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    Clinical Trial Results:
    A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and Immunogenicity of MSB11456 Compared to European Union approved RoActemra® in Patients with Moderately to Severely Active Rheumatoid Arthritis (APTURA I study)

    Summary
    EudraCT number
    		 2019-004369-42
    Trial protocol
    		 HU   SK   PL   BG   CZ   DE  
    Global end of trial date
    06 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jun 2023
    First version publication date
    22 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04512001
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fresenius Kabi SwissBioSim GmbH
    Sponsor organisation address
    Route de Crassier 23, Eysins, Switzerland, 1262
    Public contact
    Clinical Development, Fresenius Kabi SwissBioSim GmbH, +41 793075735, clinical.development@fresenius-kabi.com
    Scientific contact
    Clinical Development, Fresenius Kabi SwissBioSim GmbH, +41 793075735, clinical.development@fresenius-kabi.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
    06 Jun 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate equivalent efficacy of proposed biosimilar tocilizumab MSB11456 and EU-approved RoActemra when both were administered subcutaneously to patients with moderately to severely active rheumatoid arthritis.
    Protection of trial subjects
    This study was conducted in compliance with Good Clinical Practice (GCP), including the archiving of essential documents.
    Background therapy
    		 The study population comprised participants with moderately to severely active rheumatoid arthritis who had an inadequate response to at least 1 disease-modifying antirheumatic drug (either synthetic or biologic) and who were receiving a stable dose of methotrexate.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Aug 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Georgia: 94
    Country: Number of subjects enrolled
    Moldova, Republic of: 23
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Serbia: 18
    Country: Number of subjects enrolled
    Czechia: 44
    Country: Number of subjects enrolled
    Poland: 303
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Bulgaria: 34
    Country: Number of subjects enrolled
    Hungary: 42
    Worldwide total number of subjects
    604
    EEA total number of subjects
    429
    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)
    499
    From 65 to 84 years
    105
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at research centers in Bulgaria, Czechia, Georgia, Hungary, the Republic of Moldova, Poland, Russia, Serbia and Slovakia from August 2020 to June 2022.

    Pre-assignment
    Screening details
    		 604 participants were enrolled and received treatment in the Core Treatment Period. 543 participants were re-randomized and 541 participants received treatment in the Extended Treatment Period.

    Period 1
    Period 1 title
    Week 0 to Week 24
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Core Treatment Period: MSB11456
    Arm description
    		 Participants received MSB11456 subcutaneously, once a week during the core treatment period (Baseline to Week 24).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MSB11456
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection, once a week during the core treatment period (Baseline to Week 24).

    Arm title
    		 Core Treatment Period: RoActemra®
    Arm description
    		 Participants received EU-approved RoActemra® subcutaneously, once a week during the core treatment period (Baseline to Week 24).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    RoActemra®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection, once a week during the core treatment period (Baseline to Week 24).

    Number of subjects in period 1
    		Core Treatment Period: MSB11456 Core Treatment Period: RoActemra®
    Started
    302
    302
    Received Treatment
    302
    302
    Completed
    267
    276
    Not completed
    35
    26
         Discontinued treatment prior to Week 24
    4
    4
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    16
    9
         Did not meet eligibility but was randomized
    -
    1
         Adverse event, non-fatal
    14
    10
         Withdrawal By Sponsor`s Decision
    1
    -
    Period 2
    Period 2 title
    Week 24 to Week 63
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Core Period; MSB11456; Extended Period: MSB11456
    Arm description
    		 Participants who received MSB11456 during the core treatment period (Baseline to Week 24). Participants were then re-randomized to continue receiving MSB11456 subcutaneously, once a week for an additional 28-week during the extended treatment period (Week 24 to Week 52).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MSB11456
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection, once a week during the core treatment period (Baseline to Week 24) and then once a week in the extended treatment period (Week 24 to Week 52).

    Arm title
    		 Core Period: RoActemra®; Extended Period: MSB11456
    Arm description
    		 Participants who received EU-approved RoActemra® during the core treatment period (Baseline to Week 24). Participants were then re-randomized to begin receiving MSB11456 subcutaneously, once a week for an additional 28-week during the extended treatment period (Week 24 to Week 52).
    Arm type
    		 Experimental

    Investigational medicinal product name
    RoActemra®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection, once a week during the core treatment period (Week 0 to Week 24).

