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    Clinical Trial Results:
    A Randomized, Controlled Study of Sarilumab and Methotrexate (MTX) Versus Etanercept and MTX in Patients with Rheumatoid Arthritis (RA) and an Inadequate Response to 4 Months of Treatment with Adalimumab and MTX

    Summary
    EudraCT number
    2012-001984-66
    Trial protocol
    GB   DE   HU   CZ   ES   GR   LT   FI   LV   IT   NO  
    Global end of trial date
    12 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Jul 2016
    First version publication date
    24 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC11574
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01764997
    WHO universal trial number (UTN)
    U1111-1131-6653
    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
    11 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate that the combination of sarilumab and MTX was superior to the combination of etanercept and MTX for the improvement (reduction) of Disease Activity Score for 28 joints C-reactive protein (DAS28-CRP) score at Week 24, compared to the randomization treatment phase baseline evaluation, in subjects with RA and an inadequate response to 4 months of treatment with adalimumab and MTX.
    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
    A stable dose of MTX was administered during the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    09 May 2013
    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
    Poland: 91
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Czech Republic: 43
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Chile: 58
    Country: Number of subjects enrolled
    Colombia: 22
    Country: Number of subjects enrolled
    Ecuador: 5
    Country: Number of subjects enrolled
    Israel: 20
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Country: Number of subjects enrolled
    Malaysia: 21
    Country: Number of subjects enrolled
    Mexico: 61
    Country: Number of subjects enrolled
    New Zealand: 11
    Country: Number of subjects enrolled
    Peru: 38
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Russian Federation: 105
    Country: Number of subjects enrolled
    South Africa: 23
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Thailand: 5
    Country: Number of subjects enrolled
    Ukraine: 95
    Country: Number of subjects enrolled
    United States: 77
    Worldwide total number of subjects
    776
    EEA total number of subjects
    212
    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)
    0
    From 65 to 84 years
    668
    85 years and over
    108

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 228 sites in 31 countries. A total of 1949 subjects were screened between 09 May 2013 and 07 Aug 2014, of which 1173 subjects were screen failures and a total of 776 subjects entered in the adalimumab run-in phase of the study.

    Pre-assignment
    Screening details
    Of 776 subjects, 365 completed adalimumab run-in phase, of whom 43 non-responders were randomized(1:1:1) in double-blind fashion to receive sarilumab 150 mg, sarilumab 200 mg or etanercept 50 mg; and 322 responders entered in open label sub-study. 373 subjects did not proceed into randomized phase or sub-study and 38 discontinued from run-in phase.

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

    Arms
    Arm title
    Adalimumab Open Label Run-in
    Arm description
    Adalimumab 40 mg every 2 weeks (Q2W) for 16 weeks added to stable dose of methotrexate (MTX).
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 40 mg subcutaneous (SC) injection in lower abdomen and front of thigh or as per local labeling requirements.

    Number of subjects in period 1
    Adalimumab Open Label Run-in
    Started
    776
    Completed
    738
    Not completed
    38
         Lack of efficacy
             5
         Poor compliance to protocol
             1
         Other than specified above
             17
         Adverse Events
             15
    Period 2
    Period 2 title
    Study Drug Treatment Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Etanercept + MTX (Randomized)
    Arm description
    Etanercept 50 mg in combination with Placebo for sarilumab Q2W and etanercept 50 mg on alternating weeks for 24 weeks added to stable dose of MTX.
    Arm type
    Experimental

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etanercept 50 mg SC injection in lower abdomen, front and side of thigh and upper arm.

    Investigational medicinal product name
    Placebo (for Sarilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to sarilumab SC injection in lower abdomen, front and side of thigh and upper arm.

    Arm title
    Sarilumab 150 mg + MTX (Randomized)
    Arm description
    Sarilumab 150 mg in combination with placebo for etanercept Q2W and placebo for etanercept on alternating weeks for 24 weeks added to stable dose of MTX.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191 (REGN88)
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sarilumab 150 mg SC injection in lower abdomen, front and side of thigh and upper arm.

    Investigational medicinal product name
    Placebo (for Etanercept)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to etanercept SC injection in lower abdomen, front and side of thigh and upper arm.

    Arm title
    Sarilumab 200 mg + MTX (Randomized)
    Arm description
    Sarilumab 200 mg in combination with placebo for etanercept Q2W and placebo for etanercept on alternating weeks for 24 weeks added to stable dose of MTX.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191 (REGN88)
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sarilumab 200 mg SC injection in lower abdomen, front and side of thigh and upper arm.

