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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Parallel Group Study of CNTO 136 (sirukumab) Administered Subcutaneously as Monotherapy Compared With Adalimumab Monotherapy, in Subjects With Active Rheumatoid Arthritis

    Summary
    EudraCT number
    2013-001417-32
    Trial protocol
    DE   HU   LT   ES   BG  
    Global end of trial date
    17 Aug 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Sep 2017
    First version publication date
    01 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNTO136ARA3005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02019472
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    920 Route 202, 08869 Raritan, NJ,, United States,
    Public contact
    Janssen-Cilag International N.V., Clinical Registry Group, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen-Cilag International N.V., Clinical Registry Group, ClinicalTrialsEU@its.jnj.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
    17 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to demonstrate the superior efficacy of sirukumab monotherapy compared with adalimumab monotherapy in biologic naive subjects with active rheumatoid arthritis (RA) who were intolerant to methotrexate (MTX), who were considered inappropriate for treatment with MTX, or who were inadequate responders to MTX.
    Protection of trial subjects
    The safety assessments included the incidence and severity of adverse events (AEs), clinical laboratory tests (hematology and serum chemistry), vital signs and physical examinations which were assessed throughout the study. This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Apr 2014
    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
    Bulgaria: 2
    Country: Number of subjects enrolled
    Chile: 10
    Country: Number of subjects enrolled
    Colombia: 14
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Lithuania: 36
    Country: Number of subjects enrolled
    Moldova, Republic of: 12
    Country: Number of subjects enrolled
    Mexico: 11
    Country: Number of subjects enrolled
    Poland: 58
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Russian Federation: 92
    Country: Number of subjects enrolled
    Serbia: 65
    Country: Number of subjects enrolled
    Ukraine: 118
    Country: Number of subjects enrolled
    United States: 88
    Country: Number of subjects enrolled
    South Africa: 24
    Worldwide total number of subjects
    559
    EEA total number of subjects
    125
    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)
    486
    From 65 to 84 years
    73
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 559 subjects were randomized and treated. All subjects received atleast one administration of study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Adalimumab 40 mg
    Arm description
    Subjects received 40 mg of adalimumab subcutaneously once every 2 weeks (q2w) for 52 weeks. Subjects who met early escape (EE) criteria (had less than 20 percent improvement from baseline in swollen and tender joint counts) at Week 16 received adalimumab 40 mg once every week (q1w) through Week 52.
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 40 mg of adalimumab subcutaneously q2w for 52 weeks and q1w from Week 16 for subjects who met EE criteria.

    Arm title
    Sirukumab 50 mg
    Arm description
    Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 52 weeks and in between placebo SC injections was received at Weeks 2, 6, 10 and 14. Subjects who met EE criteria at Week 16 received 100 mg sirukumab every 2 weeks (q2w) from Week 16 through Week 52 and placebo SC injections q2w between the sirukumab injections from Week 16 through Week 50.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 50 mg of sirukumab subcutaneously q4w for 52 weeks. Subjects who met EE criteria at Week 16 received 100 mg sirukumab q2w from Week 16 onwards.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo SC injections at Weeks 2, 6, 10 and 14. Subjects who met EE criteria at Week 16 received placebo SC injections q4w from Week 16 through Week 50.

    Arm title
    Sirukumab 100 mg
    Arm description
    Subjects received 100 mg of sirukumab subcutaneous injections at Weeks 0, 2, and every 2 weeks (q2w) through Week 52. Subjects who met EE criteria at Week 16 received placebo injections q2w between the sirukumab injections through Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 100 mg of sirukumab subcutaneously q2w for 52 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo injections every week (q1w) between the sirukumab injections through Week 52.

    Number of subjects in period 1
    Adalimumab 40 mg Sirukumab 50 mg Sirukumab 100 mg
    Started
    186
    186
    187
    Completed
    149
    134
    145
    Not completed
    37
    52
    42
         Other
    3
    8
    6
         Physician decision
    1
    2
    -
         Lack of efficacy
    7
    4
    4
         Pregnancy
    1
    2
    2
         Adverse event, serious fatal
    -
    2
    1
         Adverse event, non-fatal
    8
    12
    14
         Consent withdrawn by subject
    11
    10
    11
         Adverse event, serious non-fatal
    6
    10
    3
         Lost to follow-up
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adalimumab 40 mg
    Reporting group description
    Subjects received 40 mg of adalimumab subcutaneously once every 2 weeks (q2w) for 52 weeks. Subjects who met early escape (EE) criteria (had less than 20 percent improvement from baseline in swollen and tender joint counts) at Week 16 received adalimumab 40 mg once every week (q1w) through Week 52.

