n=98,127,135)
    -21.27 ± 2.25
    -31.9 ± 2.086
    -33.65 ± 2.037
    No statistical analyses for this end point

    Secondary: Change From Baseline in Individual ACR Component - CRP Level at Week 12 and Week 24

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    End point title
    Change From Baseline in Individual ACR Component - CRP Level at Week 12 and Week 24
    End point description
    ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI & CRP. An elevated CRP level was considered a non-specific "marker" for RA. A reduction level indicates improvement. LS mean and SE at Week 12 & 24 by MMRM with treatment, region, number of previous anti- TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline ACR components as a covariate. Analysis was performed on ITT population. Here ’n’ signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: mg/L
    least squares mean (standard error)
        CRP at Week 12 (n=168,165,170)
    -3.63 ± 1.436
    -15.08 ± 1.452
    -22.98 ± 1.432
        CRP at Week 24 (n=100,126,137)
    -3.6 ± 1.556
    -15.24 ± 1.457
    -23.27 ± 1.421
    No statistical analyses for this end point

    Secondary: Change From Baseline in Individual ACR Component - HAQ-DI at Week 12 and Week 24

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    End point title
    Change From Baseline in Individual ACR Component - HAQ-DI at Week 12 and Week 24
    End point description
    ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI & CRP. HAQ-DI consisted of at least 2 questions per category, subject reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week rated on a 4-point scale where 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of category scores and divided by the number of categories answered, ranging from 0 to 3, where 0 = no disability and 3 = unable to do, high dependency disability. LS mean and SE at Week 12 & 24 by MMRM with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline ACR components as a covariate. Analysis was performed on ITT population. Here ’n’ signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Number of subjects analysed
    181
    181
    184
    Units: units on a scale
    least squares mean (standard error)
        HAQ-DI at Week 12 (n=170,165,171)
    -0.26 ± 0.043
    -0.46 ± 0.044
    -0.47 ± 0.043
        HAQ-DI at Week 24 (n=101,127,136)
    -0.34 ± 0.051
    -0.52 ± 0.049
    -0.58 ± 0.048
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 30) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events are treatment emergent adverse events that is AEs that developed/worsened and death during ‘on treatment period’ (time from the first dose injection of study drug to the end of follow up period). Safety population included all subjects from randomized population who received at least 1 dose or part of a dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo q2w
    Reporting group description
    Placebo matched to sarilumab q2w was added to one or a combination of the non-biologic DMARD for 24 weeks.

    Reporting group title
    Sarilumab 150 mg q2w
    Reporting group description
    Sarilumab 150 mg q2w was added to one or a combination of the non-biologic DMARD for 24 weeks.

    Reporting group title
    Sarilumab 200 mg q2w
    Reporting group description
    Sarilumab 200 mg q2w was added to one or a combination of the non-biologic DMARD for 24 weeks.

    Serious adverse events
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 181 (3.31%)
    6 / 181 (3.31%)
    10 / 184 (5.43%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Venous Thrombosis Limb
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 181 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 181 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ureteric Cancer
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 181 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular Block Second Degree
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis Noninfective
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 181 (0.55%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 181 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 181 (0.55%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic Stroke
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 181 (0.55%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 181 (0.55%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Mixed Liver Injury
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 181 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Disorder
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 181 (0.55%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 181 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 181 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 181 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 181 (0.55%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 181 (0.55%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 181 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo q2w Sarilumab 150 mg q2w Sarilumab 200 mg q2w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 181 (14.36%)
    60 / 181 (33.15%)
    57 / 184 (30.98%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    2 / 181 (1.10%)
    5 / 181 (2.76%)
    10 / 184 (5.43%)
         occurrences all number
    2
    5
    10
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 181 (1.10%)
    23 / 181 (12.71%)
    22 / 184 (11.96%)
         occurrences all number
    2
    32
    31
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    0 / 181 (0.00%)
    11 / 181 (6.08%)
    7 / 184 (3.80%)
         occurrences all number
    0
    33
    17
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 181 (1.66%)
    11 / 181 (6.08%)
    5 / 184 (2.72%)
         occurrences all number
    3
    12
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 181 (4.97%)
    11 / 181 (6.08%)
    7 / 184 (3.80%)
         occurrences all number
    9
    12
    7
    Urinary Tract Infection
         subjects affected / exposed
    12 / 181 (6.63%)
    6 / 181 (3.31%)
    13 / 184 (7.07%)
         occurrences all number
    13
    6
    16

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Sep 2012
    • To implement new safety measures to prevent the administration of sarilumab to subjects at risk for development of severe thrombocytopenia (<100 000/mm3) and grade 3/grade 4 neutropenia (based on NCI Common Terminology Criteria for Adverse Events [CTCAE]). • To delete the Visit 3 (Week2) sampling time point for “genetic RNA” or “RNA for sequencing” . • To remove the open-label rescue therapy arm within this study (EFC10832) and give subject qualifying for rescue therapy the opportunity to directly enroll into the parallel ongoing long-term safety study (LTS11210) to receive open-label rescue therapy with sarilumab. • To replace the partial EQ-5D-3L (EuroQol) instrument with the original complete instrument • To add an additional exclusion criterion related to interstitial lung disease. • To clarify instructions that for any occurrence of a serious adverse event (SAE) and for any occurrence of an adverse event of special interest (AESI) with immediate notification, investigators must report such events to the monitoring team within 24 hours of knowledge of them, and send any follow up data related to the event to the monitoring team also within 24 hours of knowledge. • To clarify in the Clinical Trial Summary and text related to categorical safety analyses, cardiovascular (CV) events, and analyses of the laboratory data, vital signs data and electrocardiogram data.
    03 Apr 2013
    • To update text related to dosage regimen of methotrexate in the Clinical Trial Summary. • To clarify the general accepted adult age limit and treatment related to dyslipidemia. • To update study medication storage conditions. • Updated text relating to treatment accountability and compliance and treatment kit disposal. • To remove text related to description of an open treatment arm with sarilumab that is no longer part of the study design in relevant sections. • To update text related to handling of subject for temporary and permanent treatment discontinuation. • To update safety reporting instructions in relevant sections.
    29 Oct 2014
    • To modify the analyses for the co-primary endpoint related to change in physical function as measured by the HAQ-DI and replace the co-primary endpoint related to change in physical function as measured by the HAQ-DI from the “average of change from baseline in the HAQ-DI from week 8 to Week 24” to the co-primary endpoint of “the change from baseline in the HAQ-DI at Week 12” This was done to ensure a robust analysis was performed at a time point where the amount of missing data was minimal and where there was a sufficiently long period of treatment with study drug to permit a correct assessment of effect on physical function. • To remove the reference related to the Committee for Medicinal Products for Human Use (CHMP) guidelines for blood pressure measurement as the current instructions in the protocol for blood pressure measurement primarily reflected practical considerations and were to serve as generic guidance to ensure consistency. • To replace the acronym “ANC (absolute neutrophil count)” with “neutrophil count,” in relevant sections. • To remove references to the bioanalytical assay and related analyses for “serum sarilumab-IL-6Rα complex (bound sarilumab)” as this assay was not performed for this study population.

    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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