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    Clinical Trial Results:
    An open-label, multicenter, efficacy and safety study of 4-month canakinumab treatment with 5-month follow-up and long-term treatment period in patients with active recurrent or chronic TNF-receptor associated periodic syndrome (TRAPS)

    Summary
    EudraCT number
    		 2010-020061-24
    Trial protocol
    		 IE   GB   IT  
    Global end of trial date
    20 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CACZ885D2203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01242813
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to assess response induced by canakinumab in subjects with active Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS) after 15 days of the first dose.
    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 (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed. Corticosteroids and nonsteroidal anti-inflammatory drugs NSAIDs were allowed as rescue medication during active TRAPS attacks at the discretion of the investigator. Corticosteroids were allowed either as increased corticosteroid maintenance dose or intermittent steroid treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Oct 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 10
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    2
    Children (2-11 years)
    4
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 6 centres in 3 countries.

    Pre-assignment
    Screening details
    		 A total of 29 subjects were screened, out of which 20 were enrolled and exposed to study medication. Nine subjects were considered as screening failures due to unacceptable laboratory value or test procedure results.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Canakinumab
    Arm description
    		 Subjects received body-weight stratified dosage of canakinumab (2 milligram/ kilogram (mg/kg) for subjects ≤ 40 kg or 150 mg for subjects > 40 kg) through subcutaneously (s.c.) route as the starting dose at baseline and monthly for 4 months. The dose was escalated at Day 8 if dose of canakinumab was not sufficient to resolve the qualifying TRAPS flare.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Body weight stratified dose of canakinumab 2 mg/kg or 150 mg injected s.c. at baseline and monthly for 4 months.

    Number of subjects in period 1
    		Canakinumab
    Started
    20
    Completed
    18
    Not completed
    2
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    		 Subjects received body-weight stratified dosage of canakinumab (2 milligram/ kilogram (mg/kg) for subjects ≤ 40 kg or 150 mg for subjects > 40 kg) through subcutaneously (s.c.) route as the starting dose at baseline and monthly for 4 months. The dose was escalated at Day 8 if dose of canakinumab was not sufficient to resolve the qualifying TRAPS flare.

    Reporting group values
    		 Canakinumab Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        Children (2­-11 years)
    		 2 2
        Adolescents (12­-17 years)
    		 4 4
        Adults (18-­64 years)
    		 13 13
        Adults (65-84 years)
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.62 ± 18.362 -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 13 13

    End points

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    End points reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    		 Subjects received body-weight stratified dosage of canakinumab (2 milligram/ kilogram (mg/kg) for subjects ≤ 40 kg or 150 mg for subjects > 40 kg) through subcutaneously (s.c.) route as the starting dose at baseline and monthly for 4 months. The dose was escalated at Day 8 if dose of canakinumab was not sufficient to resolve the qualifying TRAPS flare.

    Primary: Percentage of subjects with complete or almost complete response at Day 15

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    End point title
    		 Percentage of subjects with complete or almost complete response at Day 15 [1]
    End point description
    Complete response was defined as clinical remission (Physician’s Global Assessment of TRAPS activity absent or minimal) and serological remission (C reactive protein (CRP) and/or Serum amyloid A protein (SAA) less than 10 milligram per litre (mg/L)). Almost complete response was defined as clinical remission and a partial serological remission (equal to or more than 70% reduction of baseline (CRP) and/or (SAA)}. The primary analysis was performed on the Full Analysis Set (FAS), defined as all subjects who received at least one dose of study treatment and had at least one post-baseline assessment for primary efficacy.
    End point type
    Primary
    End point timeframe
    Day 15
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Percentage of subjects
        number (confidence interval 95%)
    95 (75.1 to 99.9)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with complete or almost complete response at Day 8

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    End point title
    		 Percentage of subjects with complete or almost complete response at Day 8
    End point description
    Complete response was defined as clinical remission (Physician’s Global Assessment of TRAPS activity absent or minimal) and serological remission (CRP and/or SAA less than 10 mg/L). Almost complete response was defined as clinical remission and a partial serological remission (equal to or more than 70% reduction of baseline (CRP) and/or (SAA)). The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    Day 8
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Percentage of subjects
        number (confidence interval 95%)
    80 (56.3 to 94.3)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with complete clinical remission at Day 8 and 15