    Reporting group title
    Sirukumab 50 mg
    Reporting group description
    Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 52 weeks and in between placebo SC injections was received at Weeks 2, 6, 10 and 14. Subjects who met EE criteria at Week 16 received 100 mg sirukumab every 2 weeks (q2w) from Week 16 through Week 52 and placebo SC injections q2w between the sirukumab injections from Week 16 through Week 50.

    Reporting group title
    Sirukumab 100 mg
    Reporting group description
    Subjects received 100 mg of sirukumab subcutaneous injections at Weeks 0, 2, and every 2 weeks (q2w) through Week 52. Subjects who met EE criteria at Week 16 received placebo injections q2w between the sirukumab injections through Week 52.

    Reporting group values
    Adalimumab 40 mg Sirukumab 50 mg Sirukumab 100 mg Total
    Number of subjects
    186 186 187 559
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    163 159 164 486
        From 65 to 84 years
    23 27 23 73
        85 years and over
    0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    52.6 ± 12.15 52.5 ± 12.46 49.8 ± 12.31 -
    Title for Gender
    Units: subjects
        Female
    156 157 154 467
        Male
    30 29 33 92

    End points

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    End points reporting groups
    Reporting group title
    Adalimumab 40 mg
    Reporting group description
    Subjects received 40 mg of adalimumab subcutaneously once every 2 weeks (q2w) for 52 weeks. Subjects who met early escape (EE) criteria (had less than 20 percent improvement from baseline in swollen and tender joint counts) at Week 16 received adalimumab 40 mg once every week (q1w) through Week 52.

    Reporting group title
    Sirukumab 50 mg
    Reporting group description
    Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 52 weeks and in between placebo SC injections was received at Weeks 2, 6, 10 and 14. Subjects who met EE criteria at Week 16 received 100 mg sirukumab every 2 weeks (q2w) from Week 16 through Week 52 and placebo SC injections q2w between the sirukumab injections from Week 16 through Week 50.

    Reporting group title
    Sirukumab 100 mg
    Reporting group description
    Subjects received 100 mg of sirukumab subcutaneous injections at Weeks 0, 2, and every 2 weeks (q2w) through Week 52. Subjects who met EE criteria at Week 16 received placebo injections q2w between the sirukumab injections through Week 52.

    Primary: Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24

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    End point title
    Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24
    End point description
    The Disease Activity Index Score 28 using ESR [DAS28 (ESR)] is a derived score combining tender joints (28 joints), swollen joints (28 joints), ESR, and Patient’s Global Assessment of Disease Activity. The 28 joints evaluated for swelling and tenderness were shoulder, elbow, wrist, MCP1, MCP2, MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of the upper right and upper left extremities as well as the knee joints of the lower right and lower left extremities. The DAS28-ESR is expressed on a score range of "0-10", with the minimum score= 0 (best) to maximum score= 10 (worst). Full analysis set (FAS) was defined as all randomized participants who received at least 1 (partial or complete) dose of study agent. Participants with missing DAS28 (ESR) at baseline were excluded from the analysis.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    Adalimumab 40 mg Sirukumab 50 mg Sirukumab 100 mg
    Number of subjects analysed
    186
    185
    185
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    6.89 ± 0.851
    6.9 ± 0.881
    6.91 ± 0.863
        Change from Baseline at Week 24
    -2.19 ± 1.437
    -2.58 ± 1.524
    -2.96 ± 1.58
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Adalimumab 40 mg v Sirukumab 100 mg
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.07
         upper limit
    -0.46
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Adalimumab 40 mg v Sirukumab 50 mg
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.013
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.69
         upper limit
    -0.08

