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    Clinical Trial Results:
    A Multi-Centre, Placebo-Controlled Phase II Study of Canakinumab for the Treatment of Adult-onset Still's disease (AOSD) Including an Open-Label Long Term Extension.

    Summary
    EudraCT number
    2011-001027-20
    Trial protocol
    DE  
    Global end of trial date
    05 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Aug 2020
    First version publication date
    01 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CACZ885GDE01T
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02204293
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Charité - Universitätsmedizin Berlin
    Sponsor organisation address
    Chariteplatz 1, Berlin, Germany, 10117
    Public contact
    Jan Zernicke, Charité - Universitätsmedizin Berlin, +49 30450513227, jan.zernicke@charite.de
    Scientific contact
    Jan Zernicke, Charité - Universitätsmedizin Berlin, +49 30450513227, jan.zernicke@charite.de
    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
    05 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to assess the efficacy of canakinumab treatment for subjects with adult-onset Still's disease (AOSD) and active joint involvement according to the proportion of subjects with a significant reduction of disease activity (DAS 28 [>1.2]) after 12 week treatment period and to evaluate the long-term safety of canakinumab in subjects with AOSD and articular involvement.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 May 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    27 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    34
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects with adult-onset Still's disease (AOSD) took part in the study from June 21, 2012 to May 5, 2018 at 14 investigative sites located in Germany to participate in two double-blind parts - Part I (Up to Week 12) and Part II (Up to Week 24) and one open-label Long-Term Extension (LTE) phase (Up to Month 27).

    Pre-assignment
    Screening details
    A total of 36 subjects entered in Part I to receive canakinumab/placebo. Out of 31, 5 subjects from the canakinumab group and 3 from placebo group did not enter Part II, 23 subjects entered Part II, and received canakinumab or placebo up to Week 24. 7 subjects who achieved clinical remission entered LTE Phase to receive canakinumab.

    Pre-assignment period milestones
    Number of subjects started
    36
    Number of subjects completed
    35

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Subject Met One or More Exclusion Criteria: 1
    Period 1
    Period 1 title
    Core Study Part I
    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
    Canakinumab
    Arm description
    Subjects received canakinumab 4 mg/kg up to a 300 mg maximum, subcutaneous (SC) injection, once in morning at Baseline (Day 0), Weeks 4, 8, and 12.
    Arm type
    Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    EU/1/09/564/004
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Canakinumab, single-dose 4 mg/kg up to 300 mg administered subcutaneously.

    Arm title
    Placebo
    Arm description
    Subjects received placebo, SC injection, once in morning at Baseline (Day 0), Weeks 4, 8, and 12.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matched placebo, administered subcutaneously.

    Number of subjects in period 1 [1]
    Canakinumab Placebo
    Started
    18
    17
    Completed
    17
    14
    Not completed
    1
    3
         Physician decision
    -
    3
         Adverse event, non-fatal
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject left the study before the start of the treatment as he/she did not meet or more exclusion criteria and was excluded from the efficacy analysis set.
    Period 2
    Period 2 title
    Core Study Part II
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Canakinumab Responders
    Arm description
    Subjects with response (change in DAS score > 1.2 at Week 12) continued to receive canakinumab 4 mg/kg up to 300 mg maximum, SC injection, once in the morning for Weeks 12, 16, and 20.
    Arm type
    Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    EU/1/09/564/004
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Canakinumab, single-dose 4 mg/kg up to 300 mg administered subcutaneously.

    Arm title
    Placebo Responders
    Arm description
    Subjects with response (change in DAS score > 1.2 at Week 12) continued to receive placebo, SC injection, once in morning for Weeks 12, 16, and 20.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matched placebo, administered subcutaneously.

    Arm title
    Placebo Non-responders
    Arm description
    Non-responders (change in DAS score ≤ 1.2 at Week 12) who switched to canakinumab were unblinded to receive canakinumab 4 mg/kg up to 300 mg maximum, SC injection, once in the morning at Weeks 12, 16, and 20.
    Arm type
    Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    EU/1/09/564/004
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Canakinumab, single-dose 4 mg/kg up to 300 mg administered subcutaneously.

    Number of subjects in period 2 [2]
    Canakinumab Responders Placebo Responders Placebo Non-responders
    Started
    12
    4
    7
    Completed
    12
    4
    7
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Out of 31, 5 subjects from the canakinumab group and 3 from placebo group did not enter Part II of the study.
    Period 3
    Period 3 title
    LTE Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Canakinumab
    Arm description
    Subjects with remission (change in DAS score > 1.2 and no signs of systemic activity for adult-onset Still’s disease at Week 20) received canakinumab 4 mg/kg up to 300 mg maximum, SC injection at Weeks 24 and 28, which was down titrated to 2 mg/kg up to 150 mg maximum if applicable after Week 28 up to Month 27 (Week 117).
    Arm type
    Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    EU/1/09/564/004
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Canakinumab, single-dose 4 mg/kg up to 300 mg administered subcutaneously.