    Investigational medicinal product name
    Placebo (for Etanercept)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to etanercept SC injection in lower abdomen, front and side of thigh and upper arm.

    Arm title
    Sarilumab 150 mg + MTX Open Label Sub-study
    Arm description
    Sarilumab 150 mg Q2W for 52 weeks added to stable dose of MTX.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191 (REGN88)
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sarilumab 150 mg SC injection in lower abdomen, front and side of thigh and upper arm.

    Number of subjects in period 2 [1]
    Etanercept + MTX (Randomized) Sarilumab 150 mg + MTX (Randomized) Sarilumab 200 mg + MTX (Randomized) Sarilumab 150 mg + MTX Open Label Sub-study
    Started
    17
    13
    13
    322
    Completed
    16
    13
    13
    286
    Not completed
    1
    0
    0
    36
         Lack of efficacy
             -
             -
             -
             2
         Other than specified above
             -
             -
             -
             10
         Adverse Events
             1
             -
             -
             24
    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: 43 subjects proceeded to randomized treatment; 322 proceeded to open-label sub-study; 373 did not proceeded into the randomized phase or sub-study and 38 discontinued from run-in phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adalimumab Open Label Run-in
    Reporting group description
    Adalimumab 40 mg every 2 weeks (Q2W) for 16 weeks added to stable dose of methotrexate (MTX).

    Reporting group values
    Adalimumab Open Label Run-in Total
    Number of subjects
    776 776
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    668 668
        From 65-84 years
    108 108
    Gender categorical
    Units: Subjects
        Female
    637 637
        Male
    139 139

    End points

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    End points reporting groups
    Reporting group title
    Adalimumab Open Label Run-in
    Reporting group description
    Adalimumab 40 mg every 2 weeks (Q2W) for 16 weeks added to stable dose of methotrexate (MTX).
    Reporting group title
    Etanercept + MTX (Randomized)
    Reporting group description
    Etanercept 50 mg in combination with Placebo for sarilumab Q2W and etanercept 50 mg on alternating weeks for 24 weeks added to stable dose of MTX.

    Reporting group title
    Sarilumab 150 mg + MTX (Randomized)
    Reporting group description
    Sarilumab 150 mg in combination with placebo for etanercept Q2W and placebo for etanercept on alternating weeks for 24 weeks added to stable dose of MTX.

    Reporting group title
    Sarilumab 200 mg + MTX (Randomized)
    Reporting group description
    Sarilumab 200 mg in combination with placebo for etanercept Q2W and placebo for etanercept on alternating weeks for 24 weeks added to stable dose of MTX.

    Reporting group title
    Sarilumab 150 mg + MTX Open Label Sub-study
    Reporting group description
    Sarilumab 150 mg Q2W for 52 weeks added to stable dose of MTX.

    Primary: Change From Baseline in DAS28-CRP Score at Week 24

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    End point title
    Change From Baseline in DAS28-CRP Score at Week 24 [1]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the study was terminated due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    End point values
    Etanercept + MTX (Randomized) Sarilumab 150 mg + MTX (Randomized) Sarilumab 200 mg + MTX (Randomized)
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [2] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    [3] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    [4] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    No statistical analyses for this end point

    Secondary: Number of Subjects With at Least 20% Improvement in American College of Rheumatology (ACR20), at Least 50% Improvement in ACR (ACR50) and at Least 70% Improvement in ACR (ACR70) Efficacy Response Rates at Week 12 and Week 24

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    End point title
    Number of Subjects With at Least 20% Improvement in American College of Rheumatology (ACR20), at Least 50% Improvement in ACR (ACR50) and at Least 70% Improvement in ACR (ACR70) Efficacy Response Rates at Week 12 and Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 24
    End point values
    Etanercept + MTX (Randomized) Sarilumab 150 mg + MTX (Randomized) Sarilumab 200 mg + MTX (Randomized)
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: Subjects
    Notes
    [5] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    [6] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    [7] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Clinical Remission Score (DAS28-CRP) <2.6 at Week 12 and Week 24

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    End point title
    Percentage of Subjects Achieving Clinical Remission Score (DAS28-CRP) <2.6 at Week 12 and Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 24
    End point values
    Etanercept + MTX (Randomized) Sarilumab 150 mg + MTX (Randomized) Sarilumab 200 mg + MTX (Randomized)
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Percentage of Subjects
        number (not applicable)
    Notes
    [8] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    [9] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    [10] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    No statistical analyses for this end point