    Primary: Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response at Week 24

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    End point title
    Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response at Week 24
    End point description
    The ACR 50 Response is defined as greater than or equal to (>=) 50 percent (%) improvement in swollen joint count (66 joints) and tender joint count (68 joints) and >= 50% improvement in 3 of following 5 assessments: subject’s assessment of pain using Visual Analog Scale (VAS) (0-10 millimeter [mm], 0 mm=no pain and 10 mm=worst possible pain), subject’s global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]), physician's global assessment of disease activity using VAS (the scale ranges from 0 to 10, [0=no arthritis activity to 10=extremely active arthritis]), subject’s assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI) (the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and serum C-Reactive Protein (CRP). FAS was defined as all randomized participants who received at least 1 dose of study agent.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg Sirukumab 50 mg Sirukumab 100 mg
    Number of subjects analysed
    186
    186
    187
    Units: percentage of Subjects
        number (not applicable)
    31.7
    26.9
    35.3
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Adalimumab 40 mg v Sirukumab 50 mg
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.306
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    -4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.1
         upper limit
    4.4
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Adalimumab 40 mg v Sirukumab 100 mg
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.464
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6
         upper limit
    13.1

    Secondary: Percentage of Subjects with Disease Activity Index Score 28 (DAS28) Using Erythrocyte Sedimentation Rate (ESR) Remission at Week 24

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    End point title
    Percentage of Subjects with Disease Activity Index Score 28 (DAS28) Using Erythrocyte Sedimentation Rate (ESR) Remission at Week 24
    End point description
    The Disease Activity Index Score 28 using ESR [DAS28 (ESR)] is a derived score combining tender joints (28 joints), swollen joints (28 joints), ESR, and Patient’s Global Assessment of Disease Activity. The 28 joints evaluated for swelling and tenderness were shoulder, elbow, wrist, MCP1, MCP2, MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of the upper right and upper left extremities as well as the knee joints of the lower right and lower left extremities. The DAS28-ESR is expressed on a score range of "0-10", with the minimum score= 0 (best) to maximum score= 10 (worst). The DAS28 (ESR) remission is defined as a DAS28 (ESR) value of less than 2.6 at a visit. FAS was defined as all randomized participants who received at least 1 dose of study agent.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg Sirukumab 50 mg Sirukumab 100 mg
    Number of subjects analysed
    186
    186
    187
    Units: Percentage of Subjects
        number (not applicable)
    7.5
    12.9
    20.3
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Sirukumab 50 mg v Adalimumab 40 mg
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.086
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    5.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    11.4
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Adalimumab 40 mg v Sirukumab 100 mg
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    12.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.9
         upper limit
    19.7

    Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response at Week 24

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    End point title
    Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response at Week 24
    End point description
    The ACR 20 Response is defined as >= 20% improvement in swollen joint count (66 joints) and tender joint count (68 joints) and >=20% improvement in 3 of following 5 assessments: subject’s assessment of pain using VAS (0-10 mm, 0 mm=no pain and 10 mm=worst possible pain), subject’s global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]), physician's global assessment of disease activity using VAS, subject’s assessment of physical function measured by HAQ-DI, defined as a 20-question instrument assessing 8 functional areas. The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and serum CRP. FAS was defined as all randomized participants who received at least 1 dose of study agent.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Adalimumab 40 mg Sirukumab 50 mg Sirukumab 100 mg
    Number of subjects analysed
    186
    186
    187
    Units: Percentage of Subjects
        number (not applicable)
    56.5
    53.8
    58.8
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Adalimumab 40 mg v Sirukumab 50 mg
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.603
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    -2.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.8
         upper limit
    7.4
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Adalimumab 40 mg v Sirukumab 100 mg
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.644
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Difference
    Point estimate
    2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.6
         upper limit
    12.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening, up to Week 68
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Adalimumab 40 mg q2w only
    Reporting group description
    Subjects received 40 mg of adalimumab subcutaneously q2w for 52 weeks.

    Reporting group title
    Adalimumab 40 mg q2w then 40 mg q1w
    Reporting group description
    Subjects received 40 mg adalimumab subcutaneously q2w until Week 16 and received 40 mg adalimumab subcutaneously weekly (q1w) (due to EE) through Week 52.

