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    Clinical Trial Results:
    A Phase IIb, Randomized, Multi-Center, Double-Blind, Dose-Ranging Study to Evaluate the Efficacy and Safety of Clazakizumab in Subjects With Moderate to Severe Active Rheumatoid Arthritis Who Have Experienced an Inadequate Response to TNF Inhibitors

    Summary
    EudraCT number
    		 2013-003780-65
    Trial protocol
    		 IT   HU  
    Global end of trial date
    17 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2019
    First version publication date
    05 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IM133-066
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to compare the efficacy of clazakizumab versus placebo on a background of methotrexate as assessed by change from baseline in DAS28-CRP at 12 weeks in subjects with moderate to severe active rheumatoid arthritis who have an inadequate response to TNF inhibitors (TNF-IR)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 38
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Hungary: 22
    Country: Number of subjects enrolled
    Mexico: 29
    Country: Number of subjects enrolled
    Argentina: 18
    Country: Number of subjects enrolled
    Japan: 16
    Worldwide total number of subjects
    143
    EEA total number of subjects
    25
    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)
    114
    From 65 to 84 years
    28
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 216 subjects were enrolled. 143 subjects were randomized.

    Period 1
    Period 1 title
    12 Week Double Blind 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
    		 PBO + MTX
    Arm description
    		 Clazakizumab placebo SC every 4 weeks with background methotrexate
    Arm type
    		 Placebo

    Investigational medicinal product name
    Clazakizumab placebo
    Investigational medicinal product code
    BMS-945429 Placebo
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab placebo SC every 4 weeks with background methotrexate

    Arm title
    		 C1 + MTX
    Arm description
    		 Clazakizumab 1 mg SC every 4 weeks with background methotrexate
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clazakizumab
    Investigational medicinal product code
    BMS-945429
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab 1 mg SC every 4 weeks with background methotrexate

    Arm title
    		 C5 + MTX
    Arm description
    		 Clazakizumab 5 mg SC every 4 weeks with background methotrexate
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clazakizumab
    Investigational medicinal product code
    BMS-945429
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab 5 mg SC every 4 weeks with background methotrexate

    Arm title
    		 C25 + MTX
    Arm description
    		 Clazakizumab 25 mg SC every 4 weeks with background methotrexate
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clazakizumab
    Investigational medicinal product code
    BMS-945429
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab 25 mg SC every 4 weeks with background methotrexate

    Number of subjects in period 1
    		PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Started
    40
    21
    42
    40
    Completed
    19
    8
    17
    19
    Not completed
    21
    13
    25
    21
         Adverse event, serious fatal
    1
    -
    -
    -
         Subject request to discontinue treatment
    1
    1
    2
    1
         Consent withdrawn by subject
    2
    2
    1
    -
         Adverse event, non-fatal
    -
    -
    -
    1
         LTE -- other
    1
    1
    -
    -
         Completed DB and cont. to follow-up
    14
    8
    16
    17
         LTE -- sponsor reason
    -
    -
    1
    -
         Completed DB, not dosed in LTE
    1
    -
    -
    -
         LTE -- withdrew consent
    -
    -
    1
    -
         Lost to follow-up
    -
    -
    1
    -
         Subject no longer meets study criteria
    -
    1
    -
    -
         Lack of efficacy
    1
    -
    3
    2
    Period 2
    Period 2 title
    Open Label Long Term Extension
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PBO + MTX
    Arm description
    		 Clazakizumab placebo SC every 4 weeks with background methotrexate
    Arm type
    		 Placebo

    Investigational medicinal product name
    Clazakizumab placebo
    Investigational medicinal product code
    BMS-945429 Placebo
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab placebo SC every 4 weeks with background methotrexate

    Arm title
    		 C1 + MTX
    Arm description
    		 Clazakizumab 1 mg SC every 4 weeks with background methotrexate (n = 20)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clazakizumab
    Investigational medicinal product code
    BMS-945429
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab 1 mg SC every 4 weeks with background methotrexate

    Arm title
    		 C5 + MTX
    Arm description
    		 Clazakizumab 5 mg SC every 4 weeks with background methotrexate
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clazakizumab
    Investigational medicinal product code
    BMS-945429
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab 5 mg SC every 4 weeks with background methotrexate

    Arm title
    		 C25 + MTX
    Arm description
    		 Clazakizumab 25 mg SC every 4 weeks with background methotrexate
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clazakizumab
    Investigational medicinal product code
    BMS-945429
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab 25 mg SC every 4 weeks with background methotrexate

    Number of subjects in period 2
    		PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Started
    19
    8
    17
    19
    Completed
    0
    1
    0
    1
    Not completed
    19
    7
    17
    18
         Consent withdrawn by subject
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    1
         Ongoing in LTE as of Apr2015
    3
    1
    2
    4
         Sponsor reason
    15
    6
    15
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PBO + MTX
    Reporting group description
    		 Clazakizumab placebo SC every 4 weeks with background methotrexate