    Investigational medicinal product name
    MSB11456
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection, once a week during the extended treatment period (Week 24 to Week 52).

    Arm title
    		 Core Period: RoActemra®; Extended Period: RoActemra®
    Arm description
    		 Participants who received EU-approved RoActemra® during the core treatment period (Baseline to Week 24). Participants were then re-randomized to continue receiving EU-approved RoActemra® subcutaneously, once a week for an additional 28-week during the extended treatment period (Week 24 to Week 52).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    RoActemra®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection, once a week during the core treatment period (Baseline to Week 24) and then once a week in the extended treatment period (Week 24 to Week 52).

    Number of subjects in period 2
    		Core Period; MSB11456; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: RoActemra®
    Started
    267
    139
    137
    Received Treatment
    266
    139
    136
    Completed
    244
    123
    122
    Not completed
    23
    16
    15
         Adverse event, serious fatal
    -
    1
    1
         Consent withdrawn by subject
    6
    4
    6
         Adverse event, non-fatal
    13
    8
    6
         Miscellaneous
    3
    2
    1
         Lost to follow-up
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Core Treatment Period: MSB11456
    Reporting group description
    		 Participants received MSB11456 subcutaneously, once a week during the core treatment period (Baseline to Week 24).

    Reporting group title
    Core Treatment Period: RoActemra®
    Reporting group description
    		 Participants received EU-approved RoActemra® subcutaneously, once a week during the core treatment period (Baseline to Week 24).

    Reporting group values
    		 Core Treatment Period: MSB11456 Core Treatment Period: RoActemra® Total
    Number of subjects
    		 302 302 604
    Age categorical
    Units: Subjects
        19 to 79 years
    		 302 302 604
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.2 ( 12.72 ) 53.2 ( 11.33 ) -
    Gender categorical
    Units: Subjects
        Female
    		 250 248 498
        Male
    		 52 54 106
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 2 3
        Not Hispanic or Latino
    		 300 300 600
        Unknown or Not Reported
    		 1 0 1
    Race
    Units: Subjects
        White
    		 302 302 604
    Region of Enrollment
    Units: Subjects
        Hungary
    		 19 23 42
        Czechia
    		 19 25 44
        Poland
    		 156 147 303
        Moldova
    		 14 9 23
        Georgia
    		 43 51 94
        Slovakia
    		 5 1 6
        Bulgaria
    		 18 16 34
        Serbia
    		 7 11 18
        Russia
    		 21 19 40

    End points

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    End points reporting groups
    Reporting group title
    Core Treatment Period: MSB11456
    Reporting group description
    		 Participants received MSB11456 subcutaneously, once a week during the core treatment period (Baseline to Week 24).

    Reporting group title
    Core Treatment Period: RoActemra®
    Reporting group description
    		 Participants received EU-approved RoActemra® subcutaneously, once a week during the core treatment period (Baseline to Week 24).
    Reporting group title
    Core Period; MSB11456; Extended Period: MSB11456
    Reporting group description
    		 Participants who received MSB11456 during the core treatment period (Baseline to Week 24). Participants were then re-randomized to continue receiving MSB11456 subcutaneously, once a week for an additional 28-week during the extended treatment period (Week 24 to Week 52).

    Reporting group title
    Core Period: RoActemra®; Extended Period: MSB11456
    Reporting group description
    		 Participants who received EU-approved RoActemra® during the core treatment period (Baseline to Week 24). Participants were then re-randomized to begin receiving MSB11456 subcutaneously, once a week for an additional 28-week during the extended treatment period (Week 24 to Week 52).

    Reporting group title
    Core Period: RoActemra®; Extended Period: RoActemra®
    Reporting group description
    		 Participants who received EU-approved RoActemra® during the core treatment period (Baseline to Week 24). Participants were then re-randomized to continue receiving EU-approved RoActemra® subcutaneously, once a week for an additional 28-week during the extended treatment period (Week 24 to Week 52).

    Subject analysis set title
    MSB11456
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received MSB11456 at any time in either the Core Treatment Period (Baseline to Week 24) and/or the Extended Treatment Period (Week 24 to Week 52). Participants received MSB11456 subcutaneously, once a week.

