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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel-Group Study Assessing the Efficacy And Safety of Sarilumab Monotherapy Versus Adalimumab Monotherapy in Patients With Rheumatoid Arthritis

    Summary
    EudraCT number
    2014-002541-22
    Trial protocol
    DE   CZ   HU   ES   GB  
    Global end of trial date
    29 Dec 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC14092
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02332590
    WHO universal trial number (UTN)
    U1111-1160-6154
    Other trial identifiers
    Study name: SARIL-RA-MONARCH
    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
    28 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that sarilumab monotherapy is superior to adalimumab monotherapy with respect to signs and symptoms as assessed by disease activity score 28 (DAS28)-erythrocyte sedimentation rate (ESR) in subjects with active rheumatoid arthritis (RA) who are either intolerant of or considered inappropriate candidates for continued treatment with methotrexate (MTX), or after at least 12 weeks of continuous treatment with MTX, are determined to be inadequate responders.
    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
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Jan 2015
    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
    Chile: 53
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 9
    Country: Number of subjects enrolled
    Peru: 18
    Country: Number of subjects enrolled
    Russian Federation: 44
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Ukraine: 39
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 22
    Country: Number of subjects enrolled
    Poland: 75
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Czechia: 25
    Worldwide total number of subjects
    369
    EEA total number of subjects
    150
    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)
    303
    From 65 to 84 years
    66
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 86 centres in 15 countries. A total of 540 subjects were involved in the study from 28 January 2015 to 29-December-2020, of whom 369 subjects were randomised and 171 were screen failures. Screen failures were mainly due to exclusion criteria met and inclusion criteria not met.

    Pre-assignment
    Screening details
    Subjects were randomised in 1:1 ratio (Adalimumab 40 milligrams [mg] every 2 weeks [q2w]: Sarilumab 200 mg q2w) and treated for 24 weeks in double-blind (DB) period of the study. Out of 321 subjects who completed DB period, 320 subjects entered the open label extension (OLE) period of the study.

    Period 1
    Period 1 title
    DB Period (Up to 24-weeks)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Adalimumab 40 mg/Sarilumab 200 mg
    Arm description
    Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One SC injection of adalimumab 40 mg in combination with matching placebo was administered q2w for 24 weeks.

    Arm title
    Sarilumab 200 mg/Sarilumab 200 mg
    Arm description
    Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).
    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
    One SC injection of sarilumab 200 mg in combination with matching placebo was administered q2w for 24 weeks.

    Number of subjects in period 1
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Started
    185
    184
    Treated
    184
    184
    Completed
    156
    165
    Not completed
    29
    19
         Other than specified above
    6
    5
         Adverse event
    15
    11
         Randomised but not treated
    1
    -
         Poor compliance to protocol
    3
    1
         Lack of efficacy
    4
    2
    Period 2
    Period 2 title
    OLE Period (Week 24 up to Week 300)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Adalimumab 40 mg/Sarilumab 200 mg
    Arm description
    Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects who completed 24 weeks in the DB period and continued in OLE period: received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks.

    Arm title
    Sarilumab 200 mg/Sarilumab 200 mg
    Arm description
    Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).
    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
    Subjects who completed 24 weeks in the DB period and continued OLE period; received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).

    Number of subjects in period 2 [1]
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Started
    155
    165
    Completed
    108
    120
    Not completed
    47
    45
         Adverse event
    20
    23
         Other- Unspecified
    20
    15
         Poor compliance to protocol
    5
    1
         Lack of efficacy
    2
    6
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 155 subjects entered OLE period and 1 did not enroll.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adalimumab 40 mg/Sarilumab 200 mg
    Reporting group description
    Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).

    Reporting group title
    Sarilumab 200 mg/Sarilumab 200 mg
    Reporting group description
    Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).

    Reporting group values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg Total
    Number of subjects
    185 184 369
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.6 ± 11.9 50.9 ± 12.6 -
    Gender categorical
    Units: Subjects
        Female
    150 157 307
        Male
    35 27 62
    Race/Ethnicity
    Units: Subjects
        Caucasian/White
    164 171 335
        Black
    3 1 4
        Asian/Oriental
    9 2 11
        Other
    9 10 19
    Disease Activity Score 28 based on erythrocyte sedimentation rate (DAS28-ESR)
    DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); General health (GH) assessment by the subject assessed from the American College of Rheumatology (ACR) rheumatoid arthritis (RA) core set questionnaire (subject global assessment) in 100 mm visual analog scale (VAS); Marker of inflammation assessed by ESR in mm/hr.
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.76 ± 0.83 6.83 ± 0.76 -

    End points

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    End points reporting groups
    Reporting group title
    Adalimumab 40 mg/Sarilumab 200 mg
    Reporting group description
    Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).

    Reporting group title
    Sarilumab 200 mg/Sarilumab 200 mg
    Reporting group description
    Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).
    Reporting group title
    Adalimumab 40 mg/Sarilumab 200 mg
    Reporting group description
    Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).

    Reporting group title
    Sarilumab 200 mg/Sarilumab 200 mg
    Reporting group description
    Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).

    Primary: DB Period: Change From Baseline in Disease Activity Score for 28 Joints - Erythrocyte Sedimentation Rate (DAS28-ESR) Score at Week 24

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    End point title
    DB Period: Change From Baseline in Disease Activity Score for 28 Joints - Erythrocyte Sedimentation Rate (DAS28-ESR) Score at Week 24
    End point description
    DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR and RA core set questionnaire (subject global assessment) in 100 mm VAS; marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Least square (LS) mean and standard error (SE) at Week 24 were obtained using Mixed-effect model with repeated measures (MMRM) approach. Intent-to-treat (ITT) population included all subjects. Here, number of subjects analysed = subjects with DAS28-ESR assessment at both baseline and Week 24.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    163
    165
    Units: units on a scale
        least squares mean (standard error)
    -2.20 ± 0.106
    -3.28 ± 0.105
    Statistical analysis title
    Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg
    Statistical analysis description
    Analysis was performed using MMRM approach with treatment, region, visits, and treatment-by-visit interaction as fixed effects and baseline DAS28-ESR score as a continuous covariate. Hierarchical testing procedure was used to control overall alpha error rate at 0.05 level and handle multiple endpoint analyses. Testing was then performed sequentially in order endpoints are reported. Hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    Comparison groups
    Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -1.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.361
         upper limit
    -0.793
    Notes
    [1] - Threshold for significance at 0.05 level.

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

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    End point title
    DB Period: Percentage of Subjects Achieving Clinical Remission Score (DAS28-ESR <2.6) at Week 24
    End point description
    DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR RA core set questionnaire (subject global assessment) in 100 mm VAS; marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Subjects who discontinued treatment prior to Week 24 were analysed as non-responders. ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    185
    184
    Units: percentage of subjects
        number (not applicable)
    7.0
    26.6
    Statistical analysis title
    Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel method stratified by region.
    Comparison groups
    Sarilumab 200 mg/Sarilumab 200 mg v Adalimumab 40 mg/Sarilumab 200 mg
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.879
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.536
         upper limit
    9.389
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: DB Period: Percentage of Subjects Achieving ACR50 Criteria at Week 24

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    End point title
    DB Period: Percentage of Subjects Achieving ACR50 Criteria at Week 24
    End point description
    ACR responses are assessed with a composite rating scale of the ACR that includes 7 variables: TJC (68 joints); SJC (66 joints); levels of an acute phase reactant (C-reactive protein [CRP] level); subject’s assessment of pain (measured on 0 [no pain]-100 mm [worst pain] VAS); subject’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); physician’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); subject’s assessment of physical function (measured by Health Assessment Questionnaire - Disability Index [HAQ-DI], with scoring range of 0 [better physical function] - 3 [worst physical function]). 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. Subjects were analysed as non-responders from the time they discontinued treatment. ITT Population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    185
    184
    Units: percentage of subjects
        number (not applicable)
    29.7
    45.7
    Statistical analysis title
    Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel method stratified by region.
    Comparison groups
    Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0017 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.976
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.289
         upper limit
    3.028
    Notes
    [3] - Threshold for significance at 0.05 level.