    Reporting group title
    C1 + MTX
    Reporting group description
    		 Clazakizumab 1 mg SC every 4 weeks with background methotrexate

    Reporting group title
    C5 + MTX
    Reporting group description
    		 Clazakizumab 5 mg SC every 4 weeks with background methotrexate

    Reporting group title
    C25 + MTX
    Reporting group description
    		 Clazakizumab 25 mg SC every 4 weeks with background methotrexate

    Reporting group values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX Total
    Number of subjects
    		 40 21 42 40 143
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 32 15 35 32 114
        From 65-84 years
    		 8 6 6 8 28
        85 years and over
    		 0 0 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.4 ± 11.21 55.8 ± 11.20 53.4 ± 13.75 52.6 ± 13.21 -
    Gender Categorical
    Units: Subjects
        Female
    		 35 18 33 35 121
        Male
    		 5 3 9 5 22
    Race (NIH/OMB)
    Units: Subjects
        White
    		 30 18 34 33 115
        Black or African American
    		 1 0 2 0 3
        Asian
    		 5 3 5 4 17
        Other
    		 4 0 1 3 8
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic/Latino
    		 4 1 4 5 14
        Not Hispanic/Latino
    		 20 12 21 17 70
        Not reported
    		 16 8 17 18 59

    End points

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    End points reporting groups
    Reporting group title
    PBO + MTX
    Reporting group description
    		 Clazakizumab placebo SC every 4 weeks with background methotrexate

    Reporting group title
    C1 + MTX
    Reporting group description
    		 Clazakizumab 1 mg SC every 4 weeks with background methotrexate

    Reporting group title
    C5 + MTX
    Reporting group description
    		 Clazakizumab 5 mg SC every 4 weeks with background methotrexate

    Reporting group title
    C25 + MTX
    Reporting group description
    		 Clazakizumab 25 mg SC every 4 weeks with background methotrexate
    Reporting group title
    PBO + MTX
    Reporting group description
    		 Clazakizumab placebo SC every 4 weeks with background methotrexate

    Reporting group title
    C1 + MTX
    Reporting group description
    		 Clazakizumab 1 mg SC every 4 weeks with background methotrexate (n = 20)

    Reporting group title
    C5 + MTX
    Reporting group description
    		 Clazakizumab 5 mg SC every 4 weeks with background methotrexate

    Reporting group title
    C25 + MTX
    Reporting group description
    		 Clazakizumab 25 mg SC every 4 weeks with background methotrexate

    Primary: Mean Change from Baseline in Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) at Week 12

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    End point title
    		 Mean Change from Baseline in Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) at Week 12
    End point description
    The DAS using the 28-count subsets of tender/painful joints and swollen joints, together with CRP to derive the DAS28-CRP, was calculated using the following formula: DAS28-CRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96; where TJC28 is number of painful joints out of 28 joints, SJC28 is number of swollen joints out of 28 joints, GH is the general health or patients’ global assessment of disease activity on a 100 mm VAS, ln is the natural logarithm, and CRP is in mg/L. A score greater than 5.1 implies active disease; less than 3.2, well controlled disease; and less than 2.6, remission.
    End point type
    Primary
    End point timeframe
    Day 1 to Week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    34
    15
    35
    37
    Units: Score
        arithmetic mean (standard error)
    -0.75 ± 0.2249
    -1.10 ± 0.3303
    -2.10 ± 0.2209
    -2.43 ± 0.2190
    Statistical analysis title
    		 P-value of (C1+MTX) vs (PBO +MTX)
    Comparison groups
    PBO + MTX v C1 + MTX
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3846 [1]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - Based on the linear mixed model analysis and a hierarchical testing procedure implemented to control the overall type I error rate at 0.05 levels (one-sided)
    Statistical analysis title
    		 P-value of (C5+MTX) vs (PBO +MTX)
    Comparison groups
    PBO + MTX v C5 + MTX
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [2] - Based on the linear mixed model analysis and a hierarchical testing procedure implemented to control the overall type I error rate at 0.05 levels (one-sided)
    Statistical analysis title
    		 P-value of (C25+MTX) vs (PBO +MTX)
    Comparison groups
    PBO + MTX v C25 + MTX
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - Based on the linear mixed model analysis and a hierarchical testing procedure implemented to control the overall type I error rate at 0.05 levels (one-sided)

    Secondary: Percentage of Subjects Meeting the Criteria of the American College of Rheumatology for 20%/50%/70% Improvement (ACR 20/50/70) Responses at Week 12

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    End point title
    		 Percentage of Subjects Meeting the Criteria of the American College of Rheumatology for 20%/50%/70% Improvement (ACR 20/50/70) Responses at Week 12
    End point description
    The ACR x is based on x% improvement (compared with baseline values) in tender and swollen joint counts and on x% improvement in 3 of the remaining 5 core set measures (participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function) and 1 acute phase reactant value. x = 20, 50,70 for ACR 20/50/70
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
    number (confidence interval 95%)
        ACR 20
    27.5 (13.7 to 41.3)
    14.3 (3.0 to 36.3)
    50.0 (34.9 to 65.1)
    47.5 (32.0 to 63.0)
        ACR 50
    7.5 (1.6 to 20.4)
    14.3 (3.0 to 36.3)
    21.4 (9.0 to 33.8)
    22.5 (9.6 to 35.4)
        ACR 70
    2.5 (0.1 to 13.2)
    4.8 (0.1 to 23.8)
    9.5 (2.7 to 22.6)
    15.0 (3.9 to 26.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clinical Disease Activity Index (CDAI) Remission Responder (CDAI <= 2.8) at Week 12