    Subject analysis set title
    EU-approved RoActemra®
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who only received EU-approved RoActemra® during the Core Treatment Period (Baseline to Week 24) and/or the Extended Treatment Period (Week 24 to Week 52). Participants received EU-approved RoActemra® subcutaneously, once a week.

    Primary: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR)

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    End point title
    		 Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR)
    End point description
    The DAS28-ESR is a measure of disease activity in 28 joints that consists of a composite numerical score of the following variables: Tender Joint Count, Swollen Joint Count, erythrocyte sedimentation rate and Patient’s Global Assessment of Disease Activity. The DAS28-ESR score was derived using the formula: DAS28-ESR = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.014*GH + 0.70*Ln(ESR), where, TJC28 = 28 joint count for tenderness, SJC28 = 28 joint count for swelling, Ln(ESR) = natural logarithm of ESR, GH = the general health component of the DAS (i.e., Patient’s Global Assessment of Disease Activity on a scale of 1 to 100 where 100 is maximal activity). Higher values mean a higher disease activity. The level of disease activity can be interpreted as: • Remission (score of <2.6). • Low (score of ≤2.6 to <3.2). • Moderate (score of ≤3.2 to ≤5.1). • High (score of >5.1) A negative change from baseline indicates an improvement.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Core Treatment Period: MSB11456 Core Treatment Period: RoActemra®
    Number of subjects analysed
    302 [1]
    302 [2]
    Units: Score on a scale
        least squares mean (standard error)
    -3.53 ( 0.106 )
    -3.54 ( 0.106 )
    Notes
    [1] - ITT Analysis Set: includes all randomized participants.
    [2] - ITT Analysis Set: includes all randomized participants.
    Statistical analysis title
    		 Core Period: MSB11456 vs Core Period: RoActemra®
    Comparison groups
    Core Treatment Period: MSB11456 v Core Treatment Period: RoActemra®
    Number of subjects included in analysis
    604
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 Least squares means difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.22
    Notes
    [3] - Margins for results to be considered equivalent: -0.6 to 0.6.

    Secondary: Core Treatment Period: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR)

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    End point title
    		 Core Treatment Period: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR)
    End point description
    The DAS28-ESR is a measure of disease activity in 28 joints that consists of a composite numerical score of the following variables: TJC, SJC, ESR and Patient's Global Assessment of Disease Activity. The DAS28-ESR score was derived using the formula: DAS28-ESR = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.014*GH + 0.70*Ln(ESR), where, TJC28 = 28 joint count for tenderness, SJC28 = 28 joint count for swelling, Ln(ESR) = natural logarithm of ESR, GH = the general health component of the DAS (i.e., Patient's Global Assessment of Disease Activity on a scale of 1 to 100 where 100 is maximal activity). Higher values mean a higher disease activity. The level of disease activity can be interpreted as: * Remission (score of <2.6) * Low (score of ≤2.6 to <3.2) * Moderate (score of ≤3.2 to ≤5.1) * High (score of >5.1) A negative change from baseline indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, and Week 16
    End point values
    		 Core Treatment Period: MSB11456 Core Treatment Period: RoActemra®
    Number of subjects analysed
    302 [4]
    302 [5]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 2 (N: 288, 295)
    -1.24 ( 1.022 )
    -1.21 ( 0.949 )
        Week 4 (N: 294, 297)
    -1.96 ( 1.184 )
    -1.98 ( 1.135 )
        Week 8 (N: 286, 293)
    -2.75 ( 1.220 )
    -2.69 ( 1.260 )
        Week 12 (N: 282, 292)
    -3.13 ( 1.249 )
    -3.09 ( 1.279 )
        Week 16 (N: 282, 292)
    -3.41 ( 1.288 )
    -3.32 ( 1.242 )
    Notes
    [4] - Includes all randomized participants who had a result at baseline and at each specific time point.
    [5] - Includes all randomized participants who had a result at baseline and at each specific time point.
    No statistical analyses for this end point

    Secondary: Extended Treatment Period: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR)

