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    Clinical Trial Results:
    A long-term outcome study with the IL-1 receptor antagonist Anakinra/Kineret® in patients with Neonatal onset multisystem inflammatory disease (Nomid/Cinca syndrome)

    Summary
    EudraCT number
    		 2013-000300-42
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    16 Aug 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Apr 2016
    First version publication date
    23 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    03-AR-0298
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00069329
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    Sponsor organisation address
    10 Center Drive, Bethesda, United States, MD 20892
    Public contact
    NIH Clinical Center , National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 001 8004111222TTY8, prpl@mail.cc.nih.gov
    Scientific contact
    NIH Clinical Center , National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 001 8004111222TTY8, prpl@mail.cc.nih.gov
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001212-PIP01-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Aug 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Aug 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Aug 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - Assess the change in the disease diary score after 3-4 months of open-label administration of anakinra/Kineret. This score is derived from the daily questionnaire filled out by the patient or patient’s parent(s). - Assess the change in SAA levels before and after 3-4 months of drug treatment - Assess the change in SAA levels after drug withdrawal of 7 days - Evaluate the safety of using anakinra/Kineret in patients with NOMID
    Protection of trial subjects
    The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonization/Good Clinical Practice (ICH/GCP) and applicable regulatory requirements and NIH guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Sep 2003
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 43
    Worldwide total number of subjects
    43
    EEA total number of subjects
    0
    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)
    13
    Children (2-11 years)
    18
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    7
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from a pool of genetically tested NOMID/CINCA patients at NIH, physicians who referred NOMID/CINCA patients to NIH, and by advertising at pediatric rheumatology meetings and via the parent organization for NOMID/CINCA. Given the rarity of the disease, the study comprised the major part of North American NOMID/CINCA patients.

    Pre-assignment
    Screening details
    		 The enrollment/observation phase lasted for up to 3 weeks to determine main baseline characteristics. If eligible, the patient was started on an open-label administration of Kineret at 1-2 mg/kg/day by s.c. injections.

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

    Arms
    Arm title
    		 Kineret
    Arm description
    		 Daily subcutaneous injection of Kineret. Starting dose of 1-2 mg/kg/day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kineret
    Investigational medicinal product code
    Other name
    Anakinra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The initial dose of Kineret given was 1-2 mg/kg body weight per day. First evaluation of the clinical response was done 1-3 months after initiation. At intervals no less than 7 days, a patient who was not in clinical remission could continue to have his/her Kineret dose increased in increments between 0.5 and 1 mg/kg to a maximum dose of 10 mg/kg per day to achieve clinical remission.

    Number of subjects in period 1
    		Kineret
    Started
    43
    Completed
    22
    Not completed
    21
         Not reached Month 60
    19
         non-compliance and withdrawal of consent
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 43 43
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 13 13
        Children (2-11 years)
    		 18 18
        Adolescents (12-17 years)
    		 5 5
        Adults (18-64 years)
    		 7 7
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 8.4 (0.7 to 46.3) -
    Gender categorical
    Units: Subjects
        Female
    		 25 25
        Male
    		 18 18
    Diagnosis
    Units: Subjects
        NOMID
    		 36 36
        NOMID/MWS
    		 7 7
    Mutation in exon 3 of CIAS1
    Units: Subjects
        Present
    		 31 31
        Not present
    		 10 10
        No data
    		 2 2
    Age at diagnosis
    Units: years
        median (full range (min-max))
    		 3.7 (0.1 to 46.3) -
    Time since diagnosis
    Units: years
        median (full range (min-max))
    		 0.3 (0 to 20.9) -
    Subject analysis sets

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled patients who received at least one dose of study treatment were included in the safety population

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all enrolled patients with pretreatment efficacy assessments

    Subject analysis set title
    ITT diary population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The ITT diary population included all enrolled patients who had valid pretreatment diary data assessments.

    Subject analysis set title
    Withdrawal population - withdrawn
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subset of the ITT population for diary data, including patients who participated in the withdrawal period.

    Subject analysis set title
    PK population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subset of the Safety population, in whom serum samples were taken for PK profiling at least once.

    Subject analysis set title
    Withdrawal population - treatment group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subset of the ITT population for diary data, including patients who provided diary data during the period corresponding to the withdrawal period.