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    End point title
    		 Percentage of Subjects with Clinical Disease Activity Index (CDAI) Remission Responder (CDAI <= 2.8) at Week 12
    End point description
    Clinical Disease Activity Index (CDAI) is calculated as the simple linear sum of the outcome parameters: tender joint count (TJC) and swollen joint count (SJC) based on a 28-joint assessment, patient global assessment of disease activity (PGA: VAS 0–10 cm), and physician global assessment of disease activity (EGA: VAS 0–10 cm): CDAI = TJC28 + SJC28 + PGA + EGA. CDAI total score=0-76. CDAI <=2.8 indicates disease remission, >2.8 to 10=low DA, >10 to 22=moderate DA, and >22=high DA. CDAI Remission responder is defined as a CDAI score less than or equal to 2.8.
    End point type
    Secondary
    End point timeframe
    At week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
        number (confidence interval 95%)
    2.5 (0.1 to 13.2)
    9.5 (1.2 to 30.4)
    9999 (9999 to 9999)
    7.5 (1.6 to 20.4)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Remission by Criteria of the Simplified Disease Activity Index (SDAI), SDAI <= 3.3, at week 12

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    End point title
    		 Percentage of Subjects Who Achieved Remission by Criteria of the Simplified Disease Activity Index (SDAI), SDAI <= 3.3, at week 12
    End point description
    The SDAI is the simple linear sum of 5 outcome parameters: tender joint count (TJC) and swollen joint count (SJC) (based on a 28-joint assessment); patient's and physician's global assessments of disease activity (assessed on 0-10 cm visual analog scale, on which higher scores=greater affection due to disease activity); and C-reactive protein level (mg/dL). SDAI total score=0-86. SDAI <=3.3 indicates disease remission, >3.4 to 11=low disease activity, >11 to 26=moderate disease activity, and >26=high disease activity. TJC is assessed and recorded at each visit, with no swelling=0, swelling=1. SJC is assessed through identification of joints that are painful under pressure or to passive motion. TJC is recorded on the joint assessment form at each visit, with no tenderness =0, tenderness = 1. Higher score indicates worst health condition.
    End point type
    Secondary
    End point timeframe
    At week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
        number (confidence interval 95%)
    2.5 (0.1 to 13.2)
    9.5 (1.2 to 30.4)
    9999 (9999 to 9999)
    7.5 (1.6 to 20.4)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects achieving Boolean Remission (Boolean Remission Rate) at Week 12

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    End point title
    		 Percentage of Subjects achieving Boolean Remission (Boolean Remission Rate) at Week 12
    End point description
    Remission by Boolean-based definition: Subject must satisfy all of the followings: TJC28 <=1; SJC28<=1; PGA<=1; CRP<=1 mg/dL where tender joint count (TJC) and swollen joint count (SJC) are based on a 28-joint assessment, patient global assessment of disease activity (PGA: VAS 0–10 cm), physician global assessment of disease activity (EGA: VAS 0–10 cm) and C-reactive protein (CRP in mg/dL). Higher scores indicate worst health condition
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
        number (confidence interval 95%)
    5.0 (0.6 to 16.9)
    4.8 (0.1 to 23.8)
    2.4 (0.1 to 12.6)
    5.0 (0.6 to 16.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Health assessment questionnaire disability index (HAQ-DI) change from baseline of at least 0.22 units at Week 12

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    End point title
    		 Percentage of Subjects with Health assessment questionnaire disability index (HAQ-DI) change from baseline of at least 0.22 units at Week 12
    End point description
    HAQ responder is defined as a reduction of at least 0.22 units from baseline in score on the Health Assessment Questionnaire Disability Index (HAQ-DI), which assesses patients' functional ability by rating their abilities over the previous week. The HAQ-DI includes at least 2 questions from each of 8 categories: dressing and grooming, hygiene, arising, reach, eating, grip, walking, and common daily activities. Patients rate difficulty performing specific tasks: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The sum of the categories score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3. When aids, devices, or help is indicated by the patient, the score for the category item is raised from a 0 or a 1 to a 2, but if the patient's highest score for a subcategory is a 3, it stays a 3.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
        number (confidence interval 95%)
    47.5 (32.0 to 63.0)
    19.0 (5.4 to 41.9)
    47.6 (32.5 to 62.7)
    50.0 (34.5 to 65.5)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With DAS28- Erythrocyte sedimentation rate (ESR) <2.6 at Week 12