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    End point title
    		 Extended Treatment Period: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR)
    End point description
    The DAS28-ESR is a measure of disease activity in 28 joints that consists of a composite numerical score of the following variables: TJC, SJC, ESR and Patient's Global Assessment of Disease Activity. The DAS28-ESR score was derived using the formula: DAS28-ESR = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.014*GH + 0.70*Ln(ESR), where, TJC28 = 28 joint count for tenderness, SJC28 = 28 joint count for swelling, Ln(ESR) = natural logarithm of ESR, GH = the general health component of the DAS (i.e., Patient's Global Assessment of Disease Activity on a scale of 1 to 100 where 100 is maximal activity). Higher values mean a higher disease activity. The level of disease activity can be interpreted as: * Remission (score of <2.6) * Low (score of ≤2.6 to <3.2) * Moderate (score of ≤3.2 to ≤5.1) * High (score of >5.1) A negative change from baseline indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Extended Period Baseline (Week 24), Week 30, Week 42, and Week 52
    End point values
    		 Core Period; MSB11456; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: RoActemra®
    Number of subjects analysed
    267 [6]
    139 [7]
    137 [8]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 30 (N: 261, 136, 133)
    -0.16 ( 0.801 )
    -0.13 ( 0.756 )
    -0.02 ( 0.863 )
        Week 42 (N: 258, 134, 132)
    -0.34 ( 1.042 )
    -0.08 ( 1.026 )
    -0.27 ( 1.031 )
        Week 52 (N: 248, 126, 126)
    -0.42 ( 1.185 )
    -0.31 ( 1.064 )
    -0.37 ( 1.086 )
    Notes
    [6] - Includes all randomized participants who had a result at baseline and at each specific time point.
    [7] - Includes all randomized participants who had a result at baseline and at each specific time point.
    [8] - Includes all randomized participants who had a result at baseline and at each specific time point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With 20% Improvement in American College of Rheumatology (ACR20) Response

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    End point title
    		 Percentage of Participants With 20% Improvement in American College of Rheumatology (ACR20) Response
    End point description
    ACR20 was defined as the number of participants with at least 20% improvement from baseline in number of tender and swollen joints (68/66 joint count), and at least 20% improvement from baseline in three or more of the 5 ACR Core Set measures: * Patient's Assessment of Arthritis Pain * Physical Function Assessment (Health Assessment Questionnaire-Disability Index) * Acute phase reactant level (erythrocyte sedimentation rate or C-reactive protein) * Patient's Global Assessment of Disease Activity and * Physician's Global Assessment of Disease Activity
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Core Treatment Period: MSB11456 Core Treatment Period: RoActemra®
    Number of subjects analysed
    302 [9]
    302 [10]
    Units: Percentage of participants
        number (not applicable)
    80.79
    84.77
    Notes
    [9] - ITT Analysis Set: includes all randomized participants.
    [10] - ITT Analysis Set: includes all randomized participants.
    Statistical analysis title
    		 Core Period: MSB11456 vs Core Period: RoActemra®
    Comparison groups
    Core Treatment Period: MSB11456 v Core Treatment Period: RoActemra®
    Number of subjects included in analysis
    604
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [11]
    Method
    Parameter type
    		 Difference in % Response Rate
    Point estimate
    -3.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.97
         upper limit
    		 2.11
    Notes
    [11] - Margins for results to be considered equivalent: -15%, 15%.

    Secondary: Number of Participants Who Experienced One or More Treatment-Emergent Serious Adverse Event (TESAE)

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    End point title
    		 Number of Participants Who Experienced One or More Treatment-Emergent Serious Adverse Event (TESAE)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to end of study, up to Week 63
    End point values
    		 Core Period: RoActemra®; Extended Period: MSB11456 MSB11456 EU-approved RoActemra®
    Number of subjects analysed
    139 [12]
    302 [13]
    163 [14]
    Units: Participants
    20
    51
    33
    Notes
    [12] - Safety Analysis Set: all participants who received at least one dose of study drug.
    [13] - Safety Analysis Set: all participants who received at least one dose of study drug.
    [14] - Safety Analysis Set: all participants who received at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced One or More Treatment-Emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants Who Experienced One or More Treatment-Emergent Adverse Event (TEAE)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to end of study, up to Week 63
    End point values
    		 Core Period: RoActemra®; Extended Period: MSB11456 MSB11456 EU-approved RoActemra®
    Number of subjects analysed
    139 [15]
    302 [16]
    163 [17]
    Units: Participants
    105
    237
    125
    Notes
    [15] - Safety Analysis Set: all participants who received at least one dose of study drug.
    [16] - Safety Analysis Set: all participants who received at least one dose of study drug.
    [17] - Safety Analysis Set: all participants who received at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Core Treatment Period: Percentage of Participants With Positive Anti-Drug Antibodies (ADAs)