    Secondary: DB Period: Percentage of Subjects Achieving ACR70 Criteria at Week 24

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    End point title
    DB Period: Percentage of Subjects Achieving ACR70 Criteria at Week 24
    End point description
    ACR responses are assessed with a composite rating scale of the ACR that includes 7 variables: TJC (68 joints); SJC (66 joints); levels of an acute phase reactant (CRP level); subject’s assessment of pain (measured on 0 [no pain]-100 mm [worst pain] VAS); subject’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); physician’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); subject’s assessment of physical function (measured by HAQ-DI, with scoring range of 0 [better physical function] - 3 [worst physical function]). ACR70 was 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. Subjects were analysed as non-responders from the time they discontinued treatment. ITT Population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    185
    184
    Units: percentage of subjects
        number (not applicable)
    11.9
    23.4
    Statistical analysis title
    Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel- Haenszel method stratified by region.
    Comparison groups
    Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0036 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.286
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    4.02
    Notes
    [4] - Threshold for significance at 0.05 level.

    Secondary: DB Period: Percentage of Subjects Achieving ACR20 Criteria at Week 24

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    End point title
    DB Period: Percentage of Subjects Achieving ACR20 Criteria at Week 24
    End point description
    ACR responses are assessed with a composite rating scale of the ACR that includes 7 variables: TJC (68 joints); SJC (66 joints); levels of an acute phase reactant (CRP level); subject’s assessment of pain (measured on 0 [no pain]-100 mm [worst pain] VAS); subject’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); physician’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); subject’s assessment of physical function (measured by HAQ-DI, with scoring range of 0 [better physical function] - 3 [worst physical function]). ACR20 was 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. Subjects were analysed as non-responders from the time they discontinued treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    185
    184
    Units: percentage of subjects
        number (not applicable)
    58.4
    71.7
    Statistical analysis title
    Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel method stratified by region.
    Comparison groups
    Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0074 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.168
         upper limit
    2.773
    Notes
    [5] - Threshold for significance 0.05 level.

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

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    End point title
    DB Period: 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 or 3 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 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with HAQ-DI assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    158
    165
    Units: units on a scale
        least squares mean (standard error)
    -0.43 ± 0.045
    -0.61 ± 0.045
    Statistical analysis title
    Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using MMRM approach with treatment, region, visits, and treatment-by-visit interaction as fixed effects and baseline HAQ-DI score as a continuous covariate.
    Comparison groups
    Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0037 [6]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.182
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.305
         upper limit
    -0.059
    Notes
    [6] - Threshold for significance at 0.05 level.

    Secondary: DB Period: Change From Baseline in Short-Form-36 (SF-36) - Physical Component Summary (PCS) Score at Week 24

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    End point title
    DB Period: Change From Baseline in Short-Form-36 (SF-36) - Physical Component Summary (PCS) Score at Week 24
    End point description
    SF-36 is a generic 36-item questionnaire of 8 sub-scales, measures health-related quality of life (HRQL) in last 4 weeks covering 2 summary measures: PCS and mental component summary (MCS). PCS with 4 sub-scales: physical function, role limitations due to physical problems, pain, general health perception; and MCS with 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Subjects self-report on items in a sub-scale that have between 2-6 choices per item using Likert-type responses (e.g. none of the time, some of the time, etc.). Summations of item scores of same sub-scale give the sub-scale scores, which are transformed into a range from 0-100; 0= worst HRQL, 100=best HRQL. Both PCS and MCS range from 0-100 with higher scores indicating better physical and mental health. LS mean and SE at Week 24 by MMRM approach. ITT population. Here, number of subjects analysed = subjects with SF-36 PCS score assessment at baseline and week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    157
    159
    Units: units on a scale
        least squares mean (standard error)
    6.09 ± 0.555
    8.74 ± 0.555
    Statistical analysis title
    Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using MMRM approach with treatment, region, visits, and treatment-by-visit interaction as fixed effects and baseline SF-36 PCS score as a continuous covariate.
    Comparison groups
    Sarilumab 200 mg/Sarilumab 200 mg v Adalimumab 40 mg/Sarilumab 200 mg
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006 [7]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    2.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.147
         upper limit
    4.153
    Notes
    [7] - Threshold for significance at 0.05 level.

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

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    End point title
    DB Period: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 24
    End point description
    The FACIT-F 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 ranges from 0 to 52, where higher score corresponds to a lower level of fatigue. A positive change from baseline score indicates an improvement. LS mean and SE at Week 24 by MMRM approach. ITT population. Here, number of subjects analysed = subjects with FACIT-F score assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    158
    165
    Units: units on a scale
        least squares mean (standard error)
    8.41 ± 0.709
    10.18 ± 0.701
    Statistical analysis title
    Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using MMRM approach with treatment, region, visits, and treatment-by-visit interaction as fixed effects and baseline FACIT-F score as a continuous covariate.
    Comparison groups
    Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0689 [8]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    1.768
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.137
         upper limit
    3.674
    Notes
    [8] - Threshold for significance at 0.05 level.

    Secondary: DB Period: Change From Baseline in SF-36 - Mental Health Component Summary Score at Week 24

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    End point title
    DB Period: Change From Baseline in SF-36 - Mental Health Component Summary Score at Week 24
    End point description
    SF-36 is a generic 36-item questionnaire consisting of 8 sub-scales, measures HRQL in the last 4 weeks covering 2 summary measures: PCS and MCS. PCS with 4 subscales: physical function, role limitations due to physical problems, pain, and general health perception; and MCS with 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 (e.g. none of the time, some of the time, etc.). Summations of item scores of the same subscale give the sub-scale scores, which are transformed into a range from 0 to 100; 0= worst HRQL, 100=best HRQL. Both PCS and MCS range from 0-100 with higher scores indicating better physical and mental health. LS mean and SE at Week 24 by MMRM approach. ITT population. Here, number of subjects analysed = subjects with SF-36 - mental health component summary score assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    157
    159
    Units: units on a scale
        least squares mean (standard error)
    6.83 ± 0.774
    7.86 ± 0.773
    No statistical analyses for this end point

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

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    End point title
    DB Period: Change From Baseline in Disease Activity Score for 28 Joints Based on C-Reactive Protein (DAS28-CRP Score) at Week 24
    End point description
    DAS28-CRP is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR RA core set questionnaire (subject global assessment) in 100 mm VAS; Marker of inflammation assessed by high sensitivity C-reactive protein (hs-CRP) in mg/L. The DAS28-CRP score provides a number indicating the current disease activity of the RA. DAS28-CRP total score ranges from 2-10. A DAS28-CRP score above 5.1 means high disease activity, whereas a DAS28-CRP score below 3.2 indicates low disease activity and a DAS28-CRP score below 2.6 means disease remission. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with DAS28-CRP score assessment at both baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    156
    163
    Units: units on a scale
        least squares mean (standard error)
    -1.97 ± 0.094
    -2.86 ± 0.093
    No statistical analyses for this end point

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

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    End point title
    DB Period: Percentage of Subjects Achieving Clinical Remission Score (DAS28-CRP <2.6) at Week 24
    End point description
    DAS28-CRP is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR RA core set questionnaire (subject global assessment) in 100 mm VAS; Marker of inflammation assessed by hs-CRP in mg/L. The DAS28-CRP score provides a number indicating the current disease activity of the RA. DAS28-CRP total score ranges from 2-10. A DAS28-CRP score above 5.1 means high disease activity, whereas a DAS28-CRP score below 3.2 indicates low disease activity and a DAS28-CRP score below 2.6 means disease remission. Subjects were analysed as non-responders from the time they discontinued treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    185
    184
    Units: percentage of subjects
        number (not applicable)
    13.5
    34.2
    No statistical analyses for this end point

    Secondary: DB Period: Percentage of Subjects Achieving Low Disease Activity (DAS28-ESR < 3.2) at Week 24

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    End point title
    DB Period: Percentage of Subjects Achieving Low Disease Activity (DAS28-ESR < 3.2) at Week 24
    End point description
    DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR RA core set questionnaire (subject global assessment) in 100 mm VAS; Marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Subjects were analysed as non-responders from the time they discontinued treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    185
    184
    Units: percentage of subjects
        number (not applicable)
    14.1
    42.9
    No statistical analyses for this end point

    Secondary: DB Period: Percentage of Subjects Achieving Clinical Disease Activity Index (CDAI) Remission (CDAI <=2.8) at Week 24

