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    Clinical Trial Results:
    A multi center, randomized, double blind, placebo-controlled, study of the safety, tolerability, and the effects on arterial structure and function of canakinumab (ACZ885) in patients with clinically evident atherosclerosis and either type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT)

    Summary
    EudraCT number
    		 2009-014618-80
    Trial protocol
    		 DE   GB  
    Global end of trial date
    05 Feb 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CACZ885I2206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00995930
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -To assess the safety and tolerability of monthly subcutaneous (sc) administration of canakinumuab (ACZ885) in patients with atherosclerosis and type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT) -To assess the effect of canakinumuab on aortic distensibility and total plaque burden
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. In addition, along with the IDMC, three Adjudication Committees were also formed to make blinded assessments of AEs related to cardiac, malignant, or infectious events. In the context of this study, rescue medications could be those medications prescribed by a caregiver or the investigator to the patient to improve the management of their diabetes or cardiovascular disease. Optimal therapy was initiated and stabilized before the subject entered the study. However, if subject’s glucose, blood pressure or lipid control was considered inadequate during the study, additional medications could have been added as appropriate.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Dec 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Germany: 76
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Israel: 66
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    189
    EEA total number of subjects
    80
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    113
    From 65 to 84 years
    76
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study included individuals who had clinically evident atherosclerotic vascular disease and T2DM (diagnosed ≤ 14 years ago) or impaired glucose tolerance (IGT). Participants were randomized in a 1:1 ratio to each treatment arm.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    In addition to the pharmacist and the statistician, the PK bioanalyst, the biomarker analysts, and the pharmacokineticist received a copy of the randomization schedule to facilitate analysis of the samples. The bioanalyst provided the sample data to the analysis team under blinded conditions. All parties kept this information confidential until clinical database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Matching placebo
    Arm description
    		 Matching placebo was administered subcutaneously monthly for a treatment period of 12 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The matching placebo lyophilizate used in this trial consisted primarily of saccharose and was reconstituted and administered in the same way as the study drug injection.

    Arm title
    		 Canakinumab (ACZ885) 150 mg
    Arm description
    		 Canakinumab was delivered at a dose of 150 mg administered subcutaneously monthly for a treatment period of 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The investigational drug was provided as lyophylized powder in glass vials containing 150 mg of canakinumuab with a 20% overfill, bringing the amount of drug in the each vial to 180 mg. The drug was reconstituted and delivered at a dose of 150 mg administered by study center personnel subcutaneously monthly for a treatment period of 12 months. Injection sites were rotated.

    Number of subjects in period 1
    		Matching placebo Canakinumab (ACZ885) 150 mg
    Started
    94
    95
    Completed
    73
    67
    Not completed
    21
    28
         Consent withdrawn by subject
    3
    4
         Adverse Event
    11
    14
         Death
    -
    1
         Administrative problems
    4
    2
         Lost to follow-up
    1
    2
         Protocol deviation
    2
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Matching placebo
    Reporting group description
    		 Matching placebo was administered subcutaneously monthly for a treatment period of 12 months.

    Reporting group title
    Canakinumab (ACZ885) 150 mg
    Reporting group description
    		 Canakinumab was delivered at a dose of 150 mg administered subcutaneously monthly for a treatment period of 12 months.

    Reporting group values
    		 Matching placebo Canakinumab (ACZ885) 150 mg Total
    Number of subjects
    		 94 95 189
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.9 ± 6.92 61.7 ± 7.85 -
    Gender categorical
    Units: Subjects
        Female
    		 14 13 27
        Male
    		 80 82 162

    End points

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    End points reporting groups
    Reporting group title
    Matching placebo
    Reporting group description
    		 Matching placebo was administered subcutaneously monthly for a treatment period of 12 months.

    Reporting group title
    Canakinumab (ACZ885) 150 mg
    Reporting group description
    		 Canakinumab was delivered at a dose of 150 mg administered subcutaneously monthly for a treatment period of 12 months.