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    End point title
    		 Core Treatment Period: Percentage of Participants With Positive Anti-Drug Antibodies (ADAs)
    End point description
    Overall category includes all time points expect Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 12, and Week 24
    End point values
    		 Core Treatment Period: MSB11456 Core Treatment Period: RoActemra®
    Number of subjects analysed
    302 [18]
    302 [19]
    Units: percentage of participants
    number (not applicable)
        Overall (N: 299, 301)
    96.0
    96.3
        Baseline (N: 302, 302)
    6.6
    8.3
        Week 2 (N: 287, 291)
    87.1
    88.7
        Week 12 (N: 281, 292)
    79.0
    74.3
        Week 24 (N: 274, 283)
    76.3
    68.6
    Notes
    [18] - Participants who received study treatment and had a valid ADA result at the specific time points.
    [19] - Participants who received study treatment and had a valid ADA result at the specific time points.
    No statistical analyses for this end point

    Secondary: Extended Treatment Period: Percentage of Participants With Positive Anti-Drug Antibodies (ADAs)

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    End point title
    		 Extended Treatment Period: Percentage of Participants With Positive Anti-Drug Antibodies (ADAs)
    End point description
    Overall category includes all time points expect for Baseline.
    End point type
    Secondary
    End point timeframe
    Extended Period Baseline (Week 24), Week 30, Week 52, and Week 55
    End point values
    		 Core Period; MSB11456; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: RoActemra®
    Number of subjects analysed
    266 [20]
    139 [21]
    136 [22]
    Units: percentage of participants
    number (not applicable)
        Overall (N: 265, 137, 135)
    97.4
    97.1
    94.1
        Extended Baseline (Week 24) (N: 266, 139, 136)
    86.8
    77.7
    87.5
        Week 30 (N: 262, 134, 132)
    76.7
    73.1
    65.9
        Week 52 (N: 246, 125, 126)
    80.9
    76.8
    61.1
        Week 55 (N: 242, 122, 122)
    81.4
    82.8
    77.9
    Notes
    [20] - Participants who received study treatment and had a valid ADA result at the specific time points.
    [21] - Participants who received study treatment and had a valid ADA result at the specific time points.
    [22] - Participants who received study treatment and had a valid ADA result at the specific time points.
    No statistical analyses for this end point

    Secondary: Core Treatment Period: Anti-Drug Antibodies (ADAs) Titer Levels

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    End point title
    		 Core Treatment Period: Anti-Drug Antibodies (ADAs) Titer Levels
    End point description
    Overall category includes all time points except Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 12, and Week 24
    End point values
    		 Core Treatment Period: MSB11456 Core Treatment Period: RoActemra®
    Number of subjects analysed
    302 [23]
    302 [24]
    Units: titer
    geometric mean (full range (min-max))
        Overall (N: 299, 301)
    106.3 (60 to 15360)
    104.0 (60 to 122880)
        Baseline (N: 302, 302)
    71.4 (60 to 960)
    130.4 (60 to 1920)
        Week 2 (N: 287, 291)
    81.2 (60 to 1920)
    88.1 (60 to 15360)
        Week 12 (N: 281, 292)
    113.8 (60 to 960)
    123.1 (60 to 122880)
        Week 24 (N: 274, 283)
    138.4 (60 to 15360)
    102.9 (60 to 1920)
    Notes
    [23] - Participants who received study treatment and had a valid ADA result at the specific time points.
    [24] - Participants who received study treatment and had a valid ADA result at the specific time points.
    No statistical analyses for this end point