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    End point title
    		 Percentage of Subjects With DAS28- Erythrocyte sedimentation rate (ESR) <2.6 at Week 12
    End point description
    The Disease Activity Score (DAS) using the 28-count subsets of tender/painful joints and swollen joints, together with erythrocyte sedimentation rate ESR, to derive the, DAS28-ESR, was calculated using the following formula: DAS28-ESR = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*ln(ESR) + 0.014*GH ; where TJC28 is number of painful joints out of 28 joints, SJC28 is number of swollen joints out of 28 joints, GH is the general health or patients’ global assessment of disease activity on a 100 mm VAS, ln is the natural logarithm, ESR is in mm/hour. DAS28-ESR scores could range from 0 to 10, where higher scores represented higher disease activity. DAS28-ESR score less than or equal to (</=) 3.2 indicates LDA, DAS28-ESR score greater than (>) 3.2 indicates moderate to high disease activity, and DAS28-ESR less than (<) 2.6 indicates remission.
    End point type
    Secondary
    End point timeframe
    At week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
        number (confidence interval 95%)
    2.5 (0.1 to 13.2)
    4.8 (0.1 to 23.8)
    7.1 (1.5 to 19.5)
    15.0 (3.9 to 26.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Remission by Disease Activity Score 28 Based on C-reactive Protein (DAS28-CRP) Criteria, DAS28<2.6, at Week 12

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    End point title
    		 Percentage of Subjects Who Achieved Remission by Disease Activity Score 28 Based on C-reactive Protein (DAS28-CRP) Criteria, DAS28<2.6, at Week 12
    End point description
    The DAS using the 28-count subsets of tender/painful joints and swollen joints, together with CRP to derive the DAS28-CRP, was calculated using the following formula: DAS28-CRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96; where TJC28 is number of painful joints out of 28 joints, SJC28 is number of swollen joints out of 28 joints, GH is the general health or patients’ global assessment of disease activity on a 100 mm VAS, ln is the natural logarithm, and CRP is in mg/L. A score greater than 5.1 implies active disease; less than 3.2, well controlled disease; and less than 2.6, remission.
    End point type
    Secondary
    End point timeframe
    At week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
        number (confidence interval 95%)
    5.0 (0.6 to 16.9)
    9.5 (1.2 to 30.4)
    14.3 (3.7 to 24.9)
    15.0 (3.9 to 26.1)
    No statistical analyses for this end point

    Secondary: Number of subjects with Adverse Events

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    End point title
    		 Number of subjects with Adverse Events
    End point description
    Adverse Events include deaths, serious adverse events, related serious adverse events, discontinuations due to serious adverse events, adverse events, related adverse events and discontinuations due to adverse events
    End point type
    Secondary
    End point timeframe
    From the 1st dose in DB period up to 150 days post the last dose if subject discontinued study medication or the first dose date in LTE period, whichever is the earlier.
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Subjects
        Deaths
    1
    0
    0
    0
        Serious Adverse Events (SAEs)
    1
    0
    0
    1
        Related SAEs
    1
    0
    0
    0
        Discontinued due to SAEs
    0
    0
    0
    0
        AEs
    14
    5
    24
    28
        Related AEs
    5
    3
    9
    16
        Discontinued due to AEs
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Vital Signs - Sitting Systolic Blood Pressure

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    End point title
    		 Vital Signs - Sitting Systolic Blood Pressure
    End point description
    On each day of study drug administration, vital signs were monitored. Body temperature, blood pressure, respiration rate and heart rate that were taken prior to and after Clazakizumab administration during scheduled visits
    End point type
    Secondary
    End point timeframe
    Screening Visit 1 to Week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: mmHg
    arithmetic mean (standard deviation)
        Screening Visit #1 (N =39,21,42,40)
    125.9 ± 14.10
    125.4 ± 15.45
    126.0 ± 12.10
    126.7 ± 16.37
        Screening Visit # 2 (N = 3,3,2, Not reported)
    121.3 ± 12.06
    122.0 ± 19.08
    121.5 ± 6.36
    9999 ± 9999
        Day 1 Pre (N = 39, 21, 42, 40)
    123.8 ± 12.67
    124.7 ± 15.44
    125.8 ± 12.94
    123.3 ± 13.04
        Day 1 1 Hr Post (N = 38,21,42,40)
    123.1 ± 12.36
    121.4 ± 18.56
    123.9 ± 13.86
    119.2 ± 12.62
        Day 1 2 hr Post (N = 39,20,42,40)
    124.1 ± 15.24
    124.7 ± 11.49
    123.6 ± 11.75
    120.9 ± 11.87
        Week 1 (N = 40,20,41,40)
    123.6 ± 16.54
    124.7 ± 13.89
    126.9 ± 13.56
    125.4 ± 15.25
        Week 2 (N = 40,20,40,40)
    122.9 ± 13.08
    121.5 ± 15.81
    121.7 ± 13.28
    124.4 ± 16.25
        Week 4 (N = 38,17,39,38)
    122.3 ± 12.27
    122.1 ± 15.27
    127.1 ± 13.31
    123.4 ± 16.25
        Week 8 (N = 34,17,38,37)
    123.5 ± 10.66
    121.5 ± 15.26
    127.9 ± 11.48
    128.6 ± 14.80
        Week 12 ( N = 27,14,25,27)
    123.4 ± 11.75
    123.6 ± 12.31
    128.2 ± 13.65
    127.0 ± 15.38
    No statistical analyses for this end point