    Subject analysis sets values
    		 Safety population ITT population ITT diary population Withdrawal population - withdrawn PK population Withdrawal population - treatment group
    Number of subjects
    43
    34
    29
    11
    21
    11
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    13
    8
    5
    0
    0
    3
        Children (2-11 years)
    18
    16
    16
    8
    13
    6
        Adolescents (12-17 years)
    5
    4
    2
    0
    4
    1
        Adults (18-64 years)
    7
    6
    6
    3
    4
    1
        From 65-84 years
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    8.4 (0.7 to 46.3)
    8.6 (0.8 to 46.3)
    8.6 (0.8 to 46.3)
    8.6 (4.2 to 27.8)
    11.4 (4.2 to 42.2)
    8.4 (0.8 to 25.8)
    Gender categorical
    Units: Subjects
        Female
    25
    18
    13
    6
    10
    5
        Male
    18
    16
    16
    5
    11
    6
    Diagnosis
    Units: Subjects
        NOMID
    36
    28
    23
    11
    20
    8
        NOMID/MWS
    7
    6
    6
    0
    1
    3
    Mutation in exon 3 of CIAS1
    Units: Subjects
        Present
    31
    27
    22
    8
    16
    9
        Not present
    10
    6
    6
    3
    5
    1
        No data
    2
    1
    1
    0
    0
    1
    Age at diagnosis
    Units: years
        median (full range (min-max))
    3.7 (0.1 to 46.3)
    4.6 (0.1 to 46.3)
    5.1 (0.1 to 46.3)
    4 (0.6 to 27.3)
    7.8 (0.6 to 42.2)
    6.5 (0.1 to 25.8)
    Time since diagnosis
    Units: years
        median (full range (min-max))
    0.3 (0 to 20.9)
    0.5 (0 to 17.1)
    0.5 (0 to 17.1)
    3.5 (0.3 to 17.1)
    1.3 (0 to 17.1)
    0.3 (0 to 6.8)

    End points

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    End points reporting groups
    Reporting group title
    Kineret
    Reporting group description
    		 Daily subcutaneous injection of Kineret. Starting dose of 1-2 mg/kg/day

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled patients who received at least one dose of study treatment were included in the safety population

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all enrolled patients with pretreatment efficacy assessments

    Subject analysis set title
    ITT diary population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The ITT diary population included all enrolled patients who had valid pretreatment diary data assessments.

    Subject analysis set title
    Withdrawal population - withdrawn
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subset of the ITT population for diary data, including patients who participated in the withdrawal period.

    Subject analysis set title
    PK population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subset of the Safety population, in whom serum samples were taken for PK profiling at least once.

    Subject analysis set title
    Withdrawal population - treatment group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subset of the ITT population for diary data, including patients who provided diary data during the period corresponding to the withdrawal period.

    Primary: Change in DSSS (fever, rash, joint pain, vomiting, and headache) from baseline to Month 3-6

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    End point title
    		 Change in DSSS (fever, rash, joint pain, vomiting, and headache) from baseline to Month 3-6
    End point description
    Diary Symptom Sum Score The severity of the main symptoms of the disease were scored on a scale from 0 (no symptoms) to 4 (highest severity) on a daily basis using a diary. Five key symptoms were included in the primary variable DSSS: fever, headache, rash, joint pain, and vomiting. Each of the diary variables was evaluated as a mean value for a period preceding the visits. The baseline value was the mean value of the 5-30 last days before the first dose of Kineret. For the subsequent visits, the mean value of the last 30 days with data before each visit was used as the response variable. Arithmetic mean is based on change from baseline to Month 3 and statistical analysis is based on change from baseline to Month 3-6.
    End point type
    Primary
    End point timeframe
    From 30 days prior to Baseline and until the end of the study up to 3-6 months.
    End point values
    		 Kineret ITT diary population
    Number of subjects analysed
    29
    29
    Units: severity score
        arithmetic mean (standard deviation)
    -3.8 ± 2.6
    -3.8 ± 2.6
    Statistical analysis title
    		 Change in DSSS from baseline to 3-6 months
    Statistical analysis description
    The change from baseline in DSSS was based on a repeated measures analysis of covariance model including visit as a fixed factor and baseline value as a covariate.
    Comparison groups
    Kineret v ITT diary population
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 -3.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [1] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Primary: Change in SAA levels from baseline to Month 3-6