    Secondary: Extended Treatment Period: Anti-Drug Antibodies (ADAs) Titer Levels

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    End point title
    		 Extended Treatment Period: Anti-Drug Antibodies (ADAs) Titer Levels
    End point description
    Overall category includes all time points except Baseline.
    End point type
    Secondary
    End point timeframe
    Extended Period Baseline (Week 24), Week 30, Week 52, and Week 55
    End point values
    		 Core Period; MSB11456; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: RoActemra®
    Number of subjects analysed
    266 [25]
    139 [26]
    137 [27]
    Units: titer
    geometric mean (full range (min-max))
        Overall (N: 265, 137, 135)
    215.4 (60 to 15360)
    166.3 (60 to 15360)
    101.1 (60 to 960)
        Extended Baseline (Week 24) (N: 266, 136, 136)
    127.7 (60 to 15360)
    106.1 (60 to 1920)
    95.6 (60 to 960)
        Week 30 (N: 262, 134, 132)
    173.0 (60 to 15360)
    130.6 (60 to 7680)
    93.7 (60 to 960)
        Week 52 (N: 246, 125, 126)
    230.9 (60 to 7680)
    174.7 (60 to 15360)
    96.7 (60 to 480)
        Week 55 (N: 242, 122, 122)
    251.2 (60 to 15360)
    200.8 (60 to 15360)
    112.4 (60 to 480)
    Notes
    [25] - Participants who received study treatment and had a valid ADA result at the specific time points.
    [26] - Participants who received study treatment and had a valid ADA result at the specific time points.
    [27] - Participants who received study treatment and had a valid ADA result at the specific time points.
    No statistical analyses for this end point

    Secondary: Core Treatment Period: Percentage of Participants With Neutralizing Antibodies (NAb)

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    End point title
    		 Core Treatment Period: Percentage of Participants With Neutralizing Antibodies (NAb)
    End point description
    Overall category includes all time points except Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 12 and Week 24
    End point values
    		 Core Treatment Period: MSB11456 Core Treatment Period: RoActemra®
    Number of subjects analysed
    302 [28]
    302 [29]
    Units: percentage of participants
    number (not applicable)
        Overall (N: 299, 301)
    8.4
    11.3
        Baseline (N: 302, 302)
    0
    0
        Week 2 (N: 287, 291)
    3.8
    3.4
        Week 12 (N: 281, 292)
    2.5
    4.1
        Week 24 (N: 274, 283)
    2.9
    4.9
    Notes
    [28] - Participants who received study treatment and had a valid ADA result at the specific time points.
    [29] - Participants who received study treatment and had a valid ADA result at the specific time points.
    No statistical analyses for this end point

    Secondary: Extended Treatment Period: Percentage of Participants With Neutralizing Antibodies (NAb)

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    End point title
    		 Extended Treatment Period: Percentage of Participants With Neutralizing Antibodies (NAb)
    End point description
    Overall category includes all time points except Baseline.
    End point type
    Secondary
    End point timeframe
    Week 24, Week 30, Week 52 and Week 55
    End point values
    		 Core Period; MSB11456; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: MSB11456 Core Period: RoActemra®; Extended Period: RoActemra®
    Number of subjects analysed
    266 [30]
    139 [31]
    136 [32]
    Units: percentage of participants
    number (not applicable)
        Overall (N: 265, 137, 135)
    13.2
    16.8
    11.9
        Extended Baseline (Week 24) (N: 266, 139, 136)
    3.8
    5.8
    5.9
        Week 30 (N: 262, 134, 132)
    6.1
    9.7
    3.0
        Week 52 (N: 246, 125, 126)
    1.6
    2.4
    1.6
        Week 55 (N: 242, 122, 122)
    7.0
    6.6
    9.0
    Notes
    [30] - Participants who received study treatment and had a valid ADA result at the specific time points.
    [31] - Participants who received study treatment and had a valid ADA result at the specific time points.
    [32] - Participants who received study treatment and had a valid ADA result at the specific time points.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 63
    Adverse event reporting additional description
    Safety Analysis Set: includes all participants who received at least one dose of study drug (MBS11456 or EU-approved RoActemra). The tables below only include treatment-emergent adverse events and "Other Adverse Events" only include non-serious TEAEs.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    MSB11456
    Reporting group description
    		 All participants who received MSB11456 in the Core Treatment Period (Baseline to Week 24) and then re-randomized to continue MSB11456 in the Extended Treatment Period (Week 24 to Week 52). Participants received MSB11456 subcutaneously, once a week.

    Reporting group title
    Core Period: RoActemra®; Extended Period: MSB11456
    Reporting group description
    		 Participants received EU-approved RoActemra® subcutaneously, once a week during the core treatment period (Baseline to Week 24). Participants were then re-randomized to begin receiving MSB11456 subcutaneously, once a week during the extended treatment period (Week 24 to Week 52).

    Reporting group title
    EU-approved RoActemra®
    Reporting group description
    		 All participants who received EU-approved RoActemra® in the Core Treatment Period (Baseline to Week 24) and then re-randomized to continue RoActemra® in the Extended Treatment Period (Week 24 to Week 52). Participants received EU-approved RoActemra® subcutaneously, once a week.