    Primary: Number of Participants With Adverse Events, Serious Adverse Events, and Death

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    End point title
    		 Number of Participants With Adverse Events, Serious Adverse Events, and Death [1]
    End point description
    Participants were monitored for adverse events, serious adverse events and death throughout the study. The population for this analysis included the safety analysis set. The safety analysis set included all randomized participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    12 months
    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: No statistical analysis was performed. The number of participants having adverse events, serious adverse events, or that died, were counted.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    94 [2]
    95 [3]
    Units: Participants
        Adverse events (serious and non-serious)
    80
    77
        Serious adverse events
    14
    25
        Deaths
    0
    1
    Notes
    [2] - Safety analysis set
    [3] - Safety analysis set
    No statistical analyses for this end point

    Primary: Change From Baseline in Aortic Distensibility (Month 3)

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    End point title
    		 Change From Baseline in Aortic Distensibility (Month 3)
    End point description
    Two axial, ECG-gated, steady state free precession (SSFP) ‘cine’ images were acquired during breath-hold to determine aortic distensibility. The first image was obtained at the level of the right pulmonary artery through the ascending and proximal descending aorta and the second through the distal aorta below the diaphragm. Imaging of the aorta also enabled evaluation of the plaque burden and additional vascular function measures. Only participants from the imaging analysis set, who had evaluable data at both baseline and the given post-baseline time point, were included in the analysis for that post baseline time point. The imaging analysis set included randomized participants who received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline, month 3
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    61 [4]
    63 [5]
    Units: units: mmHg^-1
    least squares mean (standard error)
        Month 3, proximal ascending region
    -0.0001 ± 0.0001
    -0.0001 ± 0.0001
    Notes
    [4] - Imaging analysis set
    [5] - Imaging analysis set
    Statistical analysis title
    		 Month 3 Difference in Proximal Ascending
    Statistical analysis description
    Analysis of change from baseline in aortic distensibility at month 3 for proximal ascending difference between treatments is presented.
    Comparison groups
    Matching placebo v Canakinumab (ACZ885) 150 mg
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.174 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.0002
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.0001
         upper limit
    		 0.0004
    Notes
    [6] - Analysis was assessment of effect.
    [7] - Data were analyzed using an ANCOVA model with glycemic status as a classification factor and baseline as a covariate. One-sided p-value presented.

    Primary: Change From Baseline to Month 3 in Plaque Burden (Aortic Vessel Wall Area )

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    End point title
    		 Change From Baseline to Month 3 in Plaque Burden (Aortic Vessel Wall Area )
    End point description
    For assessment of atherosclerotic plaque burden of the aorta, vessel wall images of the aorta were acquired with an ECG gated double-inversion recovery (black blood) fast spin echo sequence applied breath-holding. Using an oblique sagittal image of the aorta as a pilot, serial axial images were acquired to cover a section of the descending thoracic aorta. The midpoint of the right pulmonary artery in cross section was used as the anatomical reference for the first slice in baseline and follow-up scans.
    End point type
    Primary
    End point timeframe
    Baseline, month 3.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    69 [8]
    62 [9]
    Units: mm^2
    least squares mean (standard error)
        aortic, proximal ascending, month 3
    14.8 ± 6.86
    -0.51 ± 6.62
    Notes
    [8] - Imaging analysis set
    [9] - Imaging analysis set
    Statistical analysis title
    		 Month 3 Proximal Ascending Wall Area Change
    Comparison groups
    Matching placebo v Canakinumab (ACZ885) 150 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.03 [11]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.31
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -28.69
         upper limit
    		 -1.94
    Notes
    [10] - Assessment of effect
    [11] - One-sided.

    Primary: Change From Baseline in Aortic Distensibility (Month 12)

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    End point title
    		 Change From Baseline in Aortic Distensibility (Month 12)
    End point description
    Two axial, ECG-gated, steady state free precession (SSFP) ‘cine’ images were acquired during breathhold to determine aortic distensibility. The first image was obtained at the level of the right pulmonary artery through the ascending and proximal descending aorta and the second through the distal aorta below the diaphragm. Imaging of the aorta also enabled evaluation of the plaque burden and additional vascular function measures. Only participants from the imaging analysis set, who had evaluable data at both baseline and the given post-baseline time point, were included in the analysis for that post baseline.
    End point type
    Primary
    End point timeframe
    Baseline, month 12
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    56 [12]
    55 [13]
    Units: mmHg^-1
    least squares mean (standard error)
        Month 12, proximal ascending region
    -0.0001 ± 0.0001
    -0.0001 ± 0.0001
    Notes
    [12] - Imaging analysis set
    [13] - Imaging analysis set
    Statistical analysis title
    		 Month 12 Difference in Proximal Ascending
    Statistical analysis description
    Analysis of change from baseline in aortic distensibility at month 12 for proximal ascending difference between treatments is presented.
    Comparison groups
    Matching placebo v Canakinumab (ACZ885) 150 mg
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.459 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.0003
         upper limit
    		 0.0003
    Notes
    [14] - Analysis was assessment of effect.
    [15] - Data were analyzed using an ANCOVA model with glycemic status as a classification factor and baseline as a covariate. One-sided p-value presented.