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    End point title
    DB Period: Percentage of Subjects Achieving Clinical Disease Activity Index (CDAI) Remission (CDAI <=2.8) 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: SJC (28 joints), TJC (28 joints), subject’s global assessment of disease activity (in cm), and physician’s global assessment of disease activity (in cm). Total score ranges from 0 to 76 with a lower score indicating less disease activity. Subjects were analysed as non-responders from the time they discontinued treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    185
    184
    Units: percentage of subjects
        number (not applicable)
    2.7
    7.1
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in CDAI at Week 24

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    End point title
    DB Period: Change From Baseline in 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: SJC (28 joints), TJC (28 joints), subject’s global assessment of disease activity (in cm), and physician’s global assessment of disease activity (VAS in cm). Total score ranges from 0 to 76 with a lower score indicating less disease activity. A negative change in CDAI score indicates an improvement in disease activity and a positive change in score indicates a worsening of disease activity. LS means and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with CDAI assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    158
    165
    Units: units on a scale
        least squares mean (standard error)
    -25.20 ± 0.842
    -28.94 ± 0.834
    No statistical analyses for this end point

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

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    End point title
    DB Period: Change From Baseline in European Quality of Life-5 Dimension 3 Level (EQ-5D-3L) Scores at Week 24
    End point description
    EQ-5D-3L is a standardised, generic measure of health outcome. EQ-5D was designed for self-completion by subjects. EQ-5D was specifically included to address concerns regarding health economic impact of RA. EQ-5D-3L comprises of 5 questions on mobility, self-care, pain/discomfort, usual activities, and psychological status with 3 possible answers for each item (1=no problem, 2=moderate problems, 3=severe problems). 5-dimensional 3-level systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-3L-VAS records the subject’s self-rated health on a vertical VAS that allows the subjects to indicate their health state ranging from 0 (worst imaginable) to 100 (best imaginable). LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, "number of subjects analysed" = subjects with EQ-5D-3L score assessment both at baseline and Week 24, and "n" = subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    156
    164
    Units: units on a scale
    least squares mean (standard error)
        EQ-5D Single index utility score (n=156,160)
    0.26 ± 0.019
    0.32 ± 0.019
        EQ-5D VAS (n=156,164)
    19.94 ± 1.720
    24.22 ± 1.686
    No statistical analyses for this end point

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

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    End point title
    DB Period: Change From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) 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. Each NRS is assessed as a number between 0 and 10 that corresponds to the 7 domains. The values for each of these domains are weighed by subject assessment of relative importance and combined in a single score with a total score range of 0 (not affected, very good) to 10 (most affected). LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with RAID assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    157
    161
    Units: units on a scale
        least squares mean (standard error)
    -2.30 ± 0.168
    -3.08 ± 0.168
    No statistical analyses for this end point

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

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    End point title
    DB Period: Change From Baseline in Work Productivity Survey - Rheumatoid Arthritis (WPS-RA) at Week 24: Work Days Missed Due to Arthritis
    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 is interviewer-administered and 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 using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    60
    70
    Units: days
        least squares mean (standard error)
    0.05 ± 0.611
    -0.28 ± 0.547
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in WPS-RA at Week 24: Days With Work Productivity Reduced by >= 50% Due to Arthritis

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    End point title
    DB Period: Change From Baseline in WPS-RA at Week 24: Days With Work Productivity Reduced by >= 50% Due to Arthritis
    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 is interviewer-administered and 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 subjects was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    60
    70
    Units: days
        least squares mean (standard error)
    -3.50 ± 0.525
    -3.74 ± 0.456
    No statistical analyses for this end point

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

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    End point title
    DB Period: Change From Baseline in WPS-RA at Week 24: Arthritis 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 is interviewer-administered and 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 24 were obtained using MMRM approach. ITT Population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    60
    69
    Units: units on a scale
        least squares mean (standard error)
    -2.510 ± 0.3470
    -2.919 ± 0.3073
    No statistical analyses for this end point

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

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    End point title
    DB Period: Change From Baseline in WPS-RA at Week 24: House Work Days Missed Due to Arthritis
    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 is interviewer-administered and 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 subjects was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    163
    169
    Units: days
        least squares mean (standard error)
    -4.22 ± 0.405
    -5.49 ± 0.400
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in WPS-RA at Week 24: Days With Household Work Productivity Reduced by >= 50% Due to Arthritis

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    End point title
    DB Period: Change From Baseline in WPS-RA at Week 24: Days With Household Work Productivity Reduced by >= 50% Due to Arthritis
    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 is interviewer-administered and 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 subjects was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    163
    169
    Units: days
        least squares mean (standard error)
    -4.87 ± 0.451
    -6.70 ± 0.445
    No statistical analyses for this end point

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

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    End point title
    DB Period: Change From Baseline in WPS-RA at Week 24: Days With Family/Social/Leisure Activities Missed Due to Arthritis
    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 is interviewer-administered and 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 subjects was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    163
    169
    Units: days
        least squares mean (standard error)
    -3.33 ± 0.376
    -4.14 ± 0.371
    No statistical analyses for this end point

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

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    End point title
    DB Period: Change From Baseline in WPS-RA at Week 24: Days With Outside Help Hired Due to Arthritis
    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 is interviewer-administered and 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 using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    163
    168
    Units: days
        least squares mean (standard error)
    -2.57 ± 0.401
    -3.43 ± 0.398
    No statistical analyses for this end point

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

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    End point title
    DB Period: 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 is interviewer-administered and 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 using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    163
    168
    Units: units on a scale
        least squares mean (standard error)
    -2.605 ± 0.2110
    -3.276 ± 0.2099
    No statistical analyses for this end point

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

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    End point title
    DB Period: 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 using MMRM approach. ITT population. Here, number of subjects analysed = subjects with morning stiffness VAS assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    156
    165
    Units: mm
        least squares mean (standard error)
    -29.29 ± 1.970
    -35.08 ± 1.947
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Individual ACR Component - TJC and SJC at Week 24

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    End point title
    DB Period: Change From Baseline in Individual ACR Component - TJC and SJC at Week 24
    End point description
    ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI & acute phase reactant (hs-CRP and ESR levels). 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 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with TJC and SJC assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    158
    166
    Units: joints
    least squares mean (standard error)
        TJC
    -16.45 ± 0.781
    -18.23 ± 0.772
        SJC
    -12.20 ± 0.450
    -13.44 ± 0.444
    No statistical analyses for this end point

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

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    End point title
    DB Period: Change From Baseline in Individual ACR Component - Physician Global VAS, Subject Global VAS and Pain VAS at Week 24
    End point description
    ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI & acute phase reactant (hs-CRP and ESR levels). Physician global VAS & subject global VAS was done on 100 mm horizontal anchored VAS, ranging from 0 “no arthritis activity” to 100 “maximal arthritis activity” and Pain VAS on 100 mm VAS, ranging from 0 “no pain” to 100 “worst pain”. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with individual ACR components assessment both at baseline and Week 24, and "n" = subjects with available data for specified category for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    158
    166
    Units: mm
    least squares mean (standard error)
        Physician global VAS (n=158,166)
    -37.80 ± 1.431
    -45.33 ± 1.414
        Subject global VAS (n=158,165)
    -24.82 ± 1.752
    -33.30 ± 1.731
        Pain VAS (n=157,165)
    -27.41 ± 1.802
    -36.19 ± 1.776
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Individual ACR Component - CRP Level at Week 24

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    End point title
    DB Period: Change From Baseline in Individual ACR Component - CRP Level at Week 24
    End point description
    ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI and acute phase reactant (hs-CRP and ESR levels). An elevated CRP level is considered a non-specific "marker" for RA. A decrease indicates improvement. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with CRP assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    156
    164
    Units: mg/L
        least squares mean (standard error)
    -2.91 ± 1.461
    -17.01 ± 1.431
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Individual ACR Component- ESR Level at Week 24

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    End point title
    DB Period: Change From Baseline in Individual ACR Component- ESR Level at Week 24
    End point description
    ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI & acute phase reactant (hs-CRP and ESR levels). The ESR is a blood test that can reveal inflammatory activity. Inflammation can cause the cells to clump together. The farther the red blood cells have descended, the greater the inflammatory response. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with ESR assessment both at baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    163
    166
    Units: mm/hr
        least squares mean (standard error)
    -12.74 ± 1.398
    -32.11 ± 1.388
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    DB Period: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    Adverse event (AE) was defined as any untoward medical occurrence in subject who received investigational medicinal product (IMP) and did not necessarily had to have causal relationship with treatment. All reported AEs were TEAEs developed/worsened during 'on treatment period' (time from first dose of study drug up to day before first dose of open-label treatment for subjects who completed 24-week randomised//DB treatment). SAEs were AEs resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. DB period safety population which consisted of all randomised subjects who received at least one dose of study medication analysed according to the treatment they have actually received.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    184
    184
    Units: subjects
        TEAEs
    117
    118
        SAEs
    13
    9
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Treatment-emergent Adverse Events and Serious Adverse Events