    Number of subjects in period 3 [3]
    Canakinumab
    Started
    7
    Completed
    0
    Not completed
    7
         Study Suspended
    7
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects who achieved remission only entered LTE Phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    Subjects received canakinumab 4 mg/kg up to a 300 mg maximum, subcutaneous (SC) injection, once in morning at Baseline (Day 0), Weeks 4, 8, and 12.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo, SC injection, once in morning at Baseline (Day 0), Weeks 4, 8, and 12.

    Reporting group values
    Canakinumab Placebo Total
    Number of subjects
    18 17 35
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.06 ± 13.2 40.53 ± 13.2 -
    Gender categorical
    Units: Subjects
        Female
    10 13 23
        Male
    8 4 12

    End points

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    End points reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    Subjects received canakinumab 4 mg/kg up to a 300 mg maximum, subcutaneous (SC) injection, once in morning at Baseline (Day 0), Weeks 4, 8, and 12.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo, SC injection, once in morning at Baseline (Day 0), Weeks 4, 8, and 12.
    Reporting group title
    Canakinumab Responders
    Reporting group description
    Subjects with response (change in DAS score > 1.2 at Week 12) continued to receive canakinumab 4 mg/kg up to 300 mg maximum, SC injection, once in the morning for Weeks 12, 16, and 20.

    Reporting group title
    Placebo Responders
    Reporting group description
    Subjects with response (change in DAS score > 1.2 at Week 12) continued to receive placebo, SC injection, once in morning for Weeks 12, 16, and 20.

    Reporting group title
    Placebo Non-responders
    Reporting group description
    Non-responders (change in DAS score ≤ 1.2 at Week 12) who switched to canakinumab were unblinded to receive canakinumab 4 mg/kg up to 300 mg maximum, SC injection, once in the morning at Weeks 12, 16, and 20.
    Reporting group title
    Canakinumab
    Reporting group description
    Subjects with remission (change in DAS score > 1.2 and no signs of systemic activity for adult-onset Still’s disease at Week 20) received canakinumab 4 mg/kg up to 300 mg maximum, SC injection at Weeks 24 and 28, which was down titrated to 2 mg/kg up to 150 mg maximum if applicable after Week 28 up to Month 27 (Week 117).

    Subject analysis set title
    Part I: Canakinumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    2 subjects of the placebo group received canakinumab at Week 4, as protocol violation, thus, Safety Analysis Set included those additional 2 subjects in the canakinumab group.

    Subject analysis set title
    Part I: Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    2 subjects of the placebo group received canakinumab at Week 4, as protocol violation, thus, Safety Analysis Set included those additional 2 subjects in the canakinumab group.

    Subject analysis set title
    Part II: Canakinumab Responders
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    2 subjects of the placebo group received canakinumab at Week 4, as protocol violation, thus, Safety Analysis Set included those additional 2 subjects in the canakinumab group.

    Subject analysis set title
    Part II: Placebo Responders
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    2 subjects of the placebo group received canakinumab at Week 4, as protocol violation, thus, Safety Analysis Set included those additional 2 subjects in the canakinumab group.

    Primary: Core Study Part I: Percentage of Responders as Assessed Disease Activity Score 28 Joints (DAS28) Score at Week 12

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    End point title
    Core Study Part I: Percentage of Responders as Assessed Disease Activity Score 28 Joints (DAS28) Score at Week 12
    End point description
    Responders included subjects with change in DAS28 score > 1.2. The DAS28 index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity score, and the erythrocyte sedimentation rate (ESR) value. Total score ranged between 0-10. A DAS28-ESR score of 5.1 or above = high disease activity, a value between 3.2 and 5.1 = moderate disease activity and value between 2.6 and 3.2 = low disease activity, value < 2.6 = disease remission. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset still’s disease and disease activity based on DAS28 of greater than or equal to 3.2 at Screening.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
        number (confidence interval 95%)
    66.7 (43.1 to 85.2)
    41.2 (20.1 to 65.0)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.1811
    Method
    Fisher exact
    Confidence interval
    Notes
    [1] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Change From Baseline (CFB) in Disease Activity Score 28 Joints Erythrocyte Sedimentation Rate (DAS28 [ESR]) Score