    Primary: Change From Baseline to Month 12 in Plaque Burden (Aortic Vessel Wall Area )

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    End point title
    		 Change From Baseline to Month 12 in Plaque Burden (Aortic Vessel Wall Area )
    End point description
    For assessment of atherosclerotic plaque burden of the aorta, vessel wall images of the aorta were acquired with an ECG gated double-inversion recovery (black blood) fast spin echo sequence applied breath-holding. Using an oblique sagittal image of the aorta as a pilot, serial axial images were acquired to cover a section of the descending thoracic aorta. The midpoint of the right pulmonary artery in cross section was used as the anatomical reference for the first slice in baseline and follow-up scans.
    End point type
    Primary
    End point timeframe
    Baseline, month 12
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    69 [16]
    62 [17]
    Units: mm^2
    least squares mean (standard error)
        aortic, proximal ascending, month 12
    30.58 ± 10.46
    8.71 ± 10.49
    Notes
    [16] - Imaging analysis set
    [17] - Imaging analysis set
    Statistical analysis title
    		 Month 12 Proximal Ascending Wall Area Change
    Comparison groups
    Canakinumab (ACZ885) 150 mg v Matching placebo
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.04 [19]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -21.87
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -42.35
         upper limit
    		 -1.39
    Notes
    [18] - Assessment of effect
    [19] - One-sided.

    Secondary: Change From Baseline in Pulse Wave Velocity and Pulse Wave Velocity Error

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    End point title
    		 Change From Baseline in Pulse Wave Velocity and Pulse Wave Velocity Error
    End point description
    Utilizing the SphygmoCor Device, ECG leads placed at the carotid and femoral arteries provided the measure of the pulse wave at that particular arterial location. The distance between the two vascular beds divided by the pulse wave time shift provided a measure of the pulse wave velocity. Only participants from the imaging analysis set were included.
    End point type
    Secondary
    End point timeframe
    Baseline, month 3, and month 12.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    92 [20]
    92 [21]
    Units: ms^-1
    least squares mean (standard error)
        pulse wave velocity, month 3 (n=45,38)
    -0.39 ± 0.39
    -0.03 ± 0.39
        pulse wave velocity, month 12 (n=35,31)
    -0.36 ± 0.35
    -0.26 ± 0.35
        pulse wave velocity error, month 3 (n=45,38)
    -0.01 ± 0.05
    -0.03 ± 0.05
        pulse wave velocity error, month 12 (n=35,31)
    -0.01 ± 0.06
    0.06 ± 0.06
    Notes
    [20] - Imaging analysis set
    [21] - Imaging analysis set
    No statistical analyses for this end point