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    End point title
    OLE Period: Number of Subjects With Treatment-emergent Adverse Events and Serious Adverse Events
    End point description
    AE was defined as any untoward medical occurrence in subject who received IMP and did not necessarily had to have causal relationship with treatment. All reported AEs were TEAEs developed/worsened during 'on treatment period' (from end of week 24 [Baseline of OLE Period] up to last dose in OLE period + 6 weeks [follow-up], regardless of unplanned intermittent discontinuations). SAEs were AEs resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. OLE period safety population which included all randomised subjects who continued OLE period and received at least one dose of the study medication during OLE period, analysed according to the treatment they have actually received.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to last dose in OLE + 6 weeks of follow up (i.e. up to Week 306)
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    155
    165
    Units: subjects
        TEAE
    135
    143
        SAE
    31
    25
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities (PCSA) - Hematological Parameters

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    End point title
    DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities (PCSA) - Hematological Parameters
    End point description
    Criteria for PCSA included: • Hemoglobin (Hb): less than or equal to (<=) 115 grammes per litre (g/L)(Male), <= 95 g/L (Female); greater than or equal to (>=) 185 g/L (18.5 g/dL) (Male), >= 165 g/L (16.5 g/dL) (Female); Decrease From Baseline (DFB) = 20 g/L (2g/dL). • Hematocrit: <= 0.37 volume/volume (v/v) (Male); <= 0.32 v/v (Female); >= 0.55 v/v (Male); >= 0.5 v/v(Female). • Red Blood Cells (RBCs): >=6 Tera/ litre (L). • Platelets: < 50 Giga/L (G/L), 50 - 100 G/L, >= 700 G/L. • White blood cells (WBC): < 3.0 G/L (Non-Black); < 2.0 G/L (Black), >= 16.0 G/L. • Neutrophils: < 1.0 G/L, < 1.5 G/L (Non-Black); < 1.0 G/L (Black). • Lymphocytes: < 0.5 G/L, >= 0.5 G/L - lower limit of normal (LLN), > 4.0 G/L. • Monocytes: > 0.7 G/L. • Basophils: > 0.1 G/L. • Eosinophils: > 0.5 G/L or > upper limit of normal (ULN) (if ULN >= 0.5 G/L). DB safety population. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    184
    184
    Units: subjects
        Hb:<=115 g/L, <=95 g/L (n=184,184)
    12
    7
        Hb: >=185 g/L, >=165 g/L (n=184,184)
    0
    1
        Hb: DFB >=20 g/L (n=184,184)
    5
    5
        Hematocrit: <= 0.37 v/v; <=0.32 v/v (n=183,184)
    21
    10
        Hematocrit: >=0.55 v/v; >=0.5 v/v (n=183,184)
    1
    3
        RBCs: >=6 Tera/L (n=184,184)
    0
    1
        Platelets: < 50 G/L (n=183,184)
    0
    1
        Platelets: 50 - 100 G/L (n=183,184)
    0
    0
        Platelets: >= 700 G/L (n=183,184)
    1
    0
        WBC:<3.0G/L(Non-Black);<2.0 G/L(Black)(n=184,184)
    1
    32
        WBC: >= 16.0 G/L (n=184,184)
    8
    5
        Neutrophils: < 1.0 G/L (n=183,184)
    2
    19
        Neutrophils: <1.5 G/L; <1.0 G/L (n=183,184)
    7
    50
        Lymphocytes: < 0.5 G/L (n=183,184)
    2
    2
        Lymphocytes: >= 0.5G/L - LLN (n=183,184)
    8
    21
        Lymphocytes: > 4.0 G/L (n=183,184)
    17
    6
        Monocytes: > 0.7 G/L (n=183,184)
    46
    38
        Basophils: > 0.1 G/L (n=183,184)
    53
    37
        Eosinophils: > 0.5 G/L or > ULN (n=183,184)
    4
    9
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Hematological Parameters

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    End point title
    OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Hematological Parameters
    End point description
    Criteria for PCSA included: • Hb: <=115 g/L (Male), <= 95 g/L (Female); >=185 g/L (18.5 g/dL) (Male), >= 165 g/L (16.5 g/dL)(Female);DFB >= 20 g/L (2g/dL). • Hematocrit: <= 0.37 v/v (Male); <= 0.32 v/v (Female); >= 0.55 v/v (Male); >= 0.5 v/v (Female). • RBCs: >=6 Tera/ L. • Platelets: < 50 G/L, 50 - 100 G/L, >= 700 G/L. • WBC: < 3.0 G/L (Non-Black); < 2.0 G/L (Black), >= 16.0 G/L. • Neutrophils: < 1.0 G/L, < 1.5 G/L (Non-Black); < 1.0 G/L (Black). • Lymphocytes: < 0.5 G/L, >= 0.5 G/L - LLN, > 4.0 G/L. • Monocytes: > 0.7 G/L. • Basophils: > 0.1 G/L. • Eosinophils: > 0.5 G/L or > ULN (if ULN >= 0.5 G/L). OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to Week 300
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    154
    165
    Units: subjects
        Hb:<=115 g/L, <=95 g/L
    8
    5
        Hb: >=185 g/L, >=165 g/L
    3
    3
        Hb: DFB >=20 g/L
    13
    13
        Hematocrit: <= 0.37 v/v; <=0.32 v/v
    12
    14
        Hematocrit: >=0.55 v/v; >=0.5 v/v
    5
    8
        RBCs: >=6 Tera/L
    3
    2
        Platelets: < 50 G/L
    0
    0
        Platelets: 50 - 100 G/L
    4
    4
        Platelets: >= 700 G/L
    2
    1
        WBC: < 3.0 G/L(Non-Black); < 2.0 G/L(Black)
    34
    46
        WBC: >= 16.0 G/L
    11
    7
        Neutrophils: < 1.0 G/L
    24
    25
        Neutrophils: <1.5 G/L(Non-Black); <1.0 G/L(Black)
    62
    69
        Lymphocytes: < 0.5 G/L
    2
    3
        Lymphocytes: >= 0.5 G/L - LLN
    28
    42
        Lymphocytes: > 4.0 G/L
    15
    7
        Monocytes: > 0.7 G/L
    48
    43
        Basophils: > 0.1 G/L
    78
    70
        Eosinophils: > 0.5G/L or > ULN(if ULN >= 0.5G/L)
    11
    14
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Liver Function Tests

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    End point title
    DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Liver Function Tests
    End point description
    Criteria for PCSA: • Alanine Aminotransferase (ALT): >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN. • Aspartate aminotransferase (AST): >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN. • Alkaline phosphatase: >1.5 ULN. • Total bilirubin (TBILI): >1.5 ULN; >2 ULN. • Conjugated bilirubin (CBILI): >1.5 ULN. • Unconjugated bilirubin: >1.5 ULN, >2 ULN. • ALT >3 ULN and TBILI >2 ULN. • CBILI >35% TBILI and TBILI >1.5 ULN. • Albumin: <=25 g/L. DB Period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    183
    184
    Units: subjects
        ALT >1 ULN and <=1.5 ULN
    22
    36
        ALT >1.5 ULN and <=3 ULN
    17
    26
        ALT >3 ULN and <=5 ULN
    3
    5
        ALT >5 ULN and <=10 ULN
    1
    1
        ALT >10 ULN and <=20 ULN
    1
    0
        ALT >20 ULN
    0
    0
        AST >1 ULN and <=1.5 ULN
    16
    22
        AST >1.5 ULN and <=3 ULN
    7
    13
        AST >3 ULN and <=5 ULN
    3
    2
        AST >5 ULN and <=10 ULN
    0
    0
        AST >10 ULN and <=20 ULN
    1
    0
        AST >20 ULN
    0
    0
        Alkaline Phosphatase >1.5 ULN
    6
    2
        TBILI >1.5 ULN
    1
    7
        TBILI >2 ULN
    0
    2
        CBILI >1.5 ULN
    0
    0
        Unconjugated Bilirubin >1.5 ULN
    5
    13
        Unconjugated Bilirubin >2 ULN
    1
    7
        ALT> 3 ULN and TBILI >2ULN
    0
    0
        CBILI >35% TBILI and TBILI >1.5 ULN
    0
    0
        Albumin <=25 g/L
    0
    0
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Liver Function Tests