    Secondary: Vital Signs -- Sitting Diastolic Blood Pressure

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    End point title
    		 Vital Signs -- Sitting Diastolic Blood Pressure
    End point description
    On each day of study drug administration, vital signs were monitored. Body temperature, blood pressure, respiration rate and heart rate that were taken prior to and after Clazakizumab administration during scheduled visits
    End point type
    Secondary
    End point timeframe
    Screening visit 1 to Week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: mmHg
    arithmetic mean (standard deviation)
        Screening visit # 1 (N= 39,21,42,40)
    81.3 ± 8.55
    78.7 ± 9.28
    77.5 ± 7.27
    78.4 ± 8.88
        Screening visit # 2 (N = 3, 3,2, not reported)
    72.3 ± 9.71
    75.7 ± 4.04
    83.0 ± 1.41
    9999 ± 9999
        Day 1 Pre (N = 39,21,42,40)
    77.7 ± 8.02
    74.9 ± 9.37
    78.3 ± 9.23
    76.0 ± 8.13
        Day 1 1 Hr Post (N = 38,21,42,40)
    77.0 ± 7.53
    73.5 ± 10.93
    76.3 ± 9.86
    73.0 ± 7.90
        Day 1 2 Hr Post (N = 39,20,42,40)
    77.1 ± 8.94
    74.0 ± 7.00
    75.9 ± 8.89
    74.9 ± 6.49
        Week 1 (N = 40,20,41,40)
    76.9 ± 8.56
    74.6 ± 9.04
    78.2 ± 8.48
    76.7 ± 9.69
        Week 2 (N = 40,20,40,40)
    76.3 ± 7.98
    74.8 ± 10.18
    74.5 ± 8.76
    75.7 ± 10.53
        Week 4 (N = 38, 17, 39, 38)
    75.1 ± 9.26
    73.6 ± 7.91
    80.7 ± 8.25
    78.7 ± 10.10
        Week 8 (N = 34,17,38,37)
    75.9 ± 8.11
    73.7 ± 10.65
    79.2 ± 8.24
    78.9 ± 9.35
        Week 12 ( N = 27,14,25,27)
    77.3 ± 7.51
    71.3 ± 5.66
    78.4 ± 9.40
    76.1 ± 9.17
    No statistical analyses for this end point

    Secondary: Vital Signs -- Sitting Heart Rate

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    End point title
    		 Vital Signs -- Sitting Heart Rate
    End point description
    On each day of study drug administration, vital signs were monitored. Body temperature, blood pressure, respiration rate and heart rate that were taken prior to and after Clazakizumab administration during scheduled visits
    End point type
    Secondary
    End point timeframe
    Screening visit 1 to Week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: bpm
    arithmetic mean (standard deviation)
        Screening visit #1 (N = 39, 21, 42, 40)
    77.6 ± 10.51
    75.0 ± 10.23
    75.2 ± 12.82
    76.6 ± 9.21
        Screening visit #2 ( N = 3,3,2, Not reported)
    85.7 ± 12.01
    69.3 ± 16.65
    84.0 ± 8.49
    9999 ± 9999
        Day 1 Pre (N = 39,21,42,40)
    76.6 ± 10.41
    76.2 ± 9.80
    76.5 ± 9.33
    77.5 ± 10.19
        Day 1 1 Hr Post (N = 38,21,42,40)
    74.4 ± 9.99
    74.4 ± 10.61
    77.1 ± 8.58
    75.3 ± 8.92
        Day 1 2 Hr Post (N = 39,20,42,40)
    75.7 ± 9.94
    73.3 ± 10.22
    75.6 ± 7.50
    75.9 ± 9.27
        Week 1 (N = 40, 20, 41, 40)
    76.8 ± 9.50
    70.9 ± 11.16
    73.6 ± 8.37
    72.0 ± 9.06
        Week 2 (N = 40, 20, 40, 40)
    75.9 ± 8.42
    72.7 ± 10.18
    71.9 ± 8.68
    73.7 ± 9.26
        Week 4 ( N = 38,17,39,38)
    74.7 ± 9.64
    73.8 ± 13.06
    74.9 ± 9.45
    73.3 ± 11.17
        Week 8 (N = 34,17,38,37)
    76.0 ± 8.73
    73.0 ± 11.42
    74.1 ± 8.02
    74.4 ± 10.83
        Week 12 (N = 27,14,25,27)
    75.1 ± 11.12
    72.7 ± 9.02
    75.0 ± 7.90
    73.9 ± 9.91
    No statistical analyses for this end point