    Secondary: Change From Baseline in Plaque Composition

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    End point title
    		 Change From Baseline in Plaque Composition
    End point description
    During the carotid MRI acquisition, in addition to the PD weighted ECG gated double inversion fast spin echo sequences T1 and T2 weighted sequences were acquired. In combination with the PD weighted images, the multi-contrast images were analyzed to determine regions of interest with contrast patterns consistent with the presence of necrotic lipid core, calcification and fibrous tissue in participants who had complex carotid plaque present in the bifurcation region. This analysis only included participants from the imaging analysis set. 'n' signifies the patients with evaluable data at that time point . If 'n' is not provided in the category, it indicates that all the patients of imaging analyis set with N= 5, 3 provided evaluable data on each time point respectively. .
    End point type
    Secondary
    End point timeframe
    Baseline, month 3, and month 12.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    5 [22]
    3 [23]
    Units: mm^2
    arithmetic mean (standard deviation)
        calcium composition, left carotid, month 3
    0.002 ± 0.0045
    0.003 ± 0.0058
        calcium composition, left carotid, month 12
    0.002 ± 0.0045
    0.003 ± 0.0058
        hemorrhage area, left carotid, month 3
    0.006 ± 0.0114
    0 ± 0.02
        hemorrhage area, left carotid, month 12
    0.018 ± 0.0205
    0.007 ± 0.0115
        lipid composition, left carotid, month 3
    0 ± 0
    0.003 ± 0.0115
        lipid composition, left carotid, month 12
    0 ± 0.0122
    0.007 ± 0.0058
        calcium composition,right carotid, month 3 (n=3, 4
    -0.005 ± 0.0058
    -0.003 ± 0.0058
        calcium composition,right carotid, month 12(n=3, 4
    0 ± 0.0082
    0 ± 0
        hemorrhage area,right carotid, month 3 (n=3, 4)
    0.003 ± 0.0096
    0 ± 0.01
        hemorrhage area,right carotid, month 12 (n=3, 4)
    0.008 ± 0.033
    0.003 ± 0.0208
        lipid composition, right carotid, month 3 (n=3, 4)
    -0.005 ± 0.0058
    0.003 ± 0.0058
        lipid composition, right carotid, month 12 (n=3, 4
    0.008 ± 0.0171
    0.017 ± 0.0115
    Notes
    [22] - Imaging analysis set
    [23] - Imaging analysis set
    No statistical analyses for this end point

    Secondary: Change From Baseline in Aortic Strain

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    End point title
    		 Change From Baseline in Aortic Strain
    End point description
    Arterial strain was computed directly from the cine SSFP images and the change in lumen diameters over the cardiac cycle. The value was independent of pulse pressure and is unitless ratio derived from the maximum to minimum lumen diameters diastole and systole, respectively. Only participants from the imaging analysis set, who had evaluable data at both baseline and the given post-baseline time point, were included in the analysis for this post baseline time point.
    End point type
    Secondary
    End point timeframe
    Baseline, month 3, and month 12.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    92 [24]
    92 [25]
    Units: participants
    least squares mean (standard error)
        proximal ascending, month 3 (n=67,64)
    -0.005 ± 0.005
    0.002 ± 0.005
        proximal ascending, month 12 (n=59,59)
    0.001 ± 0.005
    -0.002 ± 0.005
    Notes
    [24] - Imaging analysis set
    [25] - Imaging analysis set
    No statistical analyses for this end point

    Secondary: Change From Baseline in High Sensitivity C-reactive Protein (hsCRP)

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    End point title
    		 Change From Baseline in High Sensitivity C-reactive Protein (hsCRP)
    End point description
    Blood samples were collected to analyze high sesitivity C-reactive protein (hsCRP). Only participants from the pharmacodynamic (PD) analysis set, who had evaluable data at both baseline and the given post-baseline time point, were included in the analysis for that post baseline time point. The PD analysis set included randomized participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, month 3, and month 12.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    92 [26]
    92 [27]
    Units: mg/L
    geometric mean (confidence interval 95%)
        Month 3 (n=82,79)
    0.93 (0.76 to 1.14)
    0.48 (0.39 to 0.58)
        Month 12 (n=73,68)
    1.04 (0.83 to 1.31)
    0.51 (0.41 to 0.64)
    Notes
    [26] - Pharmacodynamic analysis set
    [27] - Pharmacodynamic analysis set
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fasting Plasma Glucose

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    End point title
    		 Change From Baseline in Fasting Plasma Glucose
    End point description
    Blood samples were collected to analyze fasting plasma glucose. Only participants from the pharmacodynamic (PD) analysis set, who had evaluable data at both baseline and the given post-baseline time point, were included in the analysis for that post baseline time point. The PD analysis set included randomized participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, month 3, and month 12.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    92 [28]
    92 [29]
    Units: mmol/L
    geometric mean (confidence interval 95%)
        month 3 (n=79,75)
    0.95 (0.89 to 1.01)
    1 (0.94 to 1.06)
        month 12 (n=71,62)
    0.95 (0.87 to 1.02)
    0.99 (0.92 to 1.07)
    Notes
    [28] - Pharmacodynamic analysis set
    [29] - Pharmacodynamic analysis set
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemoglobin A1c (HbA1c)

