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    Clinical Trial Results:
    A Multi-Center, Open label, Repeated Dose Range Finding Study to Evaluate the Safety, Tolerability, Immunogenicity, Pharmacokinetics and Efficacy of an Anti-IL-1β; Monoclonal Antibody ACZ885 Given Subcutaneously in Pediatric Subjects with Active Systemic Juvenile Idiopathic Arthritis (SJIA)

    Summary
    EudraCT number
    		 2006-001834-42
    Trial protocol
    		 FR   IT   GB  
    Global end of trial date
    09 Mar 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CACZ885A2203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    09 Mar 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to evaluate the safety and efficacy of canakinumab after subcutaneous (s.c.) administration in paediatric subjects with active Systemic Juvenile Idiopathic Arthritis (SJIA) according to American College of Rheumatology (ACR). The study also assessed the pharmacokinetics (PK) and the relationship between PK and pharmacodynamics (PD) to derive a dosage regimen for phase III studies.
    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. Subjects defined as non-responder were provided with rescue medication. A rescue dose of increased prednisone, methotrexate, cyclosporine, or other disease-modifying antirheumatic drugs (DMARDS), possibly anakinra on which the subjects agreed, was initiated at the discretion of the investigator.
    Background therapy
    		 Subjects remained on their current medication and non-drug therapies during the study. Treatment with any biologics was not allowed during the entire study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Dec 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Italy: 7
    Worldwide total number of subjects
    26
    EEA total number of subjects
    26
    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)
    19
    Adolescents (12-17 years)
    6
    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 4 centres in 4 countries.

    Pre-assignment
    Screening details
    		 A total of 26 subjects were enrolled into Stage I of the study, out of which 3 subjects entered the study twice. So, in actual 23 subjects were enrolled. Out of 23, 11 subjects who responded during Stage I were enrolled into Stage II.

    Period 1
    Period 1 title
    Stage I
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was open label, hence no blinding was performed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Canakinumab 0.5 mg/kg
    Arm description
    		 Subjects were injected with canakinumab as 0.5 milligrams/kilograms (mg/kg). Subjects were re-dosed up to a maximum dose of 1 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received canakinumab s.c. injections (0.5 mg/kg, or 1.5 mg/kg, or 4.5 mg/kg) and re-dosed up to maximum of 1 mg/kg, 3 mg/kg and 9 mg/kg respectively based on the cohort.

    Arm title
    		 Canakinumab 1.5 mg/kg
    Arm description
    		 Subjects were injected with canakinumab as 1.5 mg/kg. Subjects were re-dosed up to a maximum dose of 3 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received canakinumab s.c. injection of 1.5 mg/kg and re-dosed up to maximum of 3 mg/kg.

    Arm title
    		 Canakinumab 4.5 mg/kg
    Arm description
    		 Subjects were injected with canakinumab as 4.5 mg/kg. Subjects were re-dosed up to a maximum dose of 9 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received canakinumab s.c. injection of 4.5 mg/kg and re-dosed up to maximum of 9 mg/kg.

    Number of subjects in period 1
    		Canakinumab 0.5 mg/kg Canakinumab 1.5 mg/kg Canakinumab 4.5 mg/kg
    Started
    5
    10
    11
    Completed
    4
    7
    9
    Not completed
    1
    3
    2
         Consent withdrawn by subject
    -
    -
    1
         Unsatisfactory therapeutic effect
    -
    3
    1
         'Unsatisfactory therapeutic effect '
    1
    -
    -
    Period 2
    Period 2 title
    Stage II
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was open label, hence no blinding was performed.

    Arms
    Arm title
    		 Canakinumab (Stage II)
    Arm description
    		 All subjects who responded in Stage I were included in Stage II. Subjects received a fixed dose of 4 mg/kg, up to a maximum single dose of 300 mg s.c of canakinumab every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received canakinumab s.c. fixed dose of 4 mg/kg, up to a maximum single dose of 300 mg every 4 weeks.