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    End point title
    OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Liver Function Tests
    End point description
    Criteria for PCSA: • ALT: >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN. • AST: >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN. • Alkaline phosphatase: >1.5 ULN. • TBILI: >1.5 ULN; >2 ULN. • CBILI: >1.5 ULN. • Unconjugated bilirubin: >1.5 ULN, >2 ULN. • ALT >3 ULN and TBILI >2 ULN. • CBILI >35% TBILI and TBILI >1.5 ULN. • Albumin: <=25 g/L. OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to Week 300
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    154
    165
    Units: subjects
        ALT >1 ULN and <=1.5 ULN
    41
    36
        ALT >1.5 ULN and <=3 ULN
    31
    34
        ALT >3 ULN and <=5 ULN
    11
    10
        ALT >5 ULN and <=10 ULN
    1
    6
        ALT >10 ULN and <=20 ULN
    0
    2
        ALT >20 ULN
    1
    1
        AST >1 ULN and <=1.5 ULN
    25
    39
        AST >1.5 ULN and <=3 ULN
    23
    17
        AST >3 ULN and <=5 ULN
    2
    7
        AST >5 ULN and <=10 ULN
    2
    2
        AST >10 ULN and <=20 ULN
    0
    0
        AST >20 ULN
    0
    1
        Alkaline Phosphatase >1.5 ULN
    0
    1
        TBILI >1.5 ULN
    11
    6
        TBILI >2 ULN
    3
    1
        CBILI >1.5 ULN
    0
    0
        Unconjugated Bilirubin >1.5 ULN
    21
    22
        Unconjugated Bilirubin >2 ULN
    11
    10
        ALT> 3 ULN and TBILI >2ULN
    1
    0
        CBILI >35% TBILI and TBILI >1.5 ULN
    0
    0
        Albumin <=25 g/L
    0
    0
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Metabolic Parameters

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    End point title
    DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Metabolic Parameters
    End point description
    Criteria for potentially clinically significant abnormalities: • Glucose: <=3.9 millimole/litre (mmol/L) and <LLN; >=11.1 mmol/L (unfasted [UF]) or >=7 mmol/L (fasted [FA]). • Hemoglobin A1c (HbA1c): >8%. • Total cholesterol: >=6.2 mmol/L; >=7.74 mmol/L. • LDL cholesterol: >=4.1 mmol/L; >=4.9 mmol/L. • Triglycerides: >=4.6 mmol/L; >=5.6 mmol/L. DB period safety population. Here "n" = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    184
    184
    Units: subjects
        Glucose <=3.9 mmol/L and <LLN (n=181,184)
    10
    8
        Glucose >=11.1mmol/L(UF)or>=7mmol/L(FA)(n=181,184)
    17
    12
        HbA1c >8% (n=178,179)
    3
    3
        Total Cholesterol >=6.2mmol/L (n=181,184)
    52
    88
        Total Cholesterol >=7.74 mmol/L (n=181,184)
    15
    14
        LDL Cholesterol >=4.1 mmol/L (n=180,184)
    35
    59
        LDL Cholesterol >=4.9 mmol/L (n=180,184)
    18
    20
        Triglycerides >=4.6 mmol/L (n=181,184)
    4
    8
        Triglycerides >=5.6 mmol/L (n=181,184)
    3
    6
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Metabolic Parameters

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    End point title
    OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Metabolic Parameters
    End point description
    Criteria for potentially clinically significant abnormalities: • Glucose: <=3.9 mmol/L and <LLN; >=11.1 mmol/L (UF) or >=7 mmol/L (FA). • HbA1c: >8%. • Total cholesterol: >=6.2 mmol/L; >=7.74 mmol/L. • LDL cholesterol: >=4.1 mmol/L; >=4.9 mmol/L. • Triglycerides: >=4.6 mmol/L; >=5.6 mmol/L. OLE period safety population. Here, "n" = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to Week 300
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    155
    165
    Units: subjects
        Glucose <=3.9 mmol/L and <LLN (n=153,165)
    5
    6
        Glucose >=11.1mmol/L(UF)or>=7mmol/L(FA)(n=153,147)
    20
    14
        HbA1c >8% (n=147,161)
    2
    2
        Total Cholesterol >=6.2mmol/L (n=153,165)
    77
    69
        Total Cholesterol >=7.74 mmol/L (n=153,165)
    22
    19
        LDL Cholesterol >=4.1 mmol/L (n=151,164)
    57
    48
        LDL Cholesterol >=4.9 mmol/L (n=151,164)
    25
    16
        Triglycerides >=4.6 mmol/L (n=153,165)
    13
    6
        Triglycerides >=5.6 mmol/L (n=153,165)
    4
    6
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Different Post-baseline Categories of High-density Lipoprotein (HDL)

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    End point title
    DB Period: Number of Subjects With Different Post-baseline Categories of High-density Lipoprotein (HDL)
    End point description
    Number of subjects with different post-baseline status of HDL: < 40 mg/dL, 40 - < 60 mg/dL, >= 60 mg/dL, is reported here. DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    181
    184
    Units: subjects
        HDL: < 40 mg/dL
    5
    7
        HDL: 40 - < 60 mg/dL
    57
    45
        HDL: >=60 mg/dL
    119
    132
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Different Post-baseline Categories of High-density Lipoprotein

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    End point title
    OLE Period: Number of Subjects With Different Post-baseline Categories of High-density Lipoprotein
    End point description
    Number of subjects with different post-baseline status of HDL: < 40 mg/dL, 40 - < 60 mg/dL, >=60 mg/dL, is reported here. OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to Week 300
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    153
    165
    Units: subjects
        HDL: < 40 mg/dL
    7
    5
        HDL: 40 - < 60 mg/dL
    52
    49
        HDL: >=60 mg/dL
    94
    111
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Renal Function

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    End point title
    DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Renal Function
    End point description
    Criteria for potentially clinically significant abnormalities: • Creatinine: >=150 micromol/L (adults); >=30% change from baseline, >=100% change from baseline. • Creatinine clearance: <15 mL/min; >=15 to <30 mL/min; >=30 to <60 mL/min; >=60 to <90 mL/min. • Blood urea nitrogen: >=17 mmol/L. • Uric acid: <120 micromol/L; >408 micromol/L. DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    183
    184
    Units: subjects
        Creatinine >=150 micromol/L (Adults)
    0
    3
        Creatinine >=30% change from baseline
    19
    23
        Creatinine >=100% change from baseline
    0
    1
        Creatinine Clearance <15 mL/min
    0
    0
        Creatinine clearance >=15 to <30 mL/min
    0
    1
        Creatinine clearance >=30 to <60 mL/min
    21
    22
        Creatinine clearance >=60 to <90 mL/min
    74
    65
        Blood Urea Nitrogen >=17 mmol/L
    0
    2
        Uric acid <120 micromol/L
    4
    3
        Uric acid >408 micromol/L
    25
    35
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Renal Function

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    End point title
    OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Renal Function
    End point description
    Criteria for potentially clinically significant abnormalities: • Creatinine: >=150 micromol/L (adults); >=30% change from baseline, >=100% change from baseline. • Creatinine clearance: <15 mL/min; >=15 to <30 mL/min; >=30 to <60 mL/min; >=60 to <90 mL/min. • Blood urea nitrogen: >=17 mmol/L. • Uric acid: <120 micromol/L; >408 micromol/L. OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to Week 300
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    154
    165
    Units: subjects
        Creatinine >=150 micromol/L (Adults)
    2
    2
        Creatinine >=30% change from baseline
    63
    62
        Creatinine >=100% change from baseline
    5
    1
        Creatinine Clearance <15 mL/min
    0
    0
        Creatinine clearance >=15 to <30 mL/min
    1
    0
        Creatinine clearance >=30 to <60 mL/min
    34
    24
        Creatinine clearance >=60 to <90 mL/min
    66
    81
        Blood Urea Nitrogen >=17 mmol/L
    1
    3
        Uric acid <120 micromol/L
    2
    3
        Uric acid >408 micromol/L
    44
    43
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Urinalysis