    Secondary: Vital Signs -- Sitting Respiration rate

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    End point title
    		 Vital Signs -- Sitting Respiration rate
    End point description
    On each day of study drug administration, vital signs were monitored. Body temperature, blood pressure, respiration rate and heart rate that were taken prior to and after Clazakizumab administration during scheduled visits
    End point type
    Secondary
    End point timeframe
    Screening visit 1 to Week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: per min
    arithmetic mean (standard deviation)
        Screening visit # 1 (N = 38,21,42,40)
    16.2 ± 2.45
    15.4 ± 2.42
    16.2 ± 2.22
    16.2 ± 2.03
        Screening visit # 2 (N = 3,3,2, Not reported)
    15.0 ± 2.65
    17.7 ± 5.13
    20.0 ± 0.00
    9999 ± 9999
        Day 1 Pre ( N = 39,21,41,40)
    16.6 ± 2.37
    15.9 ± 2.61
    16.6 ± 2.08
    16.3 ± 2.41
        Day 1 1 Hr Post (N = 38,21,41,40)
    16.4 ± 2.56
    15.8 ± 2.11
    16.4 ± 2.15
    16.1 ± 1.94
        Day 1 2 hr Post (N = 39,20,41,40)
    16.5 ± 2.45
    15.5 ± 2.35
    16.6 ± 2.27
    16.1 ± 1.95
        Week 1 (N = 40,20,41,40)
    16.5 ± 2.21
    16.0 ± 2.36
    16.5 ± 2.28
    15.8 ± 2.80
        Week 2 ( N = 40,20,40,40)
    16.5 ± 2.52
    15.9 ± 2.20
    16.4 ± 2.35
    16.1 ± 2.37
        Week 4 (N = 38,17,39,38)
    16.9 ± 2.50
    16.8 ± 2.88
    16.3 ± 1.89
    16.1 ± 2.41
        Week 8 (N = 34, 17, 38, 37)
    16.7 ± 2.40
    16.9 ± 2.99
    16.2 ± 2.03
    16.1 ± 2.21
        Week 12 (N = 27,14, 25 ,27)
    17.3 ± 2.14
    16.9 ± 2.54
    16.4 ± 2.06
    16.0 ± 2.18
    No statistical analyses for this end point

    Secondary: Vital signs -- Sitting temperature

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    End point title
    		 Vital signs -- Sitting temperature
    End point description
    On each day of study drug administration, vital signs were monitored. Body temperature, blood pressure, respiration rate and heart rate that were taken prior to and after Clazakizumab administration during scheduled visits
    End point type
    Secondary
    End point timeframe
    Screening visit 1 to Week 12
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: degree C
    arithmetic mean (standard deviation)
        Screening Visit #1 (N = 39,21,42,40)
    36.43 ± 0.326
    36.44 ± 0.291
    36.29 ± 0.582
    36.42 ± 0.372
        Screening visit # 2 (N = 3,3,2, Not reported)
    36.37 ± 0.115
    36.57 ± 0.252
    36.65 ± 0.071
    9999 ± 9999
        Day 1 Pre (N = 39,21,42,40)
    36.47 ± 0.294
    36.49 ± 0.399
    36.36 ± 0.561
    36.27 ± 0.504
        Day 1 1 Hr Post (N = 38,21,42,40)
    36.46 ± 0.308
    36.55 ± 0.364
    36.40 ± 0.449
    36.28 ± 0.522
        Day 1 2 Hr Post (N = 39,20,42,40)
    36.46 ± 0.264
    36.52 ± 0.341
    36.39 ± 0.524
    36.31 ± 0.402
        Week 1 (N = 40,20,41,40)
    36.42 ± 0.365
    36.41 ± 0.380
    36.33 ± 0.420
    36.29 ± 0.498
        Week 2 (N = 40,20,40,40)
    36.43 ± 0.387
    36.35 ± 0.389
    36.32 ± 0.533
    36.26 ± 0.546
        Week 4 (N = 38,17,39, 38)
    36.37 ± 0.342
    36.46 ± 0.453
    36.31 ± 0.526
    36.26 ± 0.493
        Week 8 (N = 34,17,38,37)
    36.44 ± 0.341
    36.35 ± 0.332
    36.32 ± 0.477
    36.36 ± 0.396
        Week 12 (N = 27,14,25,27)
    36.52 ± 0.414
    36.36 ± 0.282
    36.38 ± 0.512
    36.36 ± 0.465
    No statistical analyses for this end point

    Secondary: Marked Laboratory Abnormality -- Hematology I

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    End point title
    		 Marked Laboratory Abnormality -- Hematology I
    End point description
    ERYTHROCYTE/PLATELET ATTRIBUTES: HEMOGLOBIN HB G/L LOW IF < 80 FOR FEMALES LOW IF < 90 FOR MALES; HIGH IF > 185 FOR BOTH FEMALES AND MALES; PLATELET COUNT PLAT X10*9 C/L LOW IF VALUE < 50
    End point type
    Secondary
    End point timeframe
    From 1st dose in double blind period up to 150 days post the last dose if subject discontinued study medication, or the first dose date in LTE period, whichever is the earlier.
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
    number (not applicable)
        Hemoglobin Low
    0
    0
    0
    0
        Hemoglobin High
    0
    0
    0
    0
        Platelet Count, Low
    0
    0
    0
    2.5
        Platelet Count, High
    9999
    9999
    9999
    9999
    No statistical analyses for this end point