    Number of subjects in period 2 [1]
    		Canakinumab (Stage II)
    Started
    11
    Completed
    11
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of 17 subjects who completed the Stage I, only 11 subjects were enrolled in Stage II.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Canakinumab 0.5 mg/kg
    Reporting group description
    		 Subjects were injected with canakinumab as 0.5 milligrams/kilograms (mg/kg). Subjects were re-dosed up to a maximum dose of 1 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Reporting group title
    Canakinumab 1.5 mg/kg
    Reporting group description
    		 Subjects were injected with canakinumab as 1.5 mg/kg. Subjects were re-dosed up to a maximum dose of 3 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Reporting group title
    Canakinumab 4.5 mg/kg
    Reporting group description
    		 Subjects were injected with canakinumab as 4.5 mg/kg. Subjects were re-dosed up to a maximum dose of 9 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Reporting group values
    		 Canakinumab 0.5 mg/kg Canakinumab 1.5 mg/kg Canakinumab 4.5 mg/kg Total
    Number of subjects
    		 5 10 11 26
    Age categorical
    Units: Subjects
        4 - 19 years
    		 5 10 11 26
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11 ( 2.2 ) 10 ( 4.7 ) 9 ( 3.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4 6 14
        Male
    		 1 6 5 12

    End points

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    End points reporting groups
    Reporting group title
    Canakinumab 0.5 mg/kg
    Reporting group description
    		 Subjects were injected with canakinumab as 0.5 milligrams/kilograms (mg/kg). Subjects were re-dosed up to a maximum dose of 1 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Reporting group title
    Canakinumab 1.5 mg/kg
    Reporting group description
    		 Subjects were injected with canakinumab as 1.5 mg/kg. Subjects were re-dosed up to a maximum dose of 3 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Reporting group title
    Canakinumab 4.5 mg/kg
    Reporting group description
    		 Subjects were injected with canakinumab as 4.5 mg/kg. Subjects were re-dosed up to a maximum dose of 9 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.
    Reporting group title
    Canakinumab (Stage II)
    Reporting group description
    		 All subjects who responded in Stage I were included in Stage II. Subjects received a fixed dose of 4 mg/kg, up to a maximum single dose of 300 mg s.c of canakinumab every 4 weeks.

    Subject analysis set title
    Canakinumab (Stage I)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects during Stage I were injected with canakinumab in 3 cohorts; Cohort I as 0.5 mg/kg, Cohort II as 1.5 mg/kg, Cohort III 4.5 mg/kg. Subjects were re-dosed up to a maximum dose of 1 mg/kg, 3 mg/kg and 9 mg/kg in Cohort I, II and III, respectively if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Primary: Number of subjects with adverse events and serious adverse events

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    End point title
    		 Number of subjects with adverse events and serious adverse events [1]
    End point description
    Adverse events (AEs) were defined as any unfavourable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalisation, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. The analysis was performed in the Safety Set (SAF) population, defined as all subjects who received at least one dose of study drug with at least one post-baseline safety assessment.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 928 (End of study)
    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 0.5 mg/kg Canakinumab 1.5 mg/kg Canakinumab 4.5 mg/kg Canakinumab (Stage II)
    Number of subjects analysed
    5
    10
    11
    11
    Units: Number of subjects
        AEs
    5
    10
    10
    11
        SAEs
    0
    6
    4
    3
    No statistical analyses for this end point

    Primary: Number of subjects with anti-canakinumab antibodies at any visit

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    End point title
    		 Number of subjects with anti-canakinumab antibodies at any visit [2]
    End point description
    Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system. The analysis was performed in all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 918 (End of study)
    Notes
    [2] - 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 0.5 mg/kg Canakinumab 1.5 mg/kg Canakinumab 4.5 mg/kg Canakinumab (Stage II)
    Number of subjects analysed
    5
    10
    11
    11
    Units: Number of subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of responders to treatment in Stage I

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    End point title
    		 Percentage of responders to treatment in Stage I [3]
    End point description
    Adapted ACR Paediatric 30/50/70/90/100 criteria was assessed based on following 7 variables: 1. Physician’s Global Assessment on a 0-100 millimetres (mm) visual analog scale (VAS); 2. Patient Global Assessment on a 0-100 mm VAS in the Child Health Assessment Questionnaire (CHAQ); 3. Functional ability; 4. Joints count with active arthritis; 5. Joints count with limitation of motion; 6. Laboratory measure of C-reactive protein (CRP) and 7. Absence of intermittent fever (i.e. body temperature ≤ 38°C) due to SJIA during the preceding week. Response was defined as more than or equal to (≥) 30%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 7, with no more than one variable 1-6 worsening by more than 30%. The analysis was performed on Full analysis set (FAS), defined as all randomized subjects who received at least one dose of study drug. The ‘n’ signifies those subject evaluable for this measure at specified time point for each group, respectively.
    End point type
    Primary
    End point timeframe
    Day 15
    Notes
    [3] - 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 0.5 mg/kg Canakinumab 1.5 mg/kg Canakinumab 4.5 mg/kg
    Number of subjects analysed
    5
    10
    11
    Units: Percentage of subjects
        number (not applicable)
    40
    80
    46
    No statistical analyses for this end point

