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    Clinical Trial Results:
    A Phase 2b, Multi-center, Randomized, Placebo-controlled, Dose-ranging Study to Investigate the Safety and Tolerability of Multiple Dose Administration of CSL112 in Subjects with Acute Myocardial Infarction

    Summary
    EudraCT number
    2013-003458-26
    Trial protocol
    DE   GB   IT   CZ   AT   DK   HU   NL   ES   FR  
    Global end of trial date
    21 Mar 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Mar 2017
    First version publication date
    22 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSLCT-HDL-12-77
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02108262
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CSL Behring LLC
    Sponsor organisation address
    1020 First Avenue, King of Prussia, United States, 19406
    Public contact
    Clin.Trial Registration Coordinator, CSL Behring, clinicaltrials@cslbehring.com
    Scientific contact
    Clin.Trial Registration Coordinator, CSL Behring, clinicaltrials@cslbehring.com
    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
    13 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the hepatic and renal safety of multiple dose administration of two dose levels of CSL112 (low dose [2 g] or high dose [6 g]) compared with placebo in subjects with acute myocardial infarction.
    Protection of trial subjects
    Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study. The investigator may cease study treatment and withdraw the subject, or the subject may withdraw himself from participation in the study at any time. In accordance with International Conference on Harmonisation principles of Good Clinical Practice, the Investigator always had the option to advise a subject to stop further administration of investigational product (IP) if the subject's safety or well-being was compromised by the continued administration of IP. Concern for the interests of the subject was always to prevail over the interests of the study. However, subjects were to continue to be followed for safety and the occurrence of Major Adverse Cardiovascular Events (MACE). At minimum, all efforts were to be made to confirm vital status if a subject was unwilling or unable to return for scheduled on-site visits or refused to be contacted by telephone for the MACE follow-up visits.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Aug 2014
    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
    Netherlands: 145
    Country: Number of subjects enrolled
    Poland: 204
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Bulgaria: 140
    Country: Number of subjects enrolled
    Czech Republic: 104
    Country: Number of subjects enrolled
    Denmark: 28
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 86
    Country: Number of subjects enrolled
    Hungary: 202
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Israel: 81
    Country: Number of subjects enrolled
    United States: 167
    Worldwide total number of subjects
    1258
    EEA total number of subjects
    967
    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)
    903
    From 65 to 84 years
    350
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    A safety lead-in was conducted before enrollment into the main study, and provided an early assessment of safety in subjects with acute myocardial infarction and mild renal impairment or normal renal function. Upon confirmation of safety in the lead-in, additional subjects were screened for enrollment in the main study.

    