    Secondary: Change From Baseline in DAS28-CRP Score at Week 12

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    End point title
    Change From Baseline in DAS28-CRP Score at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Etanercept + MTX (Randomized) Sarilumab 150 mg + MTX (Randomized) Sarilumab 200 mg + MTX (Randomized)
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [11] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    [12] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    [13] - Due to small number of subjects entering randomization, efficacy endpoints were not analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 16 for run-in period and Week 58 for treatment period) regardless of seriousness or relationship to investigational product
    Adverse event reporting additional description
    Reported AEs are treatment-emergent AEs that is AEs that developed/worsened during the ‘on-treatment period’ (the time from the first dose of adalimumab to the end of follow-up period). All subjects who entered open-label run-in period were included for safety assessment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Adalimumab Open Label Run-in
    Reporting group description
    Adalimumab 40 mg Q2W for 16 weeks added to stable dose of MTX. AEs in this group were those collected from signature of the informed consent form up to the end of Adalimumab treatment (Week 16).

    Reporting group title
    Etanercept + MTX (Randomized)
    Reporting group description
    Etanercept 50 mg in combination with Placebo for sarilumab Q2W and etanercept 50 mg on alternating weeks for 24 weeks added to stable dose of MTX. AEs in this group were those collected post randomization up to the final visit (Week 30).

    Reporting group title
    Sarilumab 150 mg + MTX (Randomized)
    Reporting group description
    Sarilumab 150 mg in combination with placebo for etanercept Q2W and placebo for etanercept on alternating weeks for 24 weeks added to stable dose of MTX. AEs in this group were those collected post randomization up to the final visit (Week 30).

    Reporting group title
    Sarilumab 200 mg + MTX (Randomized)
    Reporting group description
    Sarilumab 200 mg in combination with placebo for etanercept Q2W and placebo for etanercept on alternating weeks for 24 weeks added to stable dose of MTX. AEs in this group were those collected post randomization up to the final visit (Week 30).

    Reporting group title
    Sarilumab 150 mg + MTX Open Label Sub-study
    Reporting group description
    Sarilumab 150 mg Q2W for 52 weeks added to stable dose of MTX. AEs in this group were those collected from enrollment in the sub-study up to the final visit (Week 58).