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    End point title
    DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Urinalysis
    End point description
    Criteria with potentially clinically significant urine abnormalities: pH: <= 4.6; pH: >= 8.0. DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    87
    85
    Units: subjects
        pH <= 4.6
    0
    0
        pH>= 8.0
    0
    0
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Urinalysis

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    End point title
    OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Urinalysis
    End point description
    Criteria with potentially clinically significant urine abnormalities: pH: <= 4.6; pH: >= 8.0. OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to Week 300
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    105
    109
    Units: subjects
        pH <= 4.6
    0
    0
        pH >= 8.0
    0
    1
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Electrolytes

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    End point title
    DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Electrolytes
    End point description
    Criteria for potentially clinically significant abnormalities: • Sodium: <=129 mmol/L; >=160 mmol/L. • Potassium: <3 mmol/L; >=5.5 mmol/L. • Chloride: <80 mmol/L; >115 mmol/L. DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    183
    184
    Units: subjects
        Sodium <=129 mmol/L
    1
    1
        Sodium >=160 mmol/L
    0
    0
        Potassium <3 mmol/L
    3
    0
        Potassium >=5.5 mmol/L
    0
    0
        Chloride <80 mmol/L
    0
    0
        Chloride >115 mmol/L
    0
    1
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Electrolytes

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    End point title
    OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Electrolytes
    End point description
    Criteria for potentially clinically significant abnormalities: • Sodium: <=129 mmol/L; >=160 mmol/L. • Potassium: <3 mmol/L; >=5.5 mmol/L. • Chloride: <80 mmol/L; >115 mmol/L. OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to Week 300
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    154
    165
    Units: subjects
        Sodium <=129 mmol/L
    3
    0
        Sodium >=160 mmol/L
    0
    0
        Potassium <3 mmol/L
    2
    2
        Potassium >=5.5 mmol/L
    6
    7
        Chloride <80 mmol/L
    1
    0
        Chloride >115 mmol/L
    0
    0
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities

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    End point title
    DB Period: Number of Subjects With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities
    End point description
    Criteria for potentially clinically significant ECG abnormalities: • Heart rate (HR): <50 beats per minute (bpm); <50 bpm and DFB >=20 bpm; <40 bpm; <40 bpm and DFB >=20 bpm; <30 bpm; <30 bpm and DFB >=20 bpm; >90 bpm; >=90 bpm and increase from baseline (IFB) >=20 bpm; >100 bpm; >=100 bpm and IFB >=20 bpm; >120 bpm; >=120 bpm and IFB >=20 bpm. • PR Interval: >200 millisecond (ms); >200 ms and IFB >=25%; >220 ms; >220 ms and IFB >=25%; >240 ms; >240 ms and IFB >=25%. • QRS Interval: >110 ms; >110 ms and IFB >=25%; >120 ms; >120 ms and IFB >=25%. • QT Interval: >500 ms. • QTc Bazett (QTc B): >450 ms; >480 ms; >500 ms; IFB >30 and <=60 ms; IFB >60 ms. • QTc Fridericia (QTc F): >450 ms; >480 ms; >500 ms; IFB >30 and <=60 ms; IFB >60 ms. DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint and "n" = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    163
    162
    Units: subjects
        HR <50 bpm (n=162,161)
    4
    5
        HR <50 bpm and DFB >=20 bpm (n=158,158)
    0
    0
        HR <40 bpm (n= 162,161)
    0
    0
        HR <40 bpm and DFB >=20 bpm (n= 158,158)
    0
    0
        HR <30 bpm (n=162,161)
    0
    0
        HR <30 bpm and DFB >=20 bpm (n=158,158)
    0
    0
        HR >90 bpm (n= 162,161)
    11
    2
        HR <90 bpm and IFB >=20 bpm (n=158,158)
    5
    1
        HR >100 bpm (n=162,161)
    2
    1
        HR >=100 bpm and IFB >=20 bpm (n=158,158)
    2
    0
        HR >120 bpm (n=162,161)
    0
    0
        HR >=120 bpm and IFB >=20 bpm (n=158,158)
    0
    0
        PR Interval >200 ms (n=163,161)
    11
    5
        PR Interval >200 ms and IFB >=25% (n=159,158)
    1
    0
        PR Interval >220 ms (n=163,161)
    4
    1
        PR Interval >220 ms and IFB >=25% (n=159,158)
    0
    0
        PR Interval >240 ms (n=163,161)
    1
    1
        PR Interval >240 ms and IFB >=25% (n=159,158)
    0
    0
        QRS Interval >110 ms (n= 163,162)
    3
    9
        QRS Interval >110 ms and IFB >=25% (n=159,159)
    0
    0
        QRS Interval >120 ms (n=163,162)
    1
    2
        QRS Interval >120 ms and IFB >=25% (n=159,159)
    0
    0
        QT Interval >500 ms (n=163,162)
    0
    1
        QTc B >450 ms (n=163,162)
    16
    7
        QTc B >480 ms (n=163,162)
    2
    0
        QTc B >500 ms (n=163,162)
    0
    0
        QTc B IFB >30 and <=60 ms (n=159,159)
    11
    5
        QTc B IFB >60 ms (n=159,159)
    0
    0
        QTc F>450 ms (n=163,162)
    7
    5
        QTc F>480 ms (n=163,162)
    0
    0
        QTc F>500 ms (n=163,162)
    0
    0
        QTc F IFB >30 and <=60 ms (n=159,159)
    9
    3
        QTc F IFB >60 ms (n=159,159)
    0
    0
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Potentially Clinically Significant Electrocardiogram Abnormalities

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    End point title
    OLE Period: Number of Subjects With Potentially Clinically Significant Electrocardiogram Abnormalities
    End point description
    Criteria for potentially clinically significant ECG abnormalities: • HR: <50 bpm; <50 bpm and DFB >=20 bpm; <40 bpm; <40 bpm and DFB >=20 bpm; <30 bpm; <30 bpm and DFB >=20 bpm; >90 bpm; >=90 bpm and IFB >=20 bpm; >100 bpm; >=100 bpm and IFB >=20 bpm; >120 bpm; >=120 bpm and IFB >=20 bpm. • PR Interval: >200 ms; >200 ms and IFB >=25%; >220 ms; >220 ms and IFB >=25%; >240 ms; >240 ms and IFB >=25%. • QRS Interval: >110 ms; >110 ms and IFB >=25%; >120 ms; >120 ms and IFB >=25%. • QT Interval: >500 ms. • QTc B: >450 ms; >480 ms; >500 ms; IFB >30 and <=60 ms; IFB >60 ms. • QTc F: >450 ms; >480 ms; >500 ms; IFB >30 and <=60 ms; IFB >60 ms. OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint and n = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to Week 300
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    154
    163
    Units: subjects
        HR <50 bpm (n=154,163)
    10
    19
        HR <50 bpm and DFB >=20 bpm (n=152,159)
    0
    3
        HR <40 bpm (n=154,163)
    1
    1
        HR <40 bpm and DFB >=20 bpm (n=152,159)
    0
    1
        HR <30 bpm (n=154,163)
    0
    0
        HR <30 bpm and DFB >=20 bpm (n=152,159)
    0
    0
        HR >90 bpm (n=154,163)
    16
    11
        HR >=90 bpm and IFB >=20 bpm (n=152,159)
    7
    6
        HR >100 bpm (n=154,163)
    3
    3
        HR >=100 bpm and IFB >=20 bpm (n=152,159)
    2
    1
        HR >120 bpm (n=154,163)
    0
    0
        HR >=120 bpm and IFB >=20 bpm (n=152,159)
    0
    0
        PR Interval >200 ms (n=154,163)
    17
    14
        PR Interval >200 ms and IFB >=25% (n=152,158)
    6
    3
        PR Interval >220 ms (n=154,163)
    8
    6
        PR Interval >220 ms and IFB >=25% (n=152,158)
    4
    3
        PR Interval >240 ms (n=154,163)
    2
    2
        PR Interval >240 ms and IFB >=25% (n=152,158)
    2
    1
        QRS Interval >110 ms (n=154,163)
    8
    18
        QRS Interval >110 ms and IFB >=25% (n=152,159)
    2
    1
        QRS Interval >120 ms (n=154,163)
    3
    7
        QRS Interval >120 ms and IFB >=25% (n=152,159)
    1
    0
        QT Interval >500 ms (n=154,163)
    2
    2
        QTc B >450 ms (n=154,163)
    35
    33
        QTc B >480 ms (n=154,163)
    3
    30
        QTc B >500 ms (n=154,163)
    1
    1
        QTc B IFB >30 and <=60ms (n=152,159)
    18
    23
        QTc B IFB >60 ms (n=152,159)
    3
    2
        QTc F>450 ms (n=154,163)
    16
    16
        QTc F>480 ms (n=154,163)
    3
    2
        QTc F>500 ms (n=154,163)
    0
    1
        QTc F IFB >30 and <=60 ms (n=152,159)
    19
    19
        QTc F IFB >60 ms (n=152,159)
    4
    3
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Potentially Clinically Significant Vital Signs Abnormalities