    Primary: Time to relapse after last dose of canakinumab

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    End point title
    		 Time to relapse after last dose of canakinumab [4]
    End point description
    Relapse according to the modified ACR paediatric criteria for flare was defined as subjects with more than or equal to (≥) 30% worsening in at least 3 of 6 variables, ≥ 30% improvement in not more than 1 of the 6 variables, ≥ 2 cm of worsening in Physician or Parent Global Assessment, worsening in ≥ 2 joints and CRP > 30 mg/L in responders. Time to relapse was defined as reappearance of fever not due to infection and/or symptoms that are expression of systemic manifestation, and increase of CRP more than 30 mg/L. Subjects who withdrew before the end of Stage I or before the end of Stage II and subjects who had not relapsed before the end of the study were not included for analysis. The analysis was performed in all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Day 43 up to Day 928 (End of study)
    Notes
    [4] - 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 (Stage I)
    Number of subjects analysed
    23
    Units: Days
    median (confidence interval 95%)
        Dose group <3 mg/kg
    56.11 (31.46 to 100.49)
        Dose group 3 mg/kg
    99.98 (58.1 to 172.03)
        Dose group 4 mg/kg
    90.47 (54.74 to 149.52)
        Dose group >4 mg/kg
    71.52 (41 to 124.75)
    No statistical analyses for this end point

    Primary: Area under the concentration-time curve from time zero to infinity (AUC 0-inf) of canakinumab

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    End point title
    		 Area under the concentration-time curve from time zero to infinity (AUC 0-inf) of canakinumab [5]
    End point description
    The area under the concentration-time curve from time zero to infinity (AUC 0-inf) was used to measure the total drug exposure over time. The analysis was performed in all subjects with evaluable/complete PK data.
    End point type
    Primary
    End point timeframe
    Pre-dose, Day 2 (Periods 1 and 2), Day 3 (Periods 1 and 2), Day 8 (Periods 1 and 2), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 113, Day 127, Day 141 and Day 155
    Notes
    [5] - 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 (Stage I)
    Number of subjects analysed
    21
    Units: Day*microgram/millilitre/milligram
        arithmetic mean (standard deviation)
    4.395 ( 1.4363 )
    No statistical analyses for this end point

    Primary: Maximum Plasma Concentration (Cmax) of canakinumab

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    End point title
    		 Maximum Plasma Concentration (Cmax) of canakinumab [6]
    End point description
    Maximum plasma concentration (Cmax) was defined as the peak plasma level of canakinumab, derived from plasma concentration-time data of canakinumab. The analysis was performed in all subjects with evaluable/complete PK data.
    End point type
    Primary
    End point timeframe
    Pre-dose, Day 2 (Periods 1 and 2), Day 3 (Periods 1 and 2), Day 8 (Periods 1 and 2), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 113, Day 127, Day 141 and Day 155
    Notes
    [6] - 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 (Stage I)
    Number of subjects analysed
    6
    Units: Microgram/millilite/milligram
        arithmetic mean (standard deviation)
    0.1678 ( 0.03056 )
    No statistical analyses for this end point

    Primary: Time to maximum plasma concentration (Tmax) of canakinumab

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    End point title
    		 Time to maximum plasma concentration (Tmax) of canakinumab [7]
    End point description
    Tmax was defined as the time taken to reach the maximum plasma concentration of canakinumab. The analysis was performed in all subjects with evaluable/complete PK data.
    End point type
    Primary
    End point timeframe
    Pre-dose, Day 2 (Periods 1 and 2), Day 3 (Periods 1 and 2), Day 8 (Periods 1 and 2), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 113, Day 127, Day 141 and Day 155
    Notes
    [7] - 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 (Stage I)
    Number of subjects analysed
    6
    Units: Day
        arithmetic mean (standard deviation)
    2.62 ( 2.0797 )
    No statistical analyses for this end point

    Primary: Total body clearance (CL/F) of canakinumab from serum

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    End point title
    		 Total body clearance (CL/F) of canakinumab from serum [8]
    End point description
    Clearance from serum (CL/F) was defined as the apparent body clearance of canakinumab from the serum when the systemic availability was unknown. The analysis was performed in all subjects with evaluable/complete PK data.
    End point type
    Primary
    End point timeframe
    Pre-dose, Day 2 (Periods 1 and 2), Day 3 (Periods 1 and 2), Day 8 (Periods 1 and 2), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 113, Day 127, Day 141 and Day 155
    Notes
    [8] - 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 (Stage I)
    Number of subjects analysed
    21
    Units: Millilitre(s)/day
        arithmetic mean (standard deviation)
    256.4 ( 99.374 )
    No statistical analyses for this end point