    Reporting group title
    Adalimumab 40 mg
    Reporting group description
    Subjects received 40 mg of adalimumab subcutaneously once every 2 weeks (q2w) for 52 weeks. Subjects who met early escape (EE) criteria (had less than 20 percent improvement from baseline in swollen and tender joint counts) at Week 16 received adalimumab 40 mg once every week (q1w) through Week 52.

    Reporting group title
    Sirukumab 50 mg q4w only
    Reporting group description
    Subjects received 50 mg of sirukumab subcutaneously every four weeks (q4w) for 52 weeks.

    Reporting group title
    Sirukumab 50 mg q4w then 100 mg q2w
    Reporting group description
    Subjects received 50 mg sirukumab until Week 16 and received 100 mg sirukumab subcutaneously q4w (due to EE or inadvertently) through Week 52.

    Reporting group title
    Sirukumab 50 mg
    Reporting group description
    Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 52 weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through Week 50. Subjects who met EE criteria at Week 16 received 100 mg sirukumab every 2 weeks (q2w) from Week 16 through Week 52.

    Reporting group title
    Sirukumab 100 mg
    Reporting group description
    Subjects received 100 mg of sirukumab subcutaneously every 2 weeks (q2w) for 52 weeks.

    Serious adverse events
    Adalimumab 40 mg q2w only Adalimumab 40 mg q2w then 40 mg q1w Adalimumab 40 mg Sirukumab 50 mg q4w only Sirukumab 50 mg q4w then 100 mg q2w Sirukumab 50 mg Sirukumab 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 173 (8.67%)
    1 / 13 (7.69%)
    16 / 186 (8.60%)
    23 / 160 (14.38%)
    6 / 26 (23.08%)
    29 / 186 (15.59%)
    22 / 187 (11.76%)
         number of deaths (all causes)
    0
    0
    0
    2
    1
    3
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Essential Hypertension
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Adenocarcinoma Pancreas
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Clear Cell Renal Cell Carcinoma
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial Adenocarcinoma
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gliomatosis Cerebri
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    1 / 26 (3.85%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pre-Eclampsia
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Peripheral Swelling
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 13 (0.00%)
    2 / 186 (1.08%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental Status Changes
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus Fracture
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Skin Wound
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    2 / 160 (1.25%)
    0 / 26 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    1 / 26 (3.85%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 13 (7.69%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pulmonary Fibrosis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic Stroke
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 1
    Lacunar Infarction
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis Ulcerative
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Diverticular Perforation
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    1 / 26 (3.85%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Perforation
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Chronic
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis Contact
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Skin Ulcer
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    1 / 26 (3.85%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    1 / 26 (3.85%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    1 / 26 (3.85%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Osteoporotic Fracture
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    1 / 26 (3.85%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Infections and infestations
    Acute Sinusitis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Bursitis Infective
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    2 / 160 (1.25%)
    0 / 26 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    1 / 26 (3.85%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Gastrointestinal Bacterial Infection
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Ophthalmic
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious Pleural Effusion
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    2 / 160 (1.25%)
    0 / 26 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Streptococcal
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulpitis Dental