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    End point title
    Core Study Part I: Change From Baseline (CFB) in Disease Activity Score 28 Joints Erythrocyte Sedimentation Rate (DAS28 [ESR]) Score
    End point description
    The DAS28 index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity score, and ESR value. Total score ranged between 0-10. A DAS28-ESR score of 5.1 or above = high disease activity, a value between 3.2 and 5.1 = moderate disease activity and value between 2.6 and 3.2 = low disease activity, value < 2.6 = disease remission. A positive change in score indicates worsening, and a negative change indicates improvement. Least squares (LS) mean was calculated by mixed linear model for repeated measures (MMRM) analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    5.37 (4.7 to 6.0)
    5.3 (4.6 to 6.0)
        CFB at Week 4 (n=16, 14)
    3.56 (2.9 to 4.3)
    4.27 (3.5 to 5.0)
        CFB at Week 8 (n=16, 12)
    2.86 (2.2 to 3.6)
    3.92 (3.1 to 4.7)
        CFB at Week 12 (n=16, 14)
    3.1 (2.4 to 3.8)
    4.0 (3.3 to 4.8)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in DAS28 C-reactive Protein (CRP) Score

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    End point title
    Core Study Part I: CFB in DAS28 C-reactive Protein (CRP) Score
    End point description
    The DAS28 index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity score, and CRP value. Total score ranged between 0-10. A DAS28-CRP score of 5.1 or above = high disease activity, a value between 3.2 and 5.1 = moderate disease activity and value between 2.6 and 3.2 = low disease activity, value < 2.6 = disease remission. A positive change in score indicates worsening, and a negative change indicates improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed “n” is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    5.0 (4.4 to 5.6)
    5.07 (4.4 to 5.7)
        CFB at Week 4 (n=17, 14)
    3.4 (2.8 to 4.0)
    4.01 (3.3 to 4.7)
        CFB at Week 8 (n=17, 13)
    2.8 (2.2 to 3.4)
    3.81 (3.1 to 4.5)
        CFB at Week 12 (n=17, 14)
    3.31 (2.7 to 3.9)
    4.01 (3.3 to 4.7)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in American College of Rheumatology (ACR) Component: 68 Tender Joint Count (TJC)

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    End point title
    Core Study Part I: CFB in American College of Rheumatology (ACR) Component: 68 Tender Joint Count (TJC)
    End point description
    The 68 TJC included the 8 distal interphalangeal (IP), 10 proximal IP and 10 metacarpophalangeal (MTP) joints of hands, the 10 MTP and 10 proximal IP joints of feet, the 2 wrists, 2 elbows, 2 shoulders, 2 acromioclavicular, 2 sternoclavicular, 2 temporomandibular, 2 hip, 2 knee, 2 talo-tibial, and 2 mid-tarsal joints. Joint tenderness was graded present (1) or absent (0). Total score is calculated by adding the scores, which range from 0 (no tender joint) to 68 (all tender joints). Lower scores indicate no tender joint and higher scores indicate worsening tender joints. A negative change from Baseline indicates improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: tender joints
    least squares mean (confidence interval 95%)
        Baseline
    8.89 (4.9 to 12.9)
    11.18 (7.1 to 15.3)
        CFB at Week 4 (n=18, 14)
    5.33 (1.3 to 9.3)
    5.85 (1.5 to 10.2)
        CFB at Week 8 (n=18, 13)
    3.72 (-0.3 to 7.7)
    5.1 (0.6 to 9.6)
        CFB at Week 12 (n=17, 14)
    4.66 (0.6 to 8.7)
    6.9 (2.6 to 11.2)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in ACR Component: 66 Swollen Joint Count (SJC)

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    End point title
    Core Study Part I: CFB in ACR Component: 66 Swollen Joint Count (SJC)
    End point description
    The 66 SJC included the 8 distal interphalangeal (IP), 10 proximal IP and 10 metacarpophalangeal (MTP) joints of hands, the 10 MTP and 10 proximal IP joints of feet, the 2 wrists, 2 elbows, 2 shoulders, 2 acromioclavicular, 2 sternoclavicular, 2 temporomandibular, 2 knee, 2 talo-tibial, and 2 mid-tarsal joints. Swelling was graded present (1) or absent (0). Total score is calculated by adding the scores, which range from 0 (no swollen joint) to 66 (all swollen joints). Lower scores indicate no swollen joint and higher scores indicate worsening swollen joints. A negative change in Baseline indicates improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: swollen joints
    least squares mean (confidence interval 95%)
        Baseline
    5.78 (3.6 to 7.9)
    8.0 (5.8 to 10.2)
        CFB at Week 4 (n=18, 14)
    2.5 (0.4 to 4.6)
    2.5 (0.1 to 4.9)
        CFB at Week 8 (n=18, 13)
    1.33 (-0.8 to 3.5)
    2.65 (0.2 to 5.0)
        CFB at Week 12 (n=17, 12)
    2.89 (0.7 to 5.1)
    4.71 (2.4 to 7.0)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in the 28 TJC