    Secondary: Marked Laboratory Abnormality -- Hematology II

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    End point title
    		 Marked Laboratory Abnormality -- Hematology II
    End point description
    QUANTITATIVE WBC:LEUKOCYTES WBC X10*9 C/L LOW IF VALUE < 2.0; WBC DIFFERENTIAL COUNT; NEUTROPHILS (ABSOLUTE) NEUTA X10*9 C/L LOW IF ABSOLUTE COUNT < 1.0; LYMPHOCYTES (ABSOLUTE) LYMPA X10*9 C/L LOW IF ABSOLUTE COUNT < 1.0
    End point type
    Secondary
    End point timeframe
    From the 1st dose in DB period up to 150 days post the last dose if subject discontinued study medication or the first dose date in LTE period, whichever is the earlier.
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
    number (not applicable)
        Quant. WBC Leukocytes Low
    0
    0
    0
    0
        Quant. WBC Leukocytes High
    9999
    9999
    9999
    9999
        Lymphocytes (Abs.) Low
    7.5
    5.0
    16.7
    10.0
        Lymphocytes (Abs.) High
    9999
    9999
    9999
    9999
        Neutrophils (Abs.) Low
    0
    5.0
    0
    0
        Neutrophils (Abs.) High
    9999
    9999
    9999
    9999
    No statistical analyses for this end point

    Secondary: Marked Laboratory Abnormality -- Liver and Kidney Function

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    End point title
    		 Marked Laboratory Abnormality -- Liver and Kidney Function
    End point description
    LIVER FUNCTION TESTS: ALKALINE PHOSPHATASE (ALP) ALP U/L HIGH IF VALUE > 3X ULN; ASPARTATE AMINOTRANSFERASE (AST) AST U/L HIGH IF VALUE > 5X ULN; ALANINE AMINOTRANSFERASE (ALT) ALT U/L HIGH IF VALUE > 5X ULN; BILIRUBIN, TOTAL TBILI UMOL/L HIGH IF VALUE > 2.0X ULN; BILIRUBIN, DIRECT DBILI UMOL/L HIGH IF VALUE >= 17.1
    End point type
    Secondary
    End point timeframe
    From the 1st dose in DB period up to 150 days post the last dose if subject discontinued study medication or the first dose date in LTE period, whichever is the earlier.
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
    number (not applicable)
        Alanine Aminotransferase (ALT) Low
    9999
    9999
    9999
    9999
        Alanine Aminotransferase (ALT) High
    0
    0
    0
    0
        Alkaline Phosphatase (ALP) Low
    9999
    9999
    9999
    9999
        Alkaline Phosphatase (ALP) High
    0
    0
    0
    0
        Aspartate Aminotransferase (AST) Low
    9999
    9999
    9999
    9999
        Aspartate Aminotransferase (AST) High
    0
    0
    0
    0
        Bilirubin, Direct, Low
    9999
    9999
    9999
    9999
        Bilirubin, Direct, High
    0
    0
    0
    0
        Bilirubin, Total, Low
    9999
    9999
    9999
    9999
        Bilirubin, Total, High
    0
    0
    2.4
    0
    No statistical analyses for this end point

    Secondary: Marked Laboratory Abnormality -- Other Chemistry Testing

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    End point title
    		 Marked Laboratory Abnormality -- Other Chemistry Testing
    End point description
    LIPID TESTS: CHOLESTEROL, TOTAL (TC) CHOL MMOL/L HIGH IF VALUE > 10.36; HDL CHOLESTEROL (HDL-C) HDLC MMOL/L LOW IF VALUE < 1.036; LDL CHOLESTEROL (CALCULATED) FASTING LDLF MMOL/L HIGH IF VALUE >= 4.144; TRIGLYCERIDES, FASTING TRIGF MMOL/L HIGH IF VALUE > 5.65; VLDL CHOLESTEROL (VLDL-C) VLDL MMOL/L HIGH IF VALUE >= 1.294
    End point type
    Secondary
    End point timeframe
    From the 1st dose in DB period up to 150 days post the last dose if subject discontinued study medication or the first dose date in LTE period, whichever is the earlier
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
    number (not applicable)
        Cholesterol, Total, Low
    9999
    9999
    9999
    9999
        Cholesterol, Total, High
    0
    0
    0
    0
        HDL Cholesterol, Low
    10.3
    21.1
    9.5
    10.0
        HDL, Cholesterol, High
    9999
    9999
    9999
    9999
        LDL Cholesterol (Calc.) Low
    9999
    9999
    9999
    9999
        LDL Cholesterol (Calc.) High
    10.3
    26.3
    21.4
    27.5
        Triglycerides, Fasting, Low
    9999
    9999
    9999
    9999
        Triglycerides, Fasting, High
    0
    0
    0
    0
        VLDL Cholesterol, Low
    9999
    9999
    9999
    9999
        VLDL Cholesterol, High
    12.8
    15.8
    7.1
    20.0
    No statistical analyses for this end point