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    End point title
    		 Change From Baseline in Hemoglobin A1c (HbA1c)
    End point description
    Blood samples were collected to analyze hemoglobin A1c (HbA1c). Only participants from the pharmacodynamic (PD) analysis set, who had evaluable data at both baseline and the given post-baseline time point, were included in the analysis for that post baseline time point. The PD analysis set included randomized participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, month 3, and month 12.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    92 [30]
    92 [31]
    Units: Percentage
    geometric mean (confidence interval 95%)
        month 3 (n=81,77)
    1 (0.97 to 1.02)
    0.99 (0.97 to 1.02)
        month 12 (n=72,65)
    1 (0.96 to 1.04)
    0.96 (0.96 to 1.03)
    Notes
    [30] - Pharmacodynamic analysis set
    [31] - Pharmacodynamic analysis set
    No statistical analyses for this end point

    Secondary: Change From Baseline in 2 Hour Glucose Post Oral Glucose Tolerance Test (OGTT)

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    End point title
    		 Change From Baseline in 2 Hour Glucose Post Oral Glucose Tolerance Test (OGTT)
    End point description
    Blood samples were collected to analyze the 2 hour glucose post oral glucose tolerance tet (OGTT). Only participants from the pharmacodynamic (PD) analysis set, who had evaluable data at both baseline and the given post-baseline time point, were included in the analysis for that post baseline time point. The PD analysis set included randomized participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, month 3, and month 12.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    92 [32]
    92 [33]
    Units: mmol/L
    geometric mean (confidence interval 95%)
        month 3 (n=79,74)
    0.92 (0.85 to 0.99)
    0.98 (0.9 to 1.05)
        monht 12 (n=71,62)
    0.93 (0.84 to 1.01)
    0.95 (0.88 to 1.04)
    Notes
    [32] - Pharmacodynamic analysis set
    [33] - Pharmacodynamic analysis set
    No statistical analyses for this end point

    Secondary: Change From Baseline in Homeostatis Model Assessments Beta Cell Function (HOMA-B)

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    End point title
    		 Change From Baseline in Homeostatis Model Assessments Beta Cell Function (HOMA-B)
    End point description
    Blood samples were collected to analyze beta cell function. Beta cell function was calculated by the Homeostasis Model Assessments (of beta cell function (HOMA-B) as follows: HOMA-B: The product of 20 and basal insulin (µU/mL) levels divided by the value of basal glucose (mmol/L) concentrations minus 3.5 [i.e., HOMA-B = 20*basal insulin/(basal glucose-3.5)]. Only participants from thepharmacodynamic (PD) analysis set, who had evaluable data at both baseline and the given post-baseline time point, were included in the analysis for that post baseline time point. The PD analysis set included randomized participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, month 3, and month 12.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    92 [34]
    92 [35]
    Units: percentage of beta cell function
    geometric mean (confidence interval 95%)
        HOMA-B, month 3 (n=77,70)
    1.11 (0.91 to 1.35)
    0.99 (0.82 to 1.2)
        HOMA-B, month 12 (n=71,60)
    1.03 (0.84 to 1.26)
    0.91 (0.75 to 1.1)
    Notes
    [34] - Pharmacodynamic analysis set
    [35] - Pharmacodynamic analysis set
    No statistical analyses for this end point

    Secondary: Change From Baseline Insulin Resistance (HOMA-IR)

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    End point title
    		 Change From Baseline Insulin Resistance (HOMA-IR)
    End point description
    Blood samples were collected to analyze insulin resistance. Insulin resistance was calculated by the Homeostasis Model Assessments of insulin resistance (HOMA-IR)) as follows: HOMA-IR: The product of basal glucose (mmol/L) and insulin (µU/mL) levels divided by 22.5 [i.e., HOMA-IR = basal glucose*basal insulin/22.5]. Only participants from the pharmacodynamic (PD) analysis set, who had evaluable data at both baseline and the given post-baseline time point, were included in the analysis for that post baseline time point. The PD analysis set included randomized participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, month 3, and month 12.
    End point values
    		 Matching placebo Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    92 [36]
    92 [37]
    Units: Insulin Resisitance (IR) score
    geometric mean (confidence interval 95%)
        HOMA-R, month 3 (n=77,70)
    1 (0.85 to 1.18)
    1.09 (0.93 to 1.28)
        HOMA-R, month 12 (n=71,60)
    0.93 (0.77 to 1.13)
    0.97 (0.8 to 1.16)
    Notes
    [36] - Pharmacodynamic analysis set
    [37] - Pharmacodynamic analysis set
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Canakinumab Serum Concentrations