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    End point title
    		 Percentage of subjects with complete clinical remission at Day 8 and 15
    End point description
    Complete clinical remission was defined as Physician’s Global Assessment of TRAPS activity to be absent or minimal (1). TRAPS associated clinical signs and symptoms were assessed by the investigator at every visit on a 5-point scale: 0 = Absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    Day 8 and 15
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Percentage of subjects
    number (confidence interval 95%)
        Day 8
    90 (68.3 to 98.8)
        Day 15
    100 (83.2 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with target levels of C-reactive protein (CRP) and Serum amyloid A protein (SAA) at Day 8 and 15

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    End point title
    		 Percentage of subjects with target levels of C-reactive protein (CRP) and Serum amyloid A protein (SAA) at Day 8 and 15
    End point description
    The CRP and SAA were used as inflammatory markers. The target level concentration was equal to or less than 10 mg/L. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    Day 8 and 15
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Percentage of subjects
    number (confidence interval 95%)
        Day 8
    35 (15.4 to 59.2)
        Day 15
    60 (36.1 to 80.9)
    No statistical analyses for this end point

    Secondary: Time to physician’s assessed clinical remission

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    End point title
    		 Time to physician’s assessed clinical remission
    End point description
    Time period for complete remission after initial canakinumab treatment as assessed by subjects was defined as a Physician’s Global Assessment of TRAPS symptoms of scale 1 or less. The Patient’s Global Assessment was based on a 5-point scale: 0 = None/absent (no) ; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    From start of treatment to Day 15
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Days
        median (confidence interval 95%)
    4 (3 to 8)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with complete or almost complete response at Day 15 after receiving additional dose at Day 8

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    End point title
    		 Percentage of subjects with complete or almost complete response at Day 15 after receiving additional dose at Day 8
    End point description
    Subjects who had not achieved a complete response at Day 8 were given an additional dose of canakinumab. Complete response was defined as clinical remission (Physician’s Global Assessment of TRAPS activity absent or minimal) and serological remission (CRP and/or SAA less than 10 mg/L). Almost complete response was defined as clinical remission and a partial serological remission (equal to or more than 70% reduction of baseline (CRP) and/or (SAA)). The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Canakinumab
    Number of subjects analysed
    4 [2]
    Units: Percentage of subjects
        number (confidence interval 95%)
    100 (39.8 to 100)
    Notes
    [2] - Only 4 subjects out of 20 had not achieved complete or almost complete response at Day 8.
    No statistical analyses for this end point

    Secondary: Time to patient’s assessed clinical remission

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    End point title
    		 Time to patient’s assessed clinical remission
    End point description
    Time period for complete remission after initial canakinumab treatment as assessed by subjects was defined as a Patient’s Global Assessment of TRAPS symptoms of scale 1 or less. The Patient’s Global Assessment was based on a 5-point scale: 0 = None/absent (no) ; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Days
        median (confidence interval 95%)
    3 (1 to 11)
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in C-reactive protein (CRP) and Serum amyloid A (SAA) concentration to end of study

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    End point title
    		 Percentage change from baseline in C-reactive protein (CRP) and Serum amyloid A (SAA) concentration to end of study
    End point description
    The CRP and SAA were used as inflammatory markers. The target level concentration was equal to or less than 10 mg/L. Negative percent change in concentration of inflammatory markers indicated improvement. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline to end of study
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Percent change
    median (full range (min-max))
        CRP
    -92.19 (-99 to 43.6)
        SAA
    -96.54 (-99.8 to 68.3)
    No statistical analyses for this end point

    Secondary: Number of subjects with defined grades for skin rash, eye manifestations, extremity pain and abdominal pain

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    End point title
    		 Number of subjects with defined grades for skin rash, eye manifestations, extremity pain and abdominal pain
    End point description
    TRAPS signs and symptoms were assessed in 4 key categories: skin disease (skin rash), eye manifestations, extremity pain (musculoskeletal), and abdominal pain. Subjects were assessed for TRAPS associated signs and symptoms a 5-point Physician’s global assessment scale: None/absent (no); 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe . The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    End of study
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Number of subjects
    number (not applicable)
        Skin rash absent
    19
        Skin rash minimal
    1
        Skin rash mild
    0
        Skin rash moderate
    0
        Skin rash severe
    0
        Eye manifestations absent
    18
        Eye manifestations minimal
    2
        Eye manifestations mild
    0
        Eye manifestations moderate
    0
        Eye manifestations severe
    0
        Extremity pain absent
    18
        Extremity pain minimal
    1
        Extremity pain mild
    1
        Extremity pain moderate
    0
        Extremity pain severe
    0
        Abdominal pain absent
    19
        Abdominal pain minimal
    1
        Abdominal pain mild
    0
        Abdominal pain moderate
    0
        Abdominal pain severe
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects with defined grades in physician’s global assessment score