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    1 / 160 (0.63%)
    0 / 26 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tongue Abscess
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 13 (0.00%)
    1 / 186 (0.54%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 173 (0.00%)
    0 / 13 (0.00%)
    0 / 186 (0.00%)
    0 / 160 (0.00%)
    0 / 26 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Adalimumab 40 mg q2w only Adalimumab 40 mg q2w then 40 mg q1w Adalimumab 40 mg Sirukumab 50 mg q4w only Sirukumab 50 mg q4w then 100 mg q2w Sirukumab 50 mg Sirukumab 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 173 (41.04%)
    3 / 13 (23.08%)
    74 / 186 (39.78%)
    79 / 160 (49.38%)
    13 / 26 (50.00%)
    92 / 186 (49.46%)
    86 / 187 (45.99%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 173 (5.20%)
    1 / 13 (7.69%)
    10 / 186 (5.38%)
    8 / 160 (5.00%)
    4 / 26 (15.38%)
    12 / 186 (6.45%)
    8 / 187 (4.28%)
         occurrences all number
    9
    1
    10
    9
    4
    13
    8
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    12 / 173 (6.94%)
    0 / 13 (0.00%)
    12 / 186 (6.45%)
    18 / 160 (11.25%)
    3 / 26 (11.54%)
    21 / 186 (11.29%)
    24 / 187 (12.83%)
         occurrences all number
    16
    0
    16
    21
    4
    25
    34
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    11 / 173 (6.36%)
    0 / 13 (0.00%)
    11 / 186 (5.91%)
    9 / 160 (5.63%)
    4 / 26 (15.38%)
    13 / 186 (6.99%)
    20 / 187 (10.70%)
         occurrences all number
    14
    0
    14
    9
    4
    13
    24
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    4 / 173 (2.31%)
    0 / 13 (0.00%)
    4 / 186 (2.15%)
    16 / 160 (10.00%)
    1 / 26 (3.85%)
    17 / 186 (9.14%)
    11 / 187 (5.88%)
         occurrences all number
    4
    0
    4
    23
    2
    25
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 173 (5.20%)
    2 / 13 (15.38%)
    11 / 186 (5.91%)
    10 / 160 (6.25%)
    1 / 26 (3.85%)
    11 / 186 (5.91%)
    13 / 187 (6.95%)
         occurrences all number
    12
    2
    14
    17
    1
    18
    19
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    13 / 173 (7.51%)
    0 / 13 (0.00%)
    13 / 186 (6.99%)
    15 / 160 (9.38%)
    2 / 26 (7.69%)
    17 / 186 (9.14%)
    33 / 187 (17.65%)
         occurrences all number
    28
    0
    28
    22
    5
    27
    156
    Injection Site Pruritus
         subjects affected / exposed
    8 / 173 (4.62%)
    0 / 13 (0.00%)
    8 / 186 (4.30%)
    6 / 160 (3.75%)
    0 / 26 (0.00%)
    6 / 186 (3.23%)
    17 / 187 (9.09%)
         occurrences all number
    12
    0
    12
    8
    0
    8
    27
    Injection Site Swelling
         subjects affected / exposed
    4 / 173 (2.31%)
    0 / 13 (0.00%)
    4 / 186 (2.15%)
    3 / 160 (1.88%)
    1 / 26 (3.85%)
    4 / 186 (2.15%)
    11 / 187 (5.88%)
         occurrences all number
    6
    0
    6
    6
    4
    10
    31
    Musculoskeletal and connective tissue disorders
    Rheumatoid Arthritis
         subjects affected / exposed
    17 / 173 (9.83%)
    0 / 13 (0.00%)
    17 / 186 (9.14%)
    17 / 160 (10.63%)
    3 / 26 (11.54%)
    20 / 186 (10.75%)
    15 / 187 (8.02%)
         occurrences all number
    18
    0
    18
    19
    4
    23
    16
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 173 (2.31%)
    0 / 13 (0.00%)
    4 / 186 (2.15%)
    8 / 160 (5.00%)
    2 / 26 (7.69%)
    10 / 186 (5.38%)
    8 / 187 (4.28%)
         occurrences all number
    4
    0
    4
    9
    2
    11
    9
    Nasopharyngitis
         subjects affected / exposed
    16 / 173 (9.25%)
    0 / 13 (0.00%)
    16 / 186 (8.60%)
    9 / 160 (5.63%)
    1 / 26 (3.85%)
    10 / 186 (5.38%)
    9 / 187 (4.81%)
         occurrences all number
    22
    0
    22
    10
    1
    11
    11
    Upper Respiratory Tract Infection
         subjects affected / exposed
    10 / 173 (5.78%)
    0 / 13 (0.00%)
    10 / 186 (5.38%)
    8 / 160 (5.00%)
    2 / 26 (7.69%)
    10 / 186 (5.38%)
    9 / 187 (4.81%)
         occurrences all number
    13
    0
    13
    12
    4
    16
    14

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jan 2014
    This amendment included the following changes: Corrected typographical errors in an inclusion criterion; Adjusted timing of biopsy and epigenetic sample collection; Clarified/corrected text throughout the protocol
    30 Apr 2014
    This amendment included the following changes: Clarified text describing pharmacogenomics and epigenetics to be studied in this trial; Clarified/corrected text throughout the protocol

    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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