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    End point title
    		 Change in SAA levels from baseline to Month 3-6
    End point description
    Arithmetic mean is based on change from baseline to Month 3 and statistical analysis is based on change from baseline to Month 3-6.
    End point type
    Primary
    End point timeframe
    From baseline to month 3-6
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    23
    23
    Units: mg/L
        arithmetic mean (standard deviation)
    -192 ± 197
    -192 ± 197
    Attachments
    		 SAA from baseline to Month 60
    Statistical analysis title
    		 Change in SAA levels from baseline to Month 3-6
    Statistical analysis description
    The change from baseline in SAA was based on a repeated measures analysis of covariance model including visit as a fixed factor and baseline value as a covariate.
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -206
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -230
         upper limit
    		 -182
    Variability estimate
    Standard error of the mean
    Dispersion value
    12
    Notes
    [2] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Primary: Change in SAA from Month 3 (before withdrawal) to end of withdrawal

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    End point title
    		 Change in SAA from Month 3 (before withdrawal) to end of withdrawal
    End point description
    End point type
    Primary
    End point timeframe
    From before to end of withdrawal period (up to 7 days)
    End point values
    		 Kineret Withdrawal population - withdrawn
    Number of subjects analysed
    11
    11
    Units: mg/L
        arithmetic mean (standard deviation)
    352 ± 229
    352 ± 229
    Statistical analysis title
    		 Change from before to end of withdrawal period
    Statistical analysis description
    The change in SAA from before to end of withdrawal period was based on a repeated measures ANCOVA model including visit as a fixed factor and the before withdrawal value as a covariate.
    Comparison groups
    Kineret v Withdrawal population - withdrawn
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from start of withdrawal
    Point estimate
    352
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 240
         upper limit
    		 465
    Variability estimate
    Standard error of the mean
    Dispersion value
    50
    Notes
    [3] - Analysis of change from before to end of withdrawal period within the group of patients that were withdrawn from treatment. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Change in DSSS from Month 3 (before withdrawal) to end of withdrawal

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    End point title
    		 Change in DSSS from Month 3 (before withdrawal) to end of withdrawal
    End point description
    Change from before to end of withdrawal period in diary symptom sum score (DSSS). Diary Symptom Sum Score The severity of the main symptoms of the disease were scored on a scale from 0 (no symptoms) to 4 (highest severity) on a daily basis using a diary. Five key symptoms were included in the primary variable DSSS: fever, headache, rash, joint pain, and vomiting.
    End point type
    Secondary
    End point timeframe
    from before to end of withdrawal period (up to 7 days)
    End point values
    		 Withdrawal population - withdrawn Withdrawal population - treatment group
    Number of subjects analysed
    11
    11
    Units: Severity score
        arithmetic mean (standard deviation)
    4.6 ± 2.5
    0.1 ± 0.7
    Statistical analysis title
    		 Change from before to end of withdrawal period
    Statistical analysis description
    The change in DSSS from before to end of withdrawal period was based on a repeated measures ANCOVA model including visit, group and the interaction between visit and group as a fixed factors and the before withdrawal period value as a covariate.
    Comparison groups
    Withdrawal population - treatment group v Withdrawal population - withdrawn
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.3
         upper limit
    		 5.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6

    Secondary: Neutrophils - Change from baseline to Month 60

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    End point title
    		 Neutrophils - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline to Month 60
    End point values
    		 Safety population
    Number of subjects analysed
    16
    Units: x10^3/μL
        arithmetic mean (standard deviation)
    -7.9 ± 5
    No statistical analyses for this end point

    Secondary: ALT - Change from baseline to Month 60

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    End point title
    		 ALT - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to Month 60
    End point values
    		 Safety population
    Number of subjects analysed
    15
    Units: U/L
        arithmetic mean (standard deviation)
    20.8 ± 23.9
    No statistical analyses for this end point

    Secondary: Hb - Change from baseline to Month 60

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    End point title
    		 Hb - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Month 60
    End point values
    		 Safety population
    Number of subjects analysed
    16
    Units: g/dL
        arithmetic mean (standard deviation)
    3.3 ± 1.5
    No statistical analyses for this end point