    Primary: Apparent volume of distribution (Vz/F) of canakinumab during terminal phase

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    End point title
    		 Apparent volume of distribution (Vz/F) of canakinumab during terminal phase [9]
    End point description
    The volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. The analysis was performed in all subjects with evaluable/complete PK data.
    End point type
    Primary
    End point timeframe
    Pre-dose, Day 2 (Periods 1 and 2), Day 3 (Periods 1 and 2), Day 8 (Periods 1 and 2), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 113, Day 127, Day 141 and Day 155
    Notes
    [9] - 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 (Stage I)
    Number of subjects analysed
    21
    Units: Millilitre(s)
        arithmetic mean (standard deviation)
    5941 ( 2541.3 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects with inactive disease at Day 15

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    End point title
    		 Percentage of subjects with inactive disease at Day 15
    End point description
    Inactive disease was defined as absence of active joints arthritis, no fever (body temperature ≤ 37.5°C), absence of rheumatoid rash, serositis, splenomegaly, hepatomegaly or lymphadenopathy; normal ESR and CRP; and no disease activity (value <= 10 mm) for Physician’s Global Assessment on a 10 cm VAS (0 cm= no disease activity to 10 cm= very severe disease activity). The analysis was performed in all subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Canakinumab (Stage I)
    Number of subjects analysed
    22
    Units: Percentage of subjects
        number (not applicable)
    18.2
    No statistical analyses for this end point

    Secondary: Percentage of subjects able to taper or discontinue steroids from baseline to end of study

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    End point title
    		 Percentage of subjects able to taper or discontinue steroids from baseline to end of study
    End point description
    The ability to taper oral steroids was defined as if dose was reduced from start of baseline to end of study, while maintaining a minimum adapted ACR 30 paediatric criterion (defined as improvement from baseline of ≥ 30% in at least 3 of the 6 response variables of adapted ACR paediatric criteria; no intermittent fever in the preceding week and no more than one of the first 6 response variables worsening by more than 30%). The analysis was performed in all subjects who received at least one dose of study drug. Here, "Number of subjects analysed" were subjects who were responders at the end of study.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 928 (End of study)
    End point values
    		 Canakinumab 0.5 mg/kg Canakinumab 1.5 mg/kg Canakinumab 4.5 mg/kg
    Number of subjects analysed
    2
    7
    10
    Units: Percentage of subjects
    number (not applicable)
        Steroids tapered
    1
    3
    7
        Steroids discontinued
    0
    2
    3
    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
    13.0
    Reporting groups
    Reporting group title
    Canakinumab 0.5 mg/kg
    Reporting group description
    		 Subjects were injected with canakinumab as 0.5 milligrams/kilograms (mg/kg). Subjects were re-dosed up to a maximum dose of 1 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Reporting group title
    Canakinumab (Stage II)
    Reporting group description
    		 All subjects who responded in Stage I were included in Stage II. Subjects received a fixed dose of 4 mg/kg, up to a maximum single dose of 300 mg s.c of canakinumab every 4 weeks.

    Reporting group title
    Canakinumab (Stage I)
    Reporting group description
    		 Subjects during Stage I were injected with canakinumab in 3 cohorts; Cohort I as 0.5 mg/kg, Cohort II as 1.5 mg/kg, Cohort III 4.5 mg/kg. Subjects were re-dosed up to a maximum dose of 1 mg/kg, 3 mg/kg and 9 mg/kg in Cohort I, II and III, respectively if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Reporting group title
    Canakinumab 1.5 mg/kg
    Reporting group description
    		 Subjects were injected with canakinumab as 1.5 mg/kg. Subjects were re-dosed up to a maximum dose of 3 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Reporting group title
    Canakinumab 4.5 mg/kg
    Reporting group description
    		 Subjects were injected with canakinumab as 4.5 mg/kg. Subjects were re-dosed up to a maximum dose of 9 mg/kg if no measurable improvement was observed within 48 hours of first dose every 4 weeks.