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    End point title
    		 Pharmacokinetics: Canakinumab Serum Concentrations [38]
    End point description
    Blood samples were collected to analyze the canakinumabserum concentrations. Only participants from the pharmacokinetic (PK) analysis set, who had evaluable data at each time point, were included in the analysis for that time point. The PK analysis set included randomized participants from the canakinumab arm who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.167 day post dose 1, 7 days post dose 1, 14 days post dose 1, every 30 days post each dose from doses 1 through 12, 60 days post dose 12, and 90 days post dose 12.
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics on canakinumab serum concentration can only be performed on patients treated with canakinumab, therefore only the canakinumab treatment group is included in the analysis.
    End point values
    		 Canakinumab (ACZ885) 150 mg
    Number of subjects analysed
    95 [39]
    Units: ng/mL
    arithmetic mean (standard deviation)
        pre-dose (n=91)
    0 ± 0
        0.167 day post dose 1 (n=94)
    480 ± 648
        7 days post dose 1 (n=95)
    10107 ± 4369
        14 days post dose 1 (n=93)
    9138 ± 3527
        30 days post dose 1 (n=90)
    5936 ± 2281
        30 days post dose 2 (n=86)
    8136 ± 3299
        30 days post dose 3 (n=81)
    9278 ± 3795
        30 days post dose 4 (n=78)
    10183 ± 4552
        30 days post dose 5 (n=78)
    10164 ± 4209
        30 days post dose 6 (n=77)
    10254 ± 3916
        30 days post dose 7 (n=76)
    10368 ± 4840
        30 days post dose 8 (n=71)
    9745 ± 4436
        30 days post dose 9 (n=69)
    10407 ± 3967
        30 days post dose 10 (n=71)
    10635 ± 4697
        30 days post dose 11 (n=70)
    10612 ± 4434
        30 days post dose 12 (n=66)
    10887 ± 4785
        60 days post dose 12 (n=66)
    4575 ± 2362
        90 days post dose 12 (n=88)
    3241 ± 2883
    Notes
    [39] - Pharmacokinetic analysis set
    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 are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    ACZ885 150mg
    Reporting group description
    		 ACZ885 150mg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 ACZ885 150mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 95 (26.32%)
    14 / 94 (14.89%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Epididymitis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery restenosis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 95 (2.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 95 (2.11%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 95 (2.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia, obstructive
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty tophus
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Epiglottitis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ACZ885 150mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 95 (48.42%)
    65 / 94 (69.15%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    5 / 95 (5.26%)
    3 / 94 (3.19%)
         occurrences all number
    5
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 95 (3.16%)
    5 / 94 (5.32%)
         occurrences all number
    3
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 95 (5.26%)
    5 / 94 (5.32%)
         occurrences all number
    6
    5
    Headache
         subjects affected / exposed
    4 / 95 (4.21%)
    5 / 94 (5.32%)
         occurrences all number
    4
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 95 (2.11%)
    5 / 94 (5.32%)
         occurrences all number
    2
    5
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 95 (3.16%)
    8 / 94 (8.51%)
         occurrences all number
    5
    9
    Influenza like illness
         subjects affected / exposed
    4 / 95 (4.21%)
    5 / 94 (5.32%)
         occurrences all number
    4
    6
    Fatigue
         subjects affected / exposed
    2 / 95 (2.11%)
    8 / 94 (8.51%)
         occurrences all number
    2
    11
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 95 (0.00%)
    5 / 94 (5.32%)
         occurrences all number
    0
    5
    Nausea
         subjects affected / exposed
    4 / 95 (4.21%)
    7 / 94 (7.45%)
         occurrences all number
    9
    10
    Diarrhoea
         subjects affected / exposed
    5 / 95 (5.26%)
    6 / 94 (6.38%)
         occurrences all number
    7
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 95 (5.26%)
    2 / 94 (2.13%)
         occurrences all number
    5
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 95 (2.11%)
    6 / 94 (6.38%)
         occurrences all number
    2
    6
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 95 (2.11%)
    6 / 94 (6.38%)
         occurrences all number
    2
    6
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    4 / 95 (4.21%)
    7 / 94 (7.45%)
         occurrences all number