    Secondary: Intracranial opening pressure - Change from baseline to Month 60

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    End point title
    		 Intracranial opening pressure - Change from baseline to Month 60
    End point description
    Intracranial opening pressure was measured with a normal value defined as less than 200 mm of water column.
    End point type
    Secondary
    End point timeframe
    From baseline to up to month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    29
    29
    Units: mm of water
        arithmetic mean (standard deviation)
    -102 ± 72
    -102 ± 72
    Statistical analysis title
    		 Opening pressure - Change fr baseline to Month 60
    Statistical analysis description
    The change from baseline in intracranial opening pressure was based on a repeated measures analysis of covariance model including visit as a fixed factor and baseline value as a covariate.
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -123
         upper limit
    		 -43
    Variability estimate
    Standard error of the mean
    Dispersion value
    20
    Notes
    [4] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Pleiocytosis - change from baseline to Month 60

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    End point title
    		 Pleiocytosis - change from baseline to Month 60
    End point description
    Measured as change from baseline to up to Month 60 in CSF WBC adjusted cellularity
    End point type
    Secondary
    End point timeframe
    From baseline up to month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    30
    30
    Units: cells/μL
        arithmetic mean (standard deviation)
    -24.7 ± 24
    -24.7 ± 24
    Statistical analysis title
    		 Pleiocytosis - change from baseline to Month 60
    Statistical analysis description
    The change from baseline was based on a repeated measures analysis of covariance model including visit as a fixed factor and baseline value as a covariate.
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.0061
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -27.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.3
         upper limit
    		 -8.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.8
    Notes
    [5] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Total number of swollen joints - Change from baseline to Month 60

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    End point title
    		 Total number of swollen joints - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    28
    28
    Units: Number of joints
        arithmetic mean (standard deviation)
    -12.4 ± 11.9
    -12.4 ± 11.9
    Statistical analysis title
    		 Swollen joints - change from baseline to Month 60
    Statistical analysis description
    Estimated change from baseline based on repeated measures ANCOVA. Model includes visit (month) as a fixed factor and baseline as a covariate.
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -9.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.9
         upper limit
    		 -7.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9
    Notes
    [6] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Total number of joints with loss of motion - Change from baseline to Month 60

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    End point title
    		 Total number of joints with loss of motion - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    27
    27
    Units: Number of joints
        arithmetic mean (standard deviation)
    -13.7 ± 10.3
    -13.7 ± 10.3
    Statistical analysis title
    		 Total number of joints with loss of motion
    Statistical analysis description
    the change from baseline was based on a repeated measures analysis of covariance model including visit as a fixed factor and baseline value as a covariate.
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -11.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 -8.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2
    Notes
    [7] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Total number of joints with pain on motion - Change from baseline to Month 60

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    End point title
    		 Total number of joints with pain on motion - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    27
    27
    Units: Number of joints
        arithmetic mean (standard deviation)
    -5.4 ± 9.2
    -5.4 ± 9.2
    Statistical analysis title
    		 Estimated change from baseline
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 -4.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Notes
    [8] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Change from baseline to Month 60 in bone mineral density in L1-L4

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    End point title
    		 Change from baseline to Month 60 in bone mineral density in L1-L4
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline up to month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    23
    23
    Units: Z-score
        arithmetic mean (standard deviation)
    0.9 ± 1.29
    0.9 ± 1.29
    Statistical analysis title
    		 L1-L4 - change from baseline to Month 60
    Statistical analysis description
    the change from baseline was based on a repeated measures analysis of covariance model including visit (month) as a fixed factor and baseline as a covariate
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23
    Notes
    [9] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Bone mineral density in total hip area - Change from baseline to Month 60

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    End point title
    		 Bone mineral density in total hip area - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to Month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    23
    23
    Units: Z-score
        arithmetic mean (standard deviation)
    1.15 ± 1.48
    1.15 ± 1.48
    Statistical analysis title
    		 Bone mineral density in total hip area
    Statistical analysis description
    The change from baseline based in bone mineral density in total hip area was based on repeated measurement analysis of covariance model including visit (month) as a fixed factor and baseline as a covariate.
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23
    Notes
    [10] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Childhood Health Assessment Questionnaire (CHAQ) overall score - Change from baseline to Month 60