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    End point title
    		 Percentage of subjects with defined grades in physician’s global assessment score
    End point description
    Subjects were assessed based on Physician’s Global Assessment on 5-point scale for TRAPS associated signs and symptoms as: 0 = None/absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    End of study
    End point values
    		 Canakinumab
    Number of subjects analysed
    18 [3]
    Units: Percent
    number (not applicable)
        None (0)
    84.2
        Minimal (1)
    10.5
        Mild (2)
    0
        Moderate (3)
    0
        Severe (4)
    0
    Notes
    [3] - Total number of subjects with non-missing assessment at the specified time point.
    No statistical analyses for this end point

    Secondary: Percentage of subjects with defined grades in patient’s global assessment score

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    End point title
    		 Percentage of subjects with defined grades in patient’s global assessment score
    End point description
    Subjects assessed the disease condition based on a 5-point Patient’s global assessment scale for were assessed based on TRAPS associated signs and symptoms as: 0 = None/absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    End of follow-up period
    End point values
    		 Canakinumab
    Number of subjects analysed
    12 [4]
    Units: Percent
    number (not applicable)
        Absent
    41.7
        Minimal
    33.3
        Mild
    8.3
        Moderate
    16.7
        Severe
    0
    Notes
    [4] - Total number of subjects with non-missing assessment at the specified time point.
    No statistical analyses for this end point

    Secondary: Percentage of relapsed subjects

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    End point title
    		 Percentage of relapsed subjects
    End point description
    Relapse was defined as a Physician’s Global Assessment score of 2 (and an increase of at least 1 point compared to Day 15) and CRP and/or SAA equal to or more than 30 mg/L representing a 30% increase from Day 15. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    At Day 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449, 533, 561, 589, 617, 645, 673, 729, 785, 841, 897, 925 and 953
    End point values
    		 Canakinumab
    Number of subjects analysed
    20 [5]
    Units: Percentage of subjects
    number (confidence interval 95%)
        Day 15
    0 (0.1 to 27.3)
        Day 29
    0 (0 to 0)
        Day 57
    0 (0 to 0)
        Day 85
    5 (0 to 0)
        Day 113
    0 (0.1 to 24.9)
        Day 141
    10 (0 to 0)
        Day 169
    10 (1.3 to 33.1)
        Day 197
    35 (1.9 to 45.5)
        Day 225
    10 (30.8 to 89.1)
        Day 253
    10 (6.8 to 93.2)
        Day 281
    0 (1.2 to 31.7)
        Day 309
    10 (0 to 0)
        Day 337
    5 (1.2 to 31.7)
        Day 365
    0 (0.1 to 24.9)
        Day 393
    0 (0 to 0)
        Day 421
    5 (0 to 0)
        Day 449
    0 (0 to 0)
        Day 477
    5 (0.1 to 26)
        Day 505
    0 (0 to 0)
        Day 533
    0 (0 to 0)
        Day 561
    0 (0 to 0)
        Day 589
    0 (0 to 0)
        Day 617
    0 (0 to 0)
        Day 645
    5 (0 to 0)
        Day 673
    15 (0.5 to 71.6)
        Day 701
    0 (3.6 to 41.4)
        Day 729
    5 (0.1 to 27.3)
        Day 757
    0 (0 to 0)
        Day 785
    0 (0 to 0)
        Day 813
    0 (0 to 0)
        Day 841
    10 (1.4 to 34.7)
        Day 869
    0 (0 to 0)
        Day 897
    10 (1.4 to 34.7)
        Day 925
    0 (0 to 0)
        End of Study (Day 953)
    0 (0 to 0)
    Notes
    [5] - Confidence Interval value (0.0) denotes that value was not applicable as number of subjects was 0
    No statistical analyses for this end point

    Secondary: Time to relapse after last dose of canakinumab

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    End point title
    		 Time to relapse after last dose of canakinumab
    End point description
    Relapse was defined as a Physician’s Global Assessment score of 2 (and an increase of at least 1 point compared to Day 15) and CRP and/or SAA equal to or more than 30 mg/L representing a 30% increase from Day 15. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Day 15 to Day 120 (4 months)
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Days
        median (confidence interval 95%)
    91.5 (65 to 117)
    No statistical analyses for this end point