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    End point title
    Core Study Part I: CFB in the 28 TJC
    End point description
    A total of 28 joints were assessed for tenderness. The number of tender joints could range from 0 to 28, where higher values represented more tender joints. The change from Baseline to any time points was averaged among all subjects, where negative changes indicated an improvement in disease activity. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: tender joints
    least squares mean (confidence interval 95%)
        Baseline
    6.78 (4.6 to 9.0)
    7.24 (5.0 to 9.5)
        CFB at Week 4 (n=18, 14)
    3.67 (1.5 to 5.9)
    4.29 (1.9 to 6.7)
        CFB at Week 8 (n=18, 13)
    2.39 (0.2 to 4.6)
    3.85 (1.4 to 6.3)
        CFB at Week 12 (n=17, 14)
    3.47 (1.2 to 5.7)
    4.43 (2.1 to 6.8)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in the 28 SJC

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    End point title
    Core Study Part I: CFB in the 28 SJC
    End point description
    A total of 28 joints were assessed for swelling. The number of swollen joints could range from 0 to 28, where higher values represented more swollen joints. The change from Baseline to any time point was averaged among all subjects, where negative changes indicated an improvement in disease activity. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: swollen joints
    least squares mean (confidence interval 95%)
        Baseline
    4.97 (3.4 to 6.6)
    6.29 (4.6 to 8.0)
        CFB at Week 4 (n=18, 14)
    2.11 (0.5 to 3.7)
    2.47 (0.7 to 4.2)
        CFB at Week 8 (n=18, 13)
    0.83 (-0.8 to 2.5)
    2.79 (1.0 to 4.6)
        CFB at Week 12 (n=17, 14)
    2.28 (0.6 to 3.9)
    4.51 (2.8 to 6.3)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in ACR Component: Acute Phase Reactant CRP

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    End point title
    Core Study Part I: CFB in ACR Component: Acute Phase Reactant CRP
    End point description
    A negative change from Baseline in CRP level indicates an improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: milligrams per liter (mg/L)
    least squares mean (confidence interval 95%)
        Baseline
    45.55 (26.1 to 65.0)
    57.26 (37.3 to 77.2)
        CFB at Week 4 (n=17, 14)
    17.53 (-2.1 to 37.1)
    36.74 (15.8 to 57.7)
        CFB at Week 8 (n=18, 13)
    14.61 (-4.8 to 34.0)
    32.51 (11.2 to 53.8)
        CFB at Week 12 (n=17, 14)
    17.05 (-2.6 to 36.7)
    28.52 (7.0 to 50.0)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in ACR Component: Acute Phase Reactant ESR

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    End point title
    Core Study Part I: CFB in ACR Component: Acute Phase Reactant ESR
    End point description
    A negative change from Baseline in ESR level indicates an improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: millimeter per hour (mm/h)
    least squares mean (confidence interval 95%)
        Baseline
    44.11 (33.8 to 54.4)
    38.82 (28.3 to 49.4)
        CFB at Week 4 (n=16, 14)
    24.28 (13.8 to 34.7)
    38.6 (27.5 to 49.7)
        CFB at Week 8 (n=17, 12)
    25.4 (15.0 to 35.8)
    25.25 (13.6 to 36.9)
        CFB at Week 12 (n=16, 14)
    15.85 (5.3 to 26.4)
    22.41 (10.8 to 34.0)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in Serum Ferritin Level at Week 12

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    End point title
    Core Study Part I: CFB in Serum Ferritin Level at Week 12
    End point description
    LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Overall number of subjects analysed signifies the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    17
    14
    Units: nanograms per milliliter (ng/mL)
        least squares mean (confidence interval 95%)
    466.9 (16.0 to 918.0)
    634.71 (170.0 to 1099.0)
    No statistical analyses for this end point

    Secondary: Core Study Part I: Percentage of Responders With Fever Episodes

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    End point title
    Core Study Part I: Percentage of Responders With Fever Episodes
    End point description
    Fever is defined as an oral or rectal body temperature greater than 38 degrees Celsius (°C). ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    0 [2]
    Units: percentage of subjects
        number (not applicable)
    8.3
    Notes
    [2] - No subjects were reported under the placebo group for fever episodes post-baseline.
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in ACR Component: Physician’s Global Assessment of Disease Activity Score

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    End point title
    Core Study Part I: CFB in ACR Component: Physician’s Global Assessment of Disease Activity Score
    End point description
    The physician’s global assessment of disease activity was assessed using a numerical rating scale of 0-10 where 0= no disease activity and 10= activity to maximal disease activity. A negative change from Baseline indicates improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    5.5 (4.5 to 6.5)
    6.0 (4.9 to 7.1)
        CFB at Week 4 (n= 18, 14)
    3.06 (2.0 to 4.1)
    3.67 (2.5 to 4.8)
        CFB at Week 4 (n= 18, 13)
    2.72 (1.7 to 3.8)
    3.56 (2.4 to 4.7)
        CFB at Week 12 (n= 17, 14)
    2.86 (1.8 to 3.9)
    4.26 (3.1 to 5.4)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in ACR Component: Subject’s Global Assessment of Disease Activity Score