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    End point title
    DB Period: Number of Subjects With Potentially Clinically Significant Vital Signs Abnormalities
    End point description
    Criteria for potentially clinically significant vital sign abnormalities: Systolic blood pressure (SBP) supine: <=95 mmHg and DFB>=20 mmHg; >=160 mmHg and IFB >=20 mmHg. Diastolic blood pressure (DBP) supine: <=45 mmHg and DFB >=10 mmHg; >=110 mmHg and IFB >=10 mmHg. SBP (Orthostatic): <=-20 mmHg. DBP (Orthostatic): <=-10 mmHg. HR supine: <=50 bpm and DFB >=20 bpm; >=120 bpm and IFB >=20 bpm. Weight: >=5% DFB; >=5% IFB. DB period safety population. Here, "n" = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    184
    184
    Units: subjects
        SBP (supine) <=95 mmHg, DFB >=20mmHg (n=182,182)
    4
    3
        SBP (supine) >=160mmHg, IFB >=20mmHg (n=182,182)
    4
    5
        DBP (supine) <=45mmHg, DFB >=10mmHg (n=182,182)
    1
    1
        DBP (supine) >=110mmHg, IFB >=10mmHg (n=182,182)
    1
    1
        SBP (orthostatic) <=-20mmHg (n=150,161)
    13
    10
        DBP (orthostatic) <=-10mmHg (n=150,161)
    20
    27
        HR (supine) <=50 bpm, DFB >= 20 bpm (n=182,182)
    2
    1
        HR (supine) >=120 bpm, IFB >=20 bpm (n=182,182)
    1
    0
        Weight >=5% DFB (n=178,180)
    12
    6
        Weight >=5% IFB (n=178,180)
    21
    23
    No statistical analyses for this end point

    Secondary: OLE Period: Number of Subjects With Potentially Clinically Significant Vital Signs Abnormalities

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    End point title
    OLE Period: Number of Subjects With Potentially Clinically Significant Vital Signs Abnormalities
    End point description
    Criteria for potentially clinically significant vital sign abnormalities: SBP supine: <=95 mmHg and DFB >=20 mmHg; >=160 mmHg and IFB >=20 mmHg. DBP supine: <=45 mmHg and DFB >=10 mmHg; >=110 mmHg and IFB >=10 mmHg. SBP (Orthostatic): <=-20 mmHg. DBP (Orthostatic): <=-10 mmHg. HR supine: <=50 bpm and DFB >=20 bpm; >=120 bpm and IFB >=20 bpm. Weight: >=5% DFB; >=5% IFB. OLE period safety population. Here, "n" = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From end of Week 24 (Baseline of OLE Period) up to Week 300
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    155
    165
    Units: subjects
        SBP (supine) <=95 mmHg, DFB >=20mmHg (n=154,164)
    3
    9
        SBP (supine) >=160 mmHg, IFB >=20mmHg (n=154,164)
    10
    11
        DBP (supine) <=45mmHg, DFB >=10mmHg (n=154,164)
    0
    0
        DBP (supine) >=110mmHg, IFB >=10mmHg (n=154,164)
    1
    2
        SBP (orthostatic) <=-20mmHg (n=150,162)
    24
    32
        DBP (orthostatic) <=-10mmHg (n=150,162)
    41
    46
        HR (supine) <=50 bpm, DFB >= 20 bpm (n=154,164)
    3
    0
        HR (supine) >=120 bpm, IFB >=20 bpm (n=154,164)
    0
    0
        Weight >=5% DFB (n=151,164)
    44
    51
        Weight >=5% IFB (n=151,164)
    82
    87
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Treatment-emergent and Treatment-boosted Anti-drug Antibody (ADA) Responses

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    End point title
    DB Period: Number of Subjects With Treatment-emergent and Treatment-boosted Anti-drug Antibody (ADA) Responses [9]
    End point description
    Anti-drug antibody response was categorised as: Treatment emergent and Treatment-boosted. Treatment emergent ADAs was defined as a subject with no positive assay response at baseline but with a positive assay response during the TEAE period. Treatment boosted ADAs: was defined as subjects with a positive ADA assay response at baseline and with at least a 4-fold increase in titer compared to baseline during the TEAE period. TEAE period: time from first dose of the study drug up to the day before first dose of open-label treatment for subjects who completed 24-week randomised/DB treatment. Analysis was performed on ADA population which consisted of all subjects who had signed informed consent and had been allocated to a randomised treatment; received at least 1 dose or part of a dose of IMP with at least 1 post-dose evaluable ADA sample. Data for this endpoint was not planned to be collected and analysed for Adalimumab 40 mg/Sarilumab 200 mg arm.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint is reporting data for applicable arms in the study.
    End point values
    Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    184
    Units: subjects
        Treatment-emergent ADA
    13
        Treatment-boosted ADA
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent and Treatment-boosted Anti-drug Antibody Response During Entire Treatment-emergent Adverse Event Period

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    End point title
    Number of Subjects With Treatment-emergent and Treatment-boosted Anti-drug Antibody Response During Entire Treatment-emergent Adverse Event Period
    End point description
    Anti-drug antibody response was categorised as: Treatment emergent ADAs was defined as a subject with no positive assay response at baseline but with a positive assay response during the entire TEAE period. Treatment boosted ADAs was defined as a subjects with a positive ADA assay response at baseline and with at least a 4-fold increase in titer compared to baseline during the entire TEAE period. Entire TEAE period: last OLE dose - first DB dose date + 6 weeks (follow-up), regardless of unplanned intermittent discontinuations. Analysis was performed on immunogenicity population which consisted of all subjects who received at least 1 dose or part of a dose with at least 1 post-dose evaluable ADA sample.
    End point type
    Secondary
    End point timeframe
    From Week 0 up to last dose in OLE + 6 weeks of follow up (i.e. up to Week 306)
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    150
    163
    Units: subjects
        Treatment-emergent ADAs
    11
    11
        Treatment-boosted ADAs
    0
    0
    No statistical analyses for this end point

    Secondary: DB Period: Pharmacokinetics: Serum Trough (Pre-Dose) Concentrations of Functional Sarilumab

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    End point title
    DB Period: Pharmacokinetics: Serum Trough (Pre-Dose) Concentrations of Functional Sarilumab [10]
    End point description
    Data for this endpoint was not planned to be collected and analysed for "Adalimumab 40 mg/Sarilumab 200 mg” arm. Analysis was performed on Pharmacokinetic (PK) population which consisted of all randomised Sarilumab subjects who received at least 1 dose of IMP with at least one post-dose, non-missing concentration of functional Sarilumab in serum concentration value. Here, "n" = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Week 0 (Baseline), 2, 4, 12, 16, 20, and 24
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint is reporting data for applicable arms in the study.
    End point values
    Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    184
    Units: nanograms per millilitre (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=177)
    0.00 ± 0.00
        Week 2 (n=176)
    5566.03 ± 4843.57
        Week 4 (n=167)
    11209.64 ± 8202.70
        Week 12 (n=152)
    21355.19 ± 14805.63
        Week 16 (n=155)
    23143.39 ± 16508.71
        Week 20 (n=152)
    25252.43 ± 17319.04
        Week 24 (n=148)
    24233.10 ± 17581.72
    No statistical analyses for this end point

    Secondary: OLE Period: Pharmacokinetics: Serum Trough (Pre-Dose) Concentrations of Functional Sarilumab