    Secondary: Percentage of subjects who relapsed and took rescue medication

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    End point title
    		 Percentage of subjects who relapsed and took rescue medication
    End point description
    Subjects who relapsed after the last dose of canakinumab and received either corticosteroid treatment or NSAID or both corticosteroid treatment and NSAID as rescue medication. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    Day 15 to Day 120 (4 months)
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Percentage of subjects
    number (confidence interval 95%)
        Corticosteroid
    25 (8.7 to 49.1)
        NSAID
    25 (8.7 to 49.1)
        Both corticosteroid and NSAID
    10 (1.2 to 31.7)
    No statistical analyses for this end point

    Secondary: Serum concentration of canakinumab

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    End point title
    		 Serum concentration of canakinumab
    End point description
    Canakinumab concentrations in serum were assessed for evaluating pharmacokinetics (PK) of the drug. The analysis was performed on the FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    At Day 3, 8, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449, 533, 561, 589, 617, 645, 673, 729, 785, 841, 897, 925 and 953
    End point values
    		 Canakinumab
    Number of subjects analysed
    20 [6]
    Units: microgram(s)/millilitre
    arithmetic mean (standard deviation)
        Day 3 (n=20)
    12.737 ± 5.3158
        Day 8 (n=19)
    13.874 ± 4.5851
        Day 15 (n=19)
    13.609 ± 5.5868
        Day 29 (n=20)
    9.911 ± 4.2272
        Day 57 (n=20)
    13.605 ± 5.4975
        Day 85 (n=20)
    15.291 ± 6.4353
        Day 113 (n=20)
    15.837 ± 6.828
        Day 141 (n=17)
    8.799 ± 3.1486
        Day 169 (n=12)
    5.655 ± 2.2158
        Day 197 (n=8)
    3.906 ± 1.6446
        Day 225 (n=2)
    2.725 ± 1.2799
        Day 253 (n=9)
    10.261 ± 7.9592
        Day 281 (n=20)
    9.759 ± 4.6194
        Day 309 (n=13)
    13.088 ± 4.6648
        Day 337 (n=11)
    13.182 ± 5.464
        Day 365 (n=9)
    15.531 ± 6.7944
        Day 393 (n=2)
    20.95 ± 1.6263
        Day 421 (n=2)
    20.9 ± 2.9698
        Day 449 (n=17)
    17.319 ± 6.496
        Day 533 (n=1)
    18.4 ± 0
        Day 561 (n=4)
    15.55 ± 2.2128
        Day 589 (n=5)
    16.48 ± 3.8134
        Day 617 (n=17)
    14.124 ± 5.8931
        Day 645 (n=1)
    7.45 ± 0
        Day 673 (n=5)
    9.802 ± 4.6757
        Day 729 (n=5)
    8.912 ± 3.4413
        Day 785 (n=18)
    7.757 ± 2.2948
        Day 841 (n=4)
    8.528 ± 2.112
        Day 897 (n=9)
    8.157 ± 2.6782
        Day 925 (n=3)
    10.527 ± 7.4405
        Day 953 (n=10)
    9.56 ± 2.9375
    Notes
    [6] - Standard deviation value (0.0) denotes that the dispersion value was not applicable.
    No statistical analyses for this end point

    Secondary: Serum concentration of total Interleukin-1β antibody (IL-1β)

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    End point title
    		 Serum concentration of total Interleukin-1β antibody (IL-1β)
    End point description
    Pharmacodynamics of canakinumab was assessed by total IL-1β (sum of free and bound canakinumab) concentration, determined in serum by means of competitive ELISA assay with limit of detection at 0.25 picogram/millilitre (pg/mL). The analysis was performed on the FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Day 1, 3, 8, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449, 533, 561, 589, 617, 645, 673, 729, 785, 841, 897, 925 and 953
    End point values
    		 Canakinumab
    Number of subjects analysed
    20 [7]
    Units: Picogram(s)/millilitre
    arithmetic mean (standard deviation)
        Day 3 (n=20)
    12.616 ± 20.441
        Day 8 (n=19)
    16.811 ± 20.237
        Day 15 (n=19)
    10.662 ± 7.6915
        Day 29 (n=20)
    9.342 ± 5.1266
        Day 57 (n=20)
    10.701 ± 4.5329
        Day 85 (n=20)
    11.212 ± 4.1552
        Day 113 (n=20)
    14.401 ± 5.491
        Day 141 (n=17)
    10.779 ± 4.1092
        Day 169 (n=12)
    10.912 ± 8.2431
        Day 197 (n=8)
    30.098 ± 41.158
        Day 225 (n=2)
    3.52 ± 0.9475
        Day 253 (n=9)
    25.002 ± 28.274
        Day 281 (n=20)
    13.722 ± 7.5574
        Day 309 (n=13)
    22.478 ± 16.688
        Day 337 (n=11)
    19.904 ± 10.789
        Day 365 (n=9)
    16.338 ± 5.8318
        Day 393 (n=2)
    27.6 ± 10.182
        Day 421 (n=2)
    30.65 ± 12.94
        Day 449 (n=17)
    17.723 ± 8.8367
        Day 533 (n=1)
    25.2 ± 0
        Day 561 (n=4)
    15.008 ± 5.4952
        Day 589 (n=5)
    16.99 ± 5.2212
        Day 617 (n=17)
    14.34 ± 6.1663
        Day 645 (n=1)
    16 ± 0
        Day 673 (n=5)
    15.296 ± 11.908
        Day 729 (n=5)
    16.702 ± 12.386
        Day 785 (n=18)
    12.698 ± 6.0688
        Day 841 (n=4)
    12.478 ± 6.9548
        Day 897 (n=9)
    12.331 ± 8.032
        Day 925 (n=3)
    15.033 ± 1.7502
        Day 953 (n=10)
    11.701 ± 7.9172
    Notes
    [7] - Standard deviation value (0.0) denotes that the dispersion value was not applicable.
    No statistical analyses for this end point