    Serious adverse events
    		 MSB11456 Core Period: RoActemra®; Extended Period: MSB11456 EU-approved RoActemra®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 302 (16.89%)
    20 / 139 (14.39%)
    33 / 163 (20.25%)
         number of deaths (all causes)
    0
    1
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Benign ovarian tumour
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (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
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Pregnancy, puerperium and perinatal conditions
    Stillbirth
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (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
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Uterine polyp
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Ovarian cyst
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         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
    Bronchiectasis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Wrist fracture
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 139 (0.72%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (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
    Atrioventricular block complete
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Coronary artery thrombosis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Coronary artery stenosis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         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
    Carotid artery disease
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hilar lymphadenopathy
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (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
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (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
    Hepatic steatosis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Spinal stenosis
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 139 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondyloarthropathy
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Spondylolisthesis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (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
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asymptomatic COVID-19
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 139 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    38 / 302 (12.58%)
    12 / 139 (8.63%)
    19 / 163 (11.66%)
         occurrences causally related to treatment / all
    3 / 38
    1 / 12
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 139 (0.00%)
    0 / 163 (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
    Bacterial infection
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 139 (0.72%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 139 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 MSB11456 Core Period: RoActemra®; Extended Period: MSB11456 EU-approved RoActemra®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    163 / 302 (53.97%)
    82 / 139 (58.99%)
    92 / 163 (56.44%)
    Investigations
    Mycobacterium tuberculosis complex test positive
         subjects affected / exposed
    14 / 302 (4.64%)
    4 / 139 (2.88%)
    4 / 163 (2.45%)
         occurrences all number
    14
    4
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    36 / 302 (11.92%)
    22 / 139 (15.83%)
    22 / 163 (13.50%)
         occurrences all number
    48
    28
    28
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 302 (6.29%)
    9 / 139 (6.47%)
    10 / 163 (6.13%)
         occurrences all number
    20
    9
    10
    Blood bilirubin increased
         subjects affected / exposed
    11 / 302 (3.64%)
    8 / 139 (5.76%)
    3 / 163 (1.84%)
         occurrences all number
    16
    11
    3
    Blood pressure increased
         subjects affected / exposed
    6 / 302 (1.99%)
    4 / 139 (2.88%)
    6 / 163 (3.68%)
         occurrences all number
    6
    4
    6
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    5 / 302 (1.66%)
    5 / 139 (3.60%)
    4 / 163 (2.45%)
         occurrences all number
    5
    7
    5
    Low density lipoprotein increased
         subjects affected / exposed
    5 / 302 (1.66%)
    4 / 139 (2.88%)
    2 / 163 (1.23%)
         occurrences all number
    6
    5
    4
    Blood cholesterol increased
         subjects affected / exposed
    4 / 302 (1.32%)
    4 / 139 (2.88%)
    3 / 163 (1.84%)
         occurrences all number
    6
    4
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 302 (1.66%)
    2 / 139 (1.44%)
    4 / 163 (2.45%)
         occurrences all number
    7
    3
    6
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 139 (0.00%)
    4 / 163 (2.45%)
         occurrences all number
    2
    0
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 302 (4.30%)
    6 / 139 (4.32%)
    4 / 163 (2.45%)
         occurrences all number
    13
    6
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 302 (5.63%)
    2 / 139 (1.44%)
    4 / 163 (2.45%)
         occurrences all number
    25
    2
    6
    Dizziness
         subjects affected / exposed
    4 / 302 (1.32%)
    2 / 139 (1.44%)
    4 / 163 (2.45%)
         occurrences all number