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    End point title
    OLE Period: Pharmacokinetics: Serum Trough (Pre-Dose) Concentrations of Functional Sarilumab
    End point description
    Analysis was performed on PK population (OLE period) which consisted of all subjects from the randomised population who received at least 1 dose of IMP with at least one post-dose, non-missing serum sarilumab concentration. Here, "n" = subjects with available data for each specified category and '99999' is used as space filler which denotes that no subject was available for the assessment at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Week 24 (Baseline of OLE period), 36, 48, 60, 84, 108, 132, 156, 180, 204, 228, 252, 276, 300 and 306
    End point values
    Adalimumab 40 mg/Sarilumab 200 mg Sarilumab 200 mg/Sarilumab 200 mg
    Number of subjects analysed
    150
    163
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 24 (Baseline of OLE period) (n=128,146)
    109.38 ± 1237.44
    24403.72 ± 17588.31
        Week 36 (n=134,146)
    18952.69 ± 15125.86
    26006.07 ± 19194.79
        Week 48 (n=125,133)
    21911.87 ± 17926.01
    25571.16 ± 18958.00
        Week 60 (n=121,127)
    21583.82 ± 17594.87
    24005.78 ± 18541.46
        Week 84 (n=104,108)
    23230.92 ± 18274.09
    23873.23 ± 19794.57
        Week 108 (n=109,119)
    20405.02 ± 15553.02
    21023.55 ± 17792.89
        Week 132 (n=104,110)
    20814.89 ± 17848.70
    20021.53 ± 18580.91
        Week 156 (n=97,113)
    23604.11 ± 19660.31
    22423.29 ± 18757.11
        Week 180 (n=96,105)
    18611.01 ± 16417.46
    21856.85 ± 18612.43
        Week 204 (n=93,107)
    17982.66 ± 16640.61
    18244.96 ± 16383.47
        Week 228 (n=84,85)
    19451.40 ± 17694.09
    18315.19 ± 17525.62
        Week 252 (n=55,61)
    19663.10 ± 16020.11
    19224.47 ± 16964.41
        Week 276 (n=52,63)
    19071.00 ± 18425.13
    17014.75 ± 16207.18
        Week 300 (n=0,2)
    99999 ± 99999
    9260.00 ± 8683.27
        Week 306 (Follow-up) (n=72,86)
    1237.01 ± 2856.88
    2280.98 ± 7909.71
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from up to Week 24 in DB period and from end of Week 24 (Baseline of OLE Period) up to Week 306 in OLE Period regardless of seriousness or relationship to study drug.
    Adverse event reporting additional description
    Reported AEs are TEAEs developed/worsened during ‘on treatment period’(DB:time from first dose up to day before first dose of open-label treatment; OLE:from end of Week 24 [Baseline of OLE Period] up to the last dose in OLE + 6 weeks [follow-up]). Safety population. For OLE, data was reported for pooled population (all subjects received Sarilumab).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    DB Period - Adalimumab 40 mg
    Reporting group description
    Adalimumab 40 mg SC injection in combination with placebo for sarilumab q2w for 24 weeks during DB period. The dosing frequency of adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23.

    Reporting group title
    DB Period - Sarilumab 200mg
    Reporting group description
    Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23.

    Reporting group title
    OLE Period - Sarilumab 200mg
    Reporting group description
    All subjects who completed 24 weeks DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to maximum of additional 276 weeks (i.e. up to Week 300).

    Serious adverse events
    DB Period - Adalimumab 40 mg DB Period - Sarilumab 200mg OLE Period - Sarilumab 200mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 184 (7.07%)
    9 / 184 (4.89%)
    56 / 320 (17.50%)
         number of deaths (all causes)
    0
    1
    8
         number of deaths resulting from adverse events
    0
    1
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    0 / 320 (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
    Chronic Lymphocytic Leukaemia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Adenocarcinoma Stage Iv
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lung Squamous Cell Carcinoma Stage Ii
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant Mesenteric Neoplasm
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastases To Peritoneum
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ureteric Cancer Metastatic
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Yolk Sac Tumour Site Unspecified
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Aortic Dissection
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Iliac Artery Occlusion
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iliac Artery Stenosis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Serum Sickness
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    0 / 320 (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
    Reproductive system and breast disorders
    Cervical Dysplasia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterovaginal Prolapse
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal Prolapse
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         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 Alveolar Haemorrhage
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device Defective
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device Dislocation
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    0 / 320 (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
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Ankle Fracture
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Head Injury
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital Haematoma
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Rib Fracture
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary Muscle Rupture
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Ischaemia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Demyelinating Polyneuropathy
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Headache
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial Aneurysm
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    0 / 320 (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
    Subarachnoid Haemorrhage
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    2 / 320 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood Loss Anaemia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    2 / 320 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic Necrosis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pancreatitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    2 / 320 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    0 / 320 (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
    Hepatobiliary disorders
    Biliary Obstruction
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Cholelithiasis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    4 / 320 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic Haematoma
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Panniculitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson Syndrome
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroid Mass
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    0 / 320 (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
    Back Pain
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Lumbar Spinal Stenosis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    5 / 320 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    3 / 320 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Stenosis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis Bacterial
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    0 / 320 (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
    Bone Abscess
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bullous Erysipelas
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis Infective
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Epididymitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 184 (0.54%)
    0 / 320 (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
    Osteomyelitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    5 / 320 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 184 (0.00%)
    0 / 320 (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
    Urinary Tract Infection
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular Neuronitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 184 (0.00%)
    1 / 320 (0.31%)
         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
    DB Period - Adalimumab 40 mg DB Period - Sarilumab 200mg OLE Period - Sarilumab 200mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 184 (33.70%)
    79 / 184 (42.93%)
    220 / 320 (68.75%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    6 / 184 (3.26%)
    7 / 184 (3.80%)
    23 / 320 (7.19%)
         occurrences all number
    6
    7
    30
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    11 / 184 (5.98%)
    5 / 184 (2.72%)
    39 / 320 (12.19%)
         occurrences all number
    12
    5
    54
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 184 (1.63%)
    4 / 184 (2.17%)
    28 / 320 (8.75%)
         occurrences all number
    3
    4
    34
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 184 (6.52%)
    7 / 184 (3.80%)
    17 / 320 (5.31%)
         occurrences all number
    13
    9
    34
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 184 (0.54%)
    25 / 184 (13.59%)
    59 / 320 (18.44%)
         occurrences all number
    2
    45
    150
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    7 / 184 (3.80%)
    14 / 184 (7.61%)
    26 / 320 (8.13%)
         occurrences all number
    8
    72
    220
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 184 (3.26%)
    5 / 184 (2.72%)
    20 / 320 (6.25%)
         occurrences all number
    7
    5
    31
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    3 / 184 (1.63%)
    3 / 184 (1.63%)
    21 / 320 (6.56%)
         occurrences all number
    3
    3
    23
    Rheumatoid Arthritis
         subjects affected / exposed
    7 / 184 (3.80%)
    3 / 184 (1.63%)
    21 / 320 (6.56%)
         occurrences all number
    7
    3
    34
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    7 / 184 (3.80%)
    12 / 184 (6.52%)
    41 / 320 (12.81%)
         occurrences all number
    7
    15
    63
    Nasopharyngitis
         subjects affected / exposed
    14 / 184 (7.61%)
    11 / 184 (5.98%)
    60 / 320 (18.75%)
         occurrences all number
    15
    11
    107
    Upper Respiratory Tract Infection
         subjects affected / exposed
    7 / 184 (3.80%)
    3 / 184 (1.63%)
    36 / 320 (11.25%)
         occurrences all number
    9
    3
    52
    Urinary Tract Infection
         subjects affected / exposed
    4 / 184 (2.17%)
    5 / 184 (2.72%)
    30 / 320 (9.38%)
         occurrences all number
    5
    7
    43

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2015
    Following changes were made: i) added the assessment of potential opportunistic infections and study treatment continuation. ii) correct errors or inconsistencies in the protocol schedule of events and footnotes. iii) correct inconsistencies in criteria for dose escalation. iv) detail the requirement for an independent joint assessor.
    20 Nov 2015
    Following changes were made: modified the study duration in order to provide long-term open-label treatment with sarilumab 200 mg q2w beyond Week 48, until anticipated commercial availability of sarilumab or until 2020, and collect long-term data for sarilumab in the monotherapy setting.

    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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