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    End point title
    Core Study Part I: CFB in ACR Component: Subject’s Global Assessment of Disease Activity Score
    End point description
    The subject’s global assessment of disease activity was assessed using a numerical rating scale of 0-10, where 0= no disease activity and 10= maximal disease activity. A negative change from Baseline indicates improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    6.08 (4.9 to 7.3)
    5.85 (4.6 to 7.1)
        CFB at Week 4 (n=18, 14)
    3.78 (2.6 to 5.0)
    4.74 (3.4 to 6.0)
        CFB at Week 8 (n=17, 13)
    2.84 (1.6 to 4.0)
    4.58 (3.2 to 5.9)
        CFB at Week 12 (n=17, 14)
    3.63 (2.4 to 4.8)
    4.32 (3.0 to 5.6)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in ACR Component: Subject’s Global Assessment of Pain Score

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    End point title
    Core Study Part I: CFB in ACR Component: Subject’s Global Assessment of Pain Score
    End point description
    The subject’s global assessment of pain was assessed using a numerical rating scale of 0-10, where 0= no disease activity and 10= maximal disease activity. A negative change from Baseline indicates improvement. A negative change from baseline indicates improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still's disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8 and 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    6.61 (5.3 to 7.9)
    6.35 (5.0 to 7.7)
        CFB at Week 4 (n=18, 14)
    3.61 (2.3 to 4.9)
    4.85 (3.5 to 6.2)
        CFB at Week 8 (n=17, 13)
    2.73 (1.4 to 4.0)
    4.18 (2.7 to 5.6)
        CFB at Week 12 (n=17, 14)
    3.71 (2.4 to 5.0)
    4.25 (2.8 to 5.7)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

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    End point title
    Core Study Part I: CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score
    End point description
    The HAQ measures physical disability and functional status. It has 4 dimensions: disability, pain, drug side effects and dollar costs. The HAQ score is calculated by summing the computed scores for each category and dividing by the number of categories answered. It ranges from 0 (without any difficulty) to 3 (unable to do). A negative change from Baseline indicates improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    1.31 (0.9 to 1.7)
    1.29 (0.9 to 1.7)
        CFB at Week 12 (n=17, 14)
    0.69 (0.3 to 1.1)
    0.9 (0.6 to 1.4)
    No statistical analyses for this end point

    Secondary: Core Study Part I: Percentage of Responders With American College of Rheumatology Response of 20 (ACR20)

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    End point title
    Core Study Part I: Percentage of Responders With American College of Rheumatology Response of 20 (ACR20)
    End point description
    ACR20 response was defined as a ≥ 20% improvement (reduction) compared with Baseline for both 68 TJC and 66 SJC, as well as for three of the additional five ACR core set variables: Subject’s Assessment of Pain over the previous 24 hours: using a NRS left end of the line 0=no pain to right end of the line 10=unbearable pain; Subject’s Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a NRS where left end of the line 0=no disease activity to right end of the line 10=maximum disease activity; HAQ-DI 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant ESR. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
        number (confidence interval 95%)
    61.1 (37.7 to 81.1)
    41.2 (20.1 to 65.0)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Canakinumab
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.3175
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    19.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15
         upper limit
    51.3
    Notes
    [3] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Percentage of Responders With ACR30

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    End point title
    Core Study Part I: Percentage of Responders With ACR30
    End point description
    ACR30 response was defined as a ≥ 30% improvement (reduction) compared with Baseline for both 68 TJC and 66 SJC, as well as for three of the additional five ACR core set variables: Subject’s Assessment of Pain over the previous 24 hours: using a NRS left end of the line 0=no pain to right end of the line 10=unbearable pain; Subject’s Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a NRS where left end of the line 0=no disease activity to right end of the line 10=maximum disease activity; HAQ 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant ESR. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
        number (confidence interval 95%)
    61.1 (37.7 to 81.1)
    29.4 (11.7 to 53.7)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Canakinumab
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.0922
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    31.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.9
         upper limit
    61.8
    Notes
    [4] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Percentage of Responders With Modified ACR30

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    End point title
    Core Study Part I: Percentage of Responders With Modified ACR30
    End point description
    ACR30 response: ≥ 30% improvement compared with baseline for both TJC68 and SJC66, and for 3 of the additional 5 ACR core set variables: Assessment of Pain over last 24 hours using NRS (0=no pain -10=unbearable pain); Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over last 24 hours on NRS (0=no disease activity -10=maximum disease activity); Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant ESR. Modified ACR 30% response calculated using above definition and requiring no intermittent fever and no more than 1 variable worsening by 30% in the preceding week. ITT population: all subjects who did not violate any of following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
        number (confidence interval 95%)
    55.6 (32.7 to 76.8)
    23.5 (8.0 to 47.5)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Canakinumab
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.0858
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    61.1
    Notes
    [5] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Percentage of Responders With ACR50