    5
    3
    4
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    22 / 302 (7.28%)
    8 / 139 (5.76%)
    12 / 163 (7.36%)
         occurrences all number
    50
    17
    22
    Thrombocytopenia
         subjects affected / exposed
    11 / 302 (3.64%)
    2 / 139 (1.44%)
    7 / 163 (4.29%)
         occurrences all number
    26
    2
    11
    Neutropenia
         subjects affected / exposed
    19 / 302 (6.29%)
    8 / 139 (5.76%)
    10 / 163 (6.13%)
         occurrences all number
    43
    17
    14
    Anaemia
         subjects affected / exposed
    5 / 302 (1.66%)
    6 / 139 (4.32%)
    2 / 163 (1.23%)
         occurrences all number
    5
    6
    2
    Lymphopenia
         subjects affected / exposed
    5 / 302 (1.66%)
    1 / 139 (0.72%)
    4 / 163 (2.45%)
         occurrences all number
    6
    1
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 302 (2.98%)
    0 / 139 (0.00%)
    6 / 163 (3.68%)
         occurrences all number
    9
    0
    7
    Diarrhoea
         subjects affected / exposed
    7 / 302 (2.32%)
    3 / 139 (2.16%)
    4 / 163 (2.45%)
         occurrences all number
    7
    3
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 302 (1.32%)
    4 / 139 (2.88%)
    1 / 163 (0.61%)
         occurrences all number
    12
    4
    1
    Rash
         subjects affected / exposed
    3 / 302 (0.99%)
    2 / 139 (1.44%)
    4 / 163 (2.45%)
         occurrences all number
    3
    3
    4
    Dermatitis allergic
         subjects affected / exposed
    1 / 302 (0.33%)
    3 / 139 (2.16%)
    0 / 163 (0.00%)
         occurrences all number
    1
    3
    0
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    2 / 302 (0.66%)
    4 / 139 (2.88%)
    1 / 163 (0.61%)
         occurrences all number
    2
    4
    2
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    7 / 302 (2.32%)
    4 / 139 (2.88%)
    4 / 163 (2.45%)
         occurrences all number
    8
    5
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 302 (2.98%)
    5 / 139 (3.60%)
    9 / 163 (5.52%)
         occurrences all number
    10
    5
    12
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 302 (5.63%)
    6 / 139 (4.32%)
    10 / 163 (6.13%)
         occurrences all number
    20
    7
    11
    Urinary tract infection
         subjects affected / exposed
    5 / 302 (1.66%)
    4 / 139 (2.88%)
    3 / 163 (1.84%)
         occurrences all number
    8
    5
    3
    Bronchitis
         subjects affected / exposed
    7 / 302 (2.32%)
    0 / 139 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    7
    0
    3
    Pharyngitis
         subjects affected / exposed
    2 / 302 (0.66%)
    1 / 139 (0.72%)
    4 / 163 (2.45%)
         occurrences all number
    2
    1
    4
    COVID-19
         subjects affected / exposed
    38 / 302 (12.58%)
    12 / 139 (8.63%)
    19 / 163 (11.66%)
         occurrences all number
    39
    12
    19
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    10 / 302 (3.31%)
    5 / 139 (3.60%)
    6 / 163 (3.68%)
         occurrences all number
    13
    7
    6
    Hyperlipidaemia
         subjects affected / exposed
    10 / 302 (3.31%)
    5 / 139 (3.60%)
    5 / 163 (3.07%)
         occurrences all number
    10
    5
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2020
    The following updates were implemented: * Due to the COVID-19 pandemic, measures were implemented to increase safeguarding for the patients, including: - Implementation of risk minimization and the mitigation plan for COVID-19. - Provision of a separate ICF to inform patients of the nature and impact of COVID-19. - Updates to the exclusion criteria to exclude patients with confirmed or suspected active COVID-19 infection and to ensure that the investigator specifically evaluated the patient’s eligibility taking into consideration COVID-19 risk factors and situation. - Provided details of action to take with the IMP due to COVID-19 and confirmed details of COVID-19 AE/SAE reporting. - Permitted the inclusion of local laboratories (with preapproval of the Sponsor) instead of central laboratories, if required due to the COVID-19 situation. * Provided fuller details of injection site reactions and reporting, and instructions for the investigator to ask the patient if any such reaction had occurred since the last assessment. * Replaced predefined AESIs with a statement that any AEs that lead to interruption of IMP, permanent discontinuation of IMP, or withdrawal from the study would be considered predefined AESIs.
    01 Feb 2021
    The following changes were implemented: * Added that COVID-19 vaccination was not allowed from 4 weeks prior to randomization until the completion of the Week 30 visit (COVID-19‒related protocol deviation); noted that COVID-19 vaccination was not recommended thereafter until the completion of the Week 55 visit and provided guidance regarding the timing of any such vaccination. * Removed details regarding North America, Asia, and the Rest of the World, including stratification by geographical region, as the study was being conducted in Europe only.

    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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