    6
    7
    Back pain
         subjects affected / exposed
    4 / 95 (4.21%)
    5 / 94 (5.32%)
         occurrences all number
    4
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 95 (12.63%)
    18 / 94 (19.15%)
         occurrences all number
    22
    28
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 95 (9.47%)
    10 / 94 (10.64%)
         occurrences all number
    11
    11
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    5 / 94 (5.32%)
         occurrences all number
    1
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Sep 2009
    This amendment included the following: Allow for subjects with a negative PPD test within two months of screening to be excluded from having another placed at screening to avoid false positives from too proximate exposure to tuberculosis antigens, add for safety and efficacy reasons: lipid subfractionation and C-Peptide at visits 2, 8, and 18; soluble PD biomarkers (plasma) at Visits 3, 8, and 18; fasting plasma glucose and fasting insulin at Visit 1, add urine pregnancy testing at every dosing visit and vital sign monitoring on Day 1 every 15 minutes for the first hour post-dose and every 30 minutes for the second hour post-dose, move the 2 mL PK blood draw from visit 19 to Visit 3, 8 hours post-dose and to add the additional draws to the blood log, perform a clean catch culture in the event of a positive urine dipstick which could indicate a UTI, and allow for additional subjects to be randomized during a possible increase in cases of influenza (either seasonal or H1N1)
    03 Feb 2010
    This amendment included the following: Correct amount of blood drawn from 5 mL to 3 mL; change PK and IL1beta timepoints, clarify autoantibody analysis performed on plasma samples, add central aortic pressure language indicating that the assessment take place just prior to the MRI and to convert brachial artery imaging to an exploratory endpoint, exclude subjects who had received or were planning to receive live (attenuated) vaccination, including but not limited to live H1N1 and Seasonal Flu vaccination, and clarify inclusion/exclusion criteria and to add an exclusion criteria concerning vaccinations.
    12 May 2010
    This amendment included the following: The lower limit for HbA1c was reduced to 6.0% from 6.5%. Since potential subjects could be on any type of medication for diabetes (including insulin and sulfonylureas), their HbA1c values were below the current protocol limit of 6.5%. In order to be able to recruit subjects for the study, the lower limit of HbA1c as defined by the protocol was brought in line with the population. In addition, patients who have had events (secondary prevention, our target population) tend to have even more tightly controlled glycemic indices evidenced by lower HbA1cs. The upper limit of SGOT and SGPT was raised to 2 x ULN from 1.5 x ULN. Since potential subjects could be on statins, their SGOT or SGPT values were above the current protocol limit of 1.5 x ULN. In order to be able to recruit subjects for the study, the upper limit of SGOT and SGPT as defined by the protocol were brought in line with the population.
    30 Mar 2011
    This amendment included the following:Time from a major cardiovascular event to screening was reduced to ≥ 3 months from ≥ 6 months. Subjects in atrial fibrillation, having an implantable cardiac device or taking coumadin were excluded. Maximum non-steroidal use was clarified; additional information about concomitant medications was included. Additional information about hypertensive medication was included. Stopping rules were clarified to include additional information regarding concomitant medication.
    31 Jan 2012
    This amendment included the following: Planned number of patients was changed from approximately 140 patients enrolled and 120 patients completed to approximately 190 patients enrolled and 120 evaluable patients completed. Brachial artery imaging was changed to an optional assessment and endothelial function was changed to an exploratory objective. The human safety and tolerability data was updated to reflect the most recent IB version. Patients who had immunosuppressant treatment within one year prior to screening were excluded. Patients diagnosed with or who had a history of neutropenia were excluded. Patients diagnosed or had a history of an autoimmune disorder were excluded. New infections and immunosuppressant treatment was added to premature patient withdrawal.

    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.
    Since this is an early stage study for a new indication, a one-sided test instead of the pre-specified two-sided test was performed for between treatment comparisons of the primary imaging endpoints. Planned PK analyses and modeling not performed.
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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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