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    End point title
    Core Study Part I: Percentage of Responders With ACR50
    End point description
    ACR50 response was defined as a ≥ 50% improvement (reduction) compared with Baseline for both 68 TJC and 66 SJC, as well as for three of the additional five ACR core set variables: Subject’s Assessment of Pain over the previous 24 hours: using a NRS left end of the line 0=no pain to right end of the line 10=unbearable pain; Subject’s Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a NRS where left end of the line 0=no disease activity to right end of the line 10=maximum disease activity; HAQ-DI 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant ESR. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
        number (confidence interval 95%)
    50.0 (27.8 to 72.2)
    17.6 (4.7 to 40.9)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.075
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    32.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    60.5
    Notes
    [6] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Percentage of Responders With ACR70

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    End point title
    Core Study Part I: Percentage of Responders With ACR70
    End point description
    ACR70 response was defined as a ≥ 70% improvement (reduction) compared with Baseline for both 68 TJC and 66 SJC, as well as for three of the additional five ACR core set variables: Subject’s Assessment of Pain over the previous 24 hours: using a NRS left end of the line 0=no pain to right end of the line 10=unbearable pain; Subject’s Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a NRS where left end of the line 0=no disease activity to right end of the line 10=maximum disease activity; HAQ-DI 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant ESR. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
        number (confidence interval 95%)
    27.8 (11.0 to 51.3)
    11.8 (2.0 to 33.7)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.4018
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.6
         upper limit
    43.4
    Notes
    [7] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Percentage of Responders With ACR90

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    End point title
    Core Study Part I: Percentage of Responders With ACR90
    End point description
    ACR90 response was defined as a ≥ 90% improvement (reduction) compared with Baseline for both 68 TJC and 66 SJC, as well as for three of the additional five ACR core set variables: Subject’s Assessment of Pain over the previous 24 hours: using a NRS left end of the line 0=no pain to right end of the line 10=unbearable pain; Subject’s Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a NRS where left end of the line 0=no disease activity to right end of the line 10=maximum disease activity; HAQ-DI 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant ESR. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
        number (confidence interval 95%)
    11.1 (1.9 to 32.1)
    5.9 (0.3 to 25.8)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 1
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    5.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.8
         upper limit
    29.2
    Notes
    [8] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Percentage of Responders With European League Against Rheumatism (EULAR) Response

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    End point title
    Core Study Part I: Percentage of Responders With European League Against Rheumatism (EULAR) Response
    End point description
    EULAR response is based on DAS28-ESR and DAS28-CRP scores. The DAS28 index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, subject global assessment of disease activity score, and ESR or CRP value. A DAS28-CRP or ESR score of 5.1 or above = high disease activity, a value between 3.2 and 5.1 = moderate disease activity and value between 2.6 and 3.2 = low disease activity, value < 2.6 = disease remission. EULAR response has 3 categories: EULAR Good response: DAS28 ≤ 3.2 and a change from Baseline < -1.2. EULAR Moderate response: DAS28 >3.2 to ≤ 5.1 or a change from Baseline < -0.6 to ≥ -1.2 or EULAR No response: DAS28 >5.1 or a change from Baseline < -0.6 to ≤ -1.2. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
    number (confidence interval 95%)
        EULAR DAS28-ESR Response
    77.8 (54.7 to 92.5)
    52.9 (29.7 to 75.2)
        EULAR DAS28-CRP Response
    72.2 (48.7 to 89.0)
    47.1 (24.8 to 70.3)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    EULAR DAS28-ESR Response
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.1642
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    24.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8
         upper limit
    54.2
    Notes
    [9] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    EULAR DAS28-CRP Response
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.1756
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    25.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.1
         upper limit
    55.1
    Notes
    [10] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Percentage of Responders Achieving Low Disease Activity (LDA)

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    End point title
    Core Study Part I: Percentage of Responders Achieving Low Disease Activity (LDA)
    End point description
    Percentage of responders were defined as the subjects who achieved LDA (DAS28 score < 3.2) at Week 12. The DAS28 index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, subject global assessment of disease activity score, and ESR or CRP value. Total score ranged between 0-10. A DAS28 score greater than 5.1 implies high disease activity, equal to or less than 3.2 low disease activity, and less than 2.6 remissions. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
    number (confidence interval 95%)
        DAS28 (ESR) LDA
    33.3 (14.8 to 56.9)
    29.4 (11.7 to 53.7)
        DAS28 (CRP) LDA
    50.0 (27.8 to 72.2)
    23.5 (8.0 to 47.5)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    DAS28 (ESR) LDA
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 1
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.7
         upper limit
    35
    Notes
    [11] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    DAS28 (CRP) LDA
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    = 0.1642
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    26.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.6
         upper limit
    56
    Notes
    [12] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Percentage of Responders Achieving Disease Remission and Extended Disease Remission