    Secondary: Immunogenicity -- Percentage of Subjects with ADA Positive Response With Respect to Baseline

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    End point title
    		 Immunogenicity -- Percentage of Subjects with ADA Positive Response With Respect to Baseline
    End point description
    An ADA (anti-drug antibody) positive relative to baseline immunogenicity response using electrochemical luminescence (ECL) assay measurement is defined as: a) A missing baseline immunogenicity measurement and a positive laboratory reported immunogenicity response post-baseline. b) A negative laboratory reported baseline immunogenicity response and a positive laboratory reported immunogenicity response post-baseline. c) A positive laboratory reported baseline immunogenicity response and a positive laboratory reported immunogenicity response post-baseline that has a titer value of 9 folds or greater than the baseline titer value. All other ECL immunogenicity measurements will be classified as negative immunogenicity response.
    End point type
    Secondary
    End point timeframe
    From the first Clazakizumab dose +1 and up to and including 28 days [represents one dosing interval] after the last dose in the study period
    End point values
    		 PBO + MTX C1 + MTX C5 + MTX C25 + MTX
    Number of subjects analysed
    40
    21
    42
    40
    Units: Percentage
    number (not applicable)
        ADA +ve At Baseline Visit
    0
    0
    0
    2.5
        ADA +ve (rel. to bsl.) at only 1 On-Trt Visit
    0
    0
    0
    0
        ADA +ve (rel. to bsl.) at 1 or More On-Trt Visit
    0
    0
    0
    0
        ADA +ve (rel. to bsl.) at 2 or More On-Trt Visits
    0
    0
    0
    0
        ADA +ve (rel. to bsl.) at >= 2 Cons. Visits
    0
    0
    0
    0
        ADA +ve (rel. to bsl.) at 1 Post-Trt Visit
    0
    0
    0
    7.1
        ADA +ve (rel. to bsl.) at >=2 Post-Trt Visits
    0
    0
    0
    0
        ADA +ve (rel. to bsl.) at 2 or More Visits
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug in double blind period to 150 days post the last dose if subject discontinued study medication or the first dose date in long term extension period.
    Adverse event reporting additional description
    All SAEs were collected during the screening period and within six months of discontinuation of dosing; Collection of non-serious AE information began at initiation of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to clazakizumab subcutaneous (SC) injection once in every four weeks (q4w) for 12 weeks in double-blind period with background of methotrexate.

    Reporting group title
    Clazakizumab 1 mg
    Reporting group description
    		 Subjects received 1 milligram (mg) clazakizumab SC injection q4w for 12 weeks in double-blind period and 25 mg clazakizumab SC injection q4w in open-label long term extension period with background of methotrexate.

    Reporting group title
    Clazakizumab 5 mg
    Reporting group description
    		 Subjects received 5 mg clazakizumab SC injection q4w for 12 weeks in double-blind period and 25 mg clazakizumab SC injection q4w in open-label long term extension period with background of methotrexate.

    Reporting group title
    Clazakizumab 25 mg
    Reporting group description
    		 Subjects received 25 mg clazakizumab SC injection q4w in 12 week double-blind period then in open-label long term extension period with background of methotrexate.

    Serious adverse events
    		 Placebo Clazakizumab 1 mg Clazakizumab 5 mg Clazakizumab 25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    2 / 40 (5.00%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Clazakizumab 1 mg Clazakizumab 5 mg Clazakizumab 25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 40 (35.00%)
    6 / 21 (28.57%)
    14 / 42 (33.33%)
    15 / 40 (37.50%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 21 (4.76%)
    2 / 42 (4.76%)
    2 / 40 (5.00%)
         occurrences all number
    1
    1
    2
    2
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    2 / 40 (5.00%)
         occurrences all number
    1
    0
    1
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 21 (4.76%)
    0 / 42 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    3
    1
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    2
    0
    0
    1
    Headache
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    1
    4
    Neutropenia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    0
    4
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    1
    5
    Injection site reaction
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 21 (4.76%)
    2 / 42 (4.76%)
    5 / 40 (12.50%)
         occurrences all number
    1
    2
    2
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 21 (4.76%)
    1 / 42 (2.38%)
    2 / 40 (5.00%)
         occurrences all number
    0
    1
    1
    2
    Herpes zoster
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    1
    0
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 21 (4.76%)
    1 / 42 (2.38%)
    2 / 40 (5.00%)
         occurrences all number
    3
    1
    1
    3
    Oral herpes
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    1 / 40 (2.50%)
         occurrences all number
    2
    0
    2
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 21 (9.52%)
    2 / 42 (4.76%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    2
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 21 (4.76%)
    1 / 42 (2.38%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    2
    1
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    1
    2

    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.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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