    Secondary: Number of subjects exhibiting Anti-canakinumab antibodies at any visit

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    End point title
    		 Number of subjects exhibiting Anti-canakinumab antibodies at any visit
    End point description
    Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system. The analysis was performed on the FAS population.
    End point type
    Secondary
    End point timeframe
    From Day 1 to end of study
    End point values
    		 Canakinumab
    Number of subjects analysed
    20
    Units: Number of subjects
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    		 Subjects received body-weight stratified dosage of canakinumab (2 mg/kg for subjects ≤ 40 kg or 150 mg for subjects > 40 kg) through s.c. route as the starting dose at baseline and monthly for 4 months. The dose was escalated at Day 8 if dose of canakinumab was not sufficient to resolve the qualifying TRAPS flare.

    Serious adverse events
    		 Canakinumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 20 (35.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Meniscus injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Canakinumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 20 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    6
    Phlebitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Surgical and medical procedures
    Nasal septal operation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin neoplasm excision
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tooth extraction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    11
    Condition aggravated
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Chest pain
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    5
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    10 / 20 (50.00%)
         occurrences all number
    25
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast cyst
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Breast mass
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dysmenorrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    10
    Dysphonia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Epistaxis
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Nasal congestion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    11 / 20 (55.00%)
         occurrences all number
    19
    Rhinitis allergic
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Rhinorrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Sneezing
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Blood iron decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood triglycerides increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Occult blood positive
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Joint dislocation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Laceration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Muscle rupture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Muscle strain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skeletal injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Dizziness
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    11 / 20 (55.00%)
         occurrences all number
    25
    Hypoaesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Presyncope
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Sinus headache
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Anaemia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear pain
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Eye disorders
    Chalazion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dry eye
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye pruritus
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Eye swelling
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eyelid oedema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ocular hyperaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Periorbital oedema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    11 / 20 (55.00%)
         occurrences all number
    28
    Abdominal pain upper
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Constipation
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Dental caries
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    11
    Haemorrhoids
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Haematochezia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    7
    Toothache
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Actinic keratosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dermal cyst
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ingrown hair
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    5
    Rash erythematous
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin discolouration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Polyuria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Strangury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    10
    Back pain
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    8
    Flank pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Muscle spasms
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Musculoskeletal pain
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    8
    Myalgia
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    8
    Neck pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Osteoporosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Cystitis
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Ear infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Enterobiasis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Haemorrhoid infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gingivitis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Fungal skin infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    8
    Laryngitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Onychomycosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    12 / 20 (60.00%)
         occurrences all number
    23
    Oral herpes
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Pharyngitis
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    6
    Rhinitis
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    16
    Sinusitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tinea infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tooth abscess
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    9
    Urinary tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Urinary tract infection viral
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Viral infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolic acidosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Iron deficiency
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vitamin D deficiency
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2010
    Updated the volume of blood withdrawal for biomarker component, protocol for soluble plasma protein marker sample collection and information regarding subject diaries.
    10 Nov 2011
    Site monitoring and collection of efficacy and safety data during the 24 months of continued treatment were implemented after clarification on post follow-up period. Optimized PK/PD based dosing schedule was implemented, updated the duration of the follow-up period for actual maximum duration of the withdrawal period (5 months) and clarified almost complete response and relapse endpoints.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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