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    End point title
    		 Childhood Health Assessment Questionnaire (CHAQ) overall score - Change from baseline to Month 60
    End point description
    CHAQ - overall score, overall pain rating, overall global evaluation, subcategories for dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities
    End point type
    Secondary
    End point timeframe
    From baseline up to month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    28
    28
    Units: Score
        arithmetic mean (standard deviation)
    -0.3 ± 0.43
    -0.3 ± 0.43
    Statistical analysis title
    		 CHAQ overall - change from baseline to Month 60
    Statistical analysis description
    the change from baseline was based on a repeated measures analysis of covariance model including visit (month) as a fixed factor and baseline as a covariate
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.0367
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Notes
    [11] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: CRP - Change from baseline to Month 60

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    End point title
    		 CRP - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Month 60
    End point values
    		 Kineret Safety population
    Number of subjects analysed
    34
    34
    Units: mg/L
        arithmetic mean (standard deviation)
    -55 ± 37
    -55 ± 37
    Statistical analysis title
    		 CRP - Change from baseline to Month 60
    Statistical analysis description
    The change from bseline was based on arepeated measures analysis of covariance model including visit as a fixed factor and baseline value as a covariate.
    Comparison groups
    Kineret v Safety population
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -67
         upper limit
    		 -48
    Variability estimate
    Standard error of the mean
    Dispersion value
    5
    Notes
    [12] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Total number of tender joints - Change from baseline to Month 60

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    End point title
    		 Total number of tender joints - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    27
    27
    Units: Number of joints
        arithmetic mean (standard deviation)
    -10.1 ± 13.7
    -10.1 ± 13.7
    Statistical analysis title
    		 Tender joints - change from baseline to Month 60
    Statistical analysis description
    Estimated change from baseline based on the repeated measures ANCOVA. Model includes visit (month) as a fixed factor and baseline as a covariate.
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 -6.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6
    Notes
    [13] - Analysis of change from baseline within the Kineret treatment group. Please note that this is a single-arm study with no comparator arm. The number of subjects stated for the statistical analysis does not account for this design and is therefore stated as twice as high as the correct number of patients.

    Secondary: Total number of warm joints - Change from baseline to Month 60

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    End point title
    		 Total number of warm joints - Change from baseline to Month 60
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Month 60
    End point values
    		 Kineret ITT population
    Number of subjects analysed
    14
    14
    Units: Number of joints
        arithmetic mean (standard deviation)
    -19.4 ± 14.1
    -19.4 ± 14.1
    Statistical analysis title
    		 Total number of warm joints
    Comparison groups
    Kineret v ITT population
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean change from baseline
    Point estimate
    -14.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.5
         upper limit
    		 -12.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1
    Notes
    [14] - Analysis of change from baseline within the Kineret treatment group