    Serious adverse events
    Adalimumab Open Label Run-in Etanercept + MTX (Randomized) Sarilumab 150 mg + MTX (Randomized) Sarilumab 200 mg + MTX (Randomized) Sarilumab 150 mg + MTX Open Label Sub-study
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 776 (3.22%)
    2 / 17 (11.76%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    11 / 322 (3.42%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder Cancer
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm Malignant
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal Proliferative Breast Lesion
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide Attempt
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Postoperative Respiratory Failure
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Influenza B Virus Test Positive
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver Function Test Abnormal
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Unstable
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroduodenitis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity Vasculitis
         subjects affected / exposed
    0 / 776 (0.00%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis Bacterial
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Infective
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic Abscess
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Pyelonephritis
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Histoplasmosis Disseminated
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral Herpes
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculous Pleurisy
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 776 (0.00%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Parotitis
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Adalimumab Open Label Run-in Etanercept + MTX (Randomized) Sarilumab 150 mg + MTX (Randomized) Sarilumab 200 mg + MTX (Randomized) Sarilumab 150 mg + MTX Open Label Sub-study
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    132 / 776 (17.01%)
    7 / 17 (41.18%)
    7 / 13 (53.85%)
    8 / 13 (61.54%)
    104 / 322 (32.30%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    24 / 776 (3.09%)
    0 / 17 (0.00%)
    3 / 13 (23.08%)
    0 / 13 (0.00%)
    14 / 322 (4.35%)
         occurrences all number
    24
    0
    3
    0
    15
    Chillblains
         subjects affected / exposed
    0 / 776 (0.00%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 776 (0.00%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    5 / 776 (0.64%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
    11 / 322 (3.42%)
         occurrences all number
    5
    0
    0
    2
    11
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    3 / 322 (0.93%)
         occurrences all number
    1
    0
    0
    1
    3
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 776 (0.00%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    4 / 322 (1.24%)
         occurrences all number
    0
    0
    1
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Paranasal Sinus Hypersecretion
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 322 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Sinus Congestion
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 322 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 776 (0.26%)
    1 / 17 (5.88%)
    1 / 13 (7.69%)
    2 / 13 (15.38%)
    33 / 322 (10.25%)
         occurrences all number
    3
    1
    2
    4
    45
    Nervous system disorders
    Tremor
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 776 (0.39%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    2 / 322 (0.62%)
         occurrences all number
    3
    0
    0
    1
    2
    Injection Site Pain
         subjects affected / exposed
    9 / 776 (1.16%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    3 / 322 (0.93%)
         occurrences all number
    15
    0
    0
    2
    3
    Injection Site Erythema
         subjects affected / exposed
    9 / 776 (1.16%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    15 / 322 (4.66%)
         occurrences all number
    17
    0
    0
    2
    33
    Injection Site Rash
         subjects affected / exposed
    6 / 776 (0.77%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
    7 / 322 (2.17%)
         occurrences all number
    10
    0
    2
    1
    10
    Injection Site Swelling
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    2 / 322 (0.62%)
         occurrences all number
    0
    0
    0
    1
    14
    Injection Site Pruritus
         subjects affected / exposed
    5 / 776 (0.64%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    9 / 322 (2.80%)
         occurrences all number
    6
    2
    0
    0
    19
    Pyrexia
         subjects affected / exposed
    7 / 776 (0.90%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    1 / 322 (0.31%)
         occurrences all number
    7
    0
    0
    1
    1
    Peripheral Swelling
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 322 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal Tenderness
         subjects affected / exposed
    0 / 776 (0.00%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences all number
    0
    0
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    10 / 776 (1.29%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    5 / 322 (1.55%)
         occurrences all number
    11
    0
    0
    1
    5
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences all number
    1
    0
    1
    0
    1
    Food Poisoning
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    1 / 322 (0.31%)
         occurrences all number
    0
    0
    0
    1
    1
    Tooth Disorder
         subjects affected / exposed
    0 / 776 (0.00%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    8 / 776 (1.03%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    3 / 322 (0.93%)
         occurrences all number
    10
    1
    0
    1
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Dermatitis Allergic
         subjects affected / exposed
    4 / 776 (0.52%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    2 / 322 (0.62%)
         occurrences all number
    4
    1
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 776 (0.64%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    4 / 322 (1.24%)
         occurrences all number
    5
    1
    0
    0
    4
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    2 / 322 (0.62%)
         occurrences all number
    0
    0
    1
    0
    2
    Costochondritis
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences all number
    0
    0
    1
    0
    1
    Osteoporotic Fracture
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 322 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pain In Extremity
         subjects affected / exposed
    2 / 776 (0.26%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    2 / 322 (0.62%)
         occurrences all number
    3
    0
    0
    1
    2
    Tenosynovitis Stenosans
         subjects affected / exposed
    0 / 776 (0.00%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 776 (0.00%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 322 (0.31%)
         occurrences all number
    0
    1
    0
    0
    1
    Vitamin D Deficiency
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    1 / 322 (0.31%)
         occurrences all number
    0
    0
    0
    1
    1
    Infections and infestations
    Body Tinea
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 322 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Onychomycosis
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 322 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hordeolum
         subjects affected / exposed
    2 / 776 (0.26%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    Pharyngitis Streptococcal
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    7 / 776 (0.90%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    3 / 322 (0.93%)
         occurrences all number
    8
    0
    0
    1
    3
    Rash Pustular
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    Tinea Versicolour
         subjects affected / exposed
    1 / 776 (0.13%)
    0 / 17 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 322 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    7 / 776 (0.90%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    5 / 322 (1.55%)
         occurrences all number
    8
    0
    0
    1
    5
    Upper Respiratory Tract Infection
         subjects affected / exposed
    27 / 776 (3.48%)
    1 / 17 (5.88%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
    16 / 322 (4.97%)
         occurrences all number
    30
    1
    1
    1
    17
    Urinary Tract Infection
         subjects affected / exposed
    16 / 776 (2.06%)
    1 / 17 (5.88%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    4 / 322 (1.24%)
         occurrences all number
    19
    1
    0
    0
    4
    Viral Pharyngitis
         subjects affected / exposed
    0 / 776 (0.00%)
    0 / 17 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 322 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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.
    The study was prematurely terminated due to small number of subjects entering randomization.
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