    Serious adverse events
    		 Canakinumab 0.5 mg/kg Canakinumab (Stage II) Canakinumab (Stage I) Canakinumab 1.5 mg/kg Canakinumab 4.5 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 11 (27.27%)
    10 / 23 (43.48%)
    6 / 10 (60.00%)
    4 / 11 (36.36%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal erosion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    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
    Colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    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
    Juvenile arthritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Canakinumab 0.5 mg/kg Canakinumab (Stage II) Canakinumab (Stage I) Canakinumab 1.5 mg/kg Canakinumab 4.5 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    11 / 11 (100.00%)
    20 / 23 (86.96%)
    9 / 10 (90.00%)
    9 / 11 (81.82%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Histiocytosis haematophagic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Melanocytic naevus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Skin papilloma
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Drug intolerance
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Feeling hot
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Injection site urticaria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    2
    0
    1
    Irritability
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 11 (18.18%)
    6 / 23 (26.09%)
    2 / 10 (20.00%)
    3 / 11 (27.27%)
         occurrences all number
    1
    3
    8
    4
    3
    Thirst
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Penis disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 11 (36.36%)
    5 / 23 (21.74%)
    2 / 10 (20.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    4
    5
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Painful respiration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Pharyngeal erythema
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 11 (9.09%)
    3 / 23 (13.04%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    2
    6
    4
    0
    Pharyngeal hypertrophy
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    4
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Tonsillar disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    2 / 10 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    7
    7
    0
    Psychiatric disorders
    Fear
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Investigations
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    Excoriation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Joint sprain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Scratch
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    Cardiac disorders
    Extrasystoles
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    6 / 23 (26.09%)
    4 / 10 (40.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    11
    8
    3
    Hypersomnia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    3
    2
    0
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Eye pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Myopia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    8 / 23 (34.78%)
    5 / 10 (50.00%)
    4 / 11 (36.36%)
         occurrences all number
    0
    4
    14
    8
    6
    Abdominal discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 11 (18.18%)
    3 / 23 (13.04%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    3
    1
    1
    Anal fissure
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 11 (27.27%)
    4 / 23 (17.39%)
    2 / 10 (20.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    3
    6
    4
    1
    Gingivitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    Nausea
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    4 / 23 (17.39%)
    1 / 10 (10.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    1
    4
    1
    2
    Rectal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 11 (18.18%)
    8 / 23 (34.78%)
    3 / 10 (30.00%)
    4 / 11 (36.36%)
         occurrences all number
    1
    6
    12
    4
    7
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    3
    0
    3
    Dermatitis allergic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Heat rash
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    0
    1
    Periorbital oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    4
    3
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 23 (13.04%)
    3 / 10 (30.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    4
    4
    0
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    0
    1
    Arthralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    4
    2
    0
    2
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Muscle contracture
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Myalgia intercostal
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    2
    0
    1
    Osteoporosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Tendonitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Tenosynovitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    Acute tonsillitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 23 (13.04%)
    1 / 10 (10.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    3
    1
    2
    Cystitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Dermatophytosis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    1
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    4 / 23 (17.39%)
    3 / 10 (30.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    4
    3
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 23 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    3 / 23 (13.04%)
    2 / 10 (20.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    3
    2
    1
    Molluscum contagiosum
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    3
    0
    3
    Oral candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Pertussis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    2 / 10 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    Rash pustular
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 23 (13.04%)
    3 / 10 (30.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    5
    5
    0
    Rhinitis
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    6 / 23 (26.09%)
    4 / 10 (40.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    10
    7
    1
    Rhinotracheitis
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    1
    1
    Tooth abscess
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 23 (13.04%)
    2 / 10 (20.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    2
    1
    Varicella
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    2
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2006
    The amount of blood to be collected for pharmacodynamic (PD) determinations was reduced by using the same samples for the planned fibrinogen determinations and the PD-soluble marker determinations. The maximum total amount of blood that was going to be obtained in the first study month was also specified.
    24 Oct 2007
    This amendment was issued to decrease the number of visits and invasive procedures on study population.
    17 Dec 2008
    Minimized the burden on the subjects and simplified the study logistics, as sufficient information was available from the collected PK, PD, soluble markers, immunogenicity and PG data. The number of blood samplings was reduced and the visits schedule was simplified. Namely, the visits previously planned for days 2, 3 and 8 were skipped. After day 1 dosing the subjects were monitored with clinical visits on day 15, from then on every month or until a clear relapse was diagnosed. Blood samples were collected on day 1 and 15 for safety laboratory evaluations (blood chemistry, hematology and CRP) only and all the other blood samplings (PK, PD, PG, soluble markers and immunogenicity) were not required any longer. Only PK and immunogenicity assessments planned at follow-up and study completion were kept.
    13 Jan 2009
    All the subjects included in the study, were sampled for one more time for the newly planned pharmacogenetic exploratory assessments. The blood was collected into EDTA tubes. This amendment increased the total amount of blood sampled from each patient. Relevant Ethics committees reviewed and approved the amendment before implementation.

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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