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs recorded from first dose of study medication up to the Month 60 visit, the last day of study medication, or the data cut-off date.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Serious adverse events
    		 Overall Study
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 43 (32.56%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Catheterization cardiac
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Histiocytosis hematophagica
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Post lumbar puncture syndrome
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Traumatic lumbar puncture
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenitis bacterial
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis enteroviral
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 43 (2.33%)
         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
    		 Overall Study
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 43 (93.02%)
    Investigations
    Weight increased
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    6
    Contusion
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 43 (48.84%)
         occurrences all number
    115
    Dizziness
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    10
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 43 (39.53%)
         occurrences all number
    51
    Fatigue
         subjects affected / exposed
    10 / 43 (23.26%)
         occurrences all number
    27
    Injection site reaction
         subjects affected / exposed
    8 / 43 (18.60%)
         occurrences all number
    12
    Chest pain
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    9
    Condition aggravated
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    6
    Malaise
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    18
    Pain
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    6
    Gait disturbance
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    5
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    7
    Vertigo
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    12 / 43 (27.91%)
         occurrences all number
    35
    Eye pain
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Conjunctivitis
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 43 (23.26%)
         occurrences all number
    16
    Vomiting
         subjects affected / exposed
    7 / 43 (16.28%)
         occurrences all number
    25
    Nausea
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    14
    Abdominal pain
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    11
    Abdominal pain upper
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    9
    Constipation
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    9 / 43 (20.93%)
         occurrences all number
    27
    Cough
         subjects affected / exposed
    9 / 43 (20.93%)
         occurrences all number
    19
    Nasal congestion
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    14
    Epistaxis
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    10
    Rhinorrhoea
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    6
    Sinus congestion
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Rhinitis allergic
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    14 / 43 (32.56%)
         occurrences all number
    51
    Exfoliative rash
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    5
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    18 / 43 (41.86%)
         occurrences all number
    133
    Pain in extremity
         subjects affected / exposed
    9 / 43 (20.93%)
         occurrences all number
    27
    Neck pain
         subjects affected / exposed
    8 / 43 (18.60%)
         occurrences all number
    11
    Back pain
         subjects affected / exposed
    7 / 43 (16.28%)
         occurrences all number
    22
    Myalgia
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    7
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 43 (39.53%)
         occurrences all number
    48
    Nasopharyngitis
         subjects affected / exposed
    15 / 43 (34.88%)
         occurrences all number
    40
    Sinusitis
         subjects affected / exposed
    11 / 43 (25.58%)
         occurrences all number
    27
    Ear infection
         subjects affected / exposed
    11 / 43 (25.58%)
         occurrences all number
    23
    Otitis media
         subjects affected / exposed
    10 / 43 (23.26%)
         occurrences all number
    19
    Urinary tract infection
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    10
    Gastrointestinal viral infection
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    8
    Viral infection
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    8
    Gastroenteritis
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    6
    Bronchitis
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    6
    Pharyngitis
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    4
    Gastrointestinal infection
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Hordeolum
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Otitis externa
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2003
    Main changes in study plan: Repeat lumbar punctures and extension of the open-label treatment period. Reason for change/Comment: No placebo available at the time of first patient reaching 3 months
    23 Dec 2003
    Main changes in study plan: The randomized double-blind withdrawal period, was replaced by an open-label withdrawal in all patients. Change in primary objective and definition of flare. Reason for change/Comment: Placebo could not be obtained so the withdrawal phase was changed to an open-label withdrawal of study drug in all patients. The withdrawal period reduced to 7 days to limit the untoward effects for the patients to a minimal period of time.
    04 Mar 2004
    Main changes in study plan: Move some tests from visit Month 3 to Month 6. Allow more flexibility in scheduling follow-up appointments. Reason for change/Comment: Due to the withdrawal of treatment early during the Month 3 visit it was not possible to do all the examinations before that and it was not of value to do the exams when off treatment (the intention was to study the drug effects)
    15 Jun 2004
    Main changes in study plan: The withdrawal phase was removed after completion of 11 patients. Reason for change/Comment: Because of the significance of the study drug treatment effects in the first 11 patients and the severity of their flares upon withdrawal, the withdrawal phase was removed.
    12 Nov 2004
    Main changes in study plan: Study prolonged and patients who complete the Month 12 evaluation were eligible for continued treatment for an additional year (visits at 18 and 24 months). Maximum allowed dose 3mg/kg/day Reason for change/Comment: To allow patients to continue treatment and for individual dosing above 2 mg/kg/day
    10 Mar 2007
    Main changes in study plan: An open-ended extension was added to the study and allowed for continued evaluation. Patients were to return to the NIH every 6 months for evaluation and had monthly visits to the local physician in between. The maximum dose allowed was increased to 5 mg/kg/day. The possibility to transfer eligible NOMID patients included in other research projects at the NIH to one protocol. The possibility to recruit more patients. PK sampling and method of calculation adjusted. Reason for change/Comment: The focus of the study was modified from short term effects to long term effects in organ disease manifestations to determine if treatment could prevent the occurrence or progression of organ damage. The primary objective did however not change. To allow for individual dosing above 3 mg/kg/day
    11 Jun 2007
    Main changes in study plan: Removal of age limit. Reason for change/Comment: The treatment outcome at this time point indicated slowed progression of organ damage. It was therefore of great interest to start treatment at the earliest age to evaluate whether organ damage could be completely prevented.
    03 Mar 2009
    Main changes in study plan: Other IL-1 receptor antagonist drugs were allowed as treatment in the study. (This allowance was removed in the September 10, 2010, amendment) Reason for change/Comment: To be able to evaluate the effects of other IL-1 blockers under the same investigational protocol

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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