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    End point title
    Core Study Part I: Percentage of Responders Achieving Disease Remission and Extended Disease Remission
    End point description
    Subjects with disease remission: LDA (DAS28 score< 2.6). The DAS28 index is a composite score of weighted components including both 28 TJC an SJC, subject global assessment of disease activity score, and ESR or CRP value. A DAS28 score greater than 5.1: high disease activity, ≤ 3.2: low disease activity, and less than 2.6: remission. Extended remission criteria included DAS28 < 2.6 and no signs of systemic activity for up to two consecutive study visits till Week 12 defined as any of Yamaguchi´s primary classification criteria for AOSD which included fever attacks at 39 °C for more than a week, arthralgia, salmon red, maculate, urticarial or maculo-papular rash and leukocytosis (white blood cells increase) of > 10000/cubic millimeters (mm^3) with > 80% neutrophils. ITT population: subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: percentage of subjects
    number (confidence interval 95%)
        DAS28 (ESR) Remission
    33.3 (14.8 to 56.9)
    11.8 (2.0 to 33.7)
        DAS28 (CRP) Remission
    38.9 (18.9 to 62.3)
    11.8 (2.0 to 33.7)
        Extended Remission
    27.8 (11.0 to 51.3)
    11.8 (2.0 to 33.7)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    DAS28 (ESR) remission
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.2285
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    21.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.1
         upper limit
    49.9
    Notes
    [13] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    DAS28 (CRP) Remission
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    = 0.1212
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    27.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.6
         upper limit
    54.6
    Notes
    [14] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Extended Remission
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.4018
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.6
         upper limit
    43.4
    Notes
    [15] - Fisher’s exact test with a two-tailed level of significance of α = 0.05.

    Secondary: Core Study Part I: Change in Joint Mobility (Degrees of Motion) Assessed by Neutral Zero Method

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    End point title
    Core Study Part I: Change in Joint Mobility (Degrees of Motion) Assessed by Neutral Zero Method
    End point description
    Number of joints with limitation of motion according to neutral zero method was assessed which included mobility of joints (elbows, wrists, shoulder joints, hip joints, knee joints, and upper ankle joints) within the reference range/degree. Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from Baseline. A negative change score indicates improvement. LS mean was calculated by MMRM analyses. ITT population included all subjects who did not violate any of the following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of greater than or equal to 3.2 at Screening. Number analysed is the number of subjects with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: degrees
    least squares mean (confidence interval 95%)
        Baseline
    4.94 (3.0 to 6.9)
    6.29 (4.3 to 8.3)
        Week 12 (n=17, 14)
    5.37 (3.4 to 7.3)
    6.05 (4.0 to 8.1)
    No statistical analyses for this end point

    Secondary: Core Study Part I: CFB in Medical Outcome Short Form (SF-36) Health Survey Score

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    End point title
    Core Study Part I: CFB in Medical Outcome Short Form (SF-36) Health Survey Score
    End point description
    The SF-36 determines overall quality of life assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 contribute to physical component summary score (PCS). Items 5-8 contribute to mental component summary score (MCS). Scores on each item are summed and averaged (range = 0 "worst"-100 "best"). Positive numbers indicate improvement from Baseline. LS mean was calculated by MMRM analyses. ITT population: subjects who did not violate any of following inclusion criteria: diagnosis of adult-onset Still’s disease and disease activity based on DAS28 score of ≥ 1.2 at Screening. Number analysed is number of subjects with data available for analyses at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Canakinumab Placebo
    Number of subjects analysed
    18
    17
    Units: score on a scale
    least squares mean (confidence interval 95%)
        SF-36 Physical: Baseline
    29.39 (24.5 to 34.3)
    28.73 (23.7 to 33.8)
        SF-36 Physical: CFB at Week 12 (n=17, 14)
    41.03 (36.0 to 46.1)
    33.45 (27.9 to 39.0)
        SF-36 Mental: Baseline
    37.8 (32.0 to 43.6)
    46.31 (40.4 to 52.2)
        SF-36 Mental: Week 12 (n=17, 14)
    43.47 (37.6 to 49.3)
    49.82 (43.6 to 56.1)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is an adverse medical event which occurs in a subject of the study and which is not necessarily in a causal relationship with the treatment the subject receives. AEs include symptoms of illnesses, as well as every unfavourable and unintended reaction. SAEs are AEs leading to death, are life-threatening, require hospitalizations or prolongation of hospitalizations, represent an innate malformation or a congenital abnormality. Safety Analysis Set included all subjects randomized who received at least one dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Up to Month 27
    End point values
    Canakinumab Placebo Non-responders Part I: Canakinumab Part I: Placebo Part II: Canakinumab Responders Part II: Placebo Responders
    Number of subjects analysed
    7
    7
    20
    15
    14
    2
    Units: subjects
        AEs
    13
    6
    16
    10
    1
    2
        SAEs
    1
    1
    2
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Month 27
    Adverse event reporting additional description
    Safety Analysis Set included all subjects randomized who received at least one dose of the study drug. 2 subjects of the placebo group in Part I received canakinumab at Week 4, as protocol violation, thus, Safety Analysis Set included those additional 2 subjects in the canakinumab group.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Core Study Part I: Canakinumab
    Reporting group description
    Subjects received canakinumab 4 mg/kg up to 300 mg maximum, subcutaneous (SC) injection, once in morning at Baseline (Day 0), Weeks 4, 8, and 12.

    Reporting group title
    Core Study Part I: Placebo
    Reporting group description
    Subjects received placebo, SC injection, once in morning at Baseline (Day 0), Weeks 4, 8, and 12.

    Reporting group title
    Core Study Part II: Canakinumab Responders
    Reporting group description
    Subjects with response (change in DAS score > 1.2 at Week 12) continued to receive canakinumab 4 mg/kg up to 300 mg maximum, SC injection, once in the morning for Weeks 12, 16, and 20.

    Reporting group title
    Core Study Part II: Placebo Responders
    Reporting group description
    SUbjects with response (change in DAS score > 1.2 at Week 12) continued to receive placebo, SC injection, once in morning for Weeks 12, 16, and 20.

    Reporting group title
    Core Study Part II: Placebo Non-responder
    Reporting group description
    Non-responders (change in DAS score ≤ 1.2 at Week 12) who switched to canakinumab were unblinded to receive canakinumab 4 mg/kg up to 300 mg maximum, SC injection, once in the morning at Weeks 12, 16, and 20.

    Reporting group title
    LTE Phase: Canakinumab
    Reporting group description
    Subjects with remission (change in DAS score > 1.2 and no signs of systemic activity for adult-onset Still’s disease at Week 20) received canakinumab 4 mg/kg up to 300 mg maximum, SC injection at Weeks 24 and 28, which was down titrated to 2 mg/kg up to 150 mg maximum if applicable after Week 28 up to Month 27 (Week 117).

    Serious adverse events
    Core Study Part I: Canakinumab Core Study Part I: Placebo Core Study Part II: Canakinumab Responders Core Study Part II: Placebo Responders Core Study Part II: Placebo Non-responder LTE Phase: Canakinumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    1 / 2 (50.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical device removal
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hypotonia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    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
    Cholecystitis acute
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    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
    Hepatotoxicity
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    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
    Musculoskeletal and connective tissue disorders
    Chondromalacia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    Patellofemoral pain syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Core Study Part I: Canakinumab Core Study Part I: Placebo Core Study Part II: Canakinumab Responders Core Study Part II: Placebo Responders Core Study Part II: Placebo Non-responder LTE Phase: Canakinumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 20 (80.00%)
    10 / 15 (66.67%)
    13 / 14 (92.86%)
    2 / 2 (100.00%)
    6 / 7 (85.71%)
    7 / 7 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 15 (13.33%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    0
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    2 / 14 (14.29%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    1
    3
    0
    0
    3
    Injection site rash
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vulva cyst
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Meniscus injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    2 / 14 (14.29%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Cough
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pleurisy
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 15 (20.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
         occurrences all number
    1
    3
    1
    0
    2
    0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Visual impairment
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 15 (13.33%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Aphthous ulcer
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 15 (13.33%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 15 (6.67%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    1
    0
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hepatobiliary disorders
    Primary biliary cholangitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nail dystrophy
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    Rash
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 15 (6.67%)
    2 / 14 (14.29%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    3
    1
    2
    0
    2
    0
    Back pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Osteoporosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pseudarthrosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Still's disease
         subjects affected / exposed
    5 / 20 (25.00%)
    1 / 15 (6.67%)
    2 / 14 (14.29%)
    1 / 2 (50.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    7
    1
    3
    1
    1
    2
    Tenosynovitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infected bite
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 20 (15.00%)
    3 / 15 (20.00%)
    3 / 14 (21.43%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    3 / 7 (42.86%)
         occurrences all number
    3
    3
    5
    0
    1
    6
    Oral herpes
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Periodontitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pertussis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    05 May 2018
    The study terminated prior to the planned completion date due to recruitment issues because of the marketing authorization of the study drug.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination due to recruitment issues as adult-onset Still’s disease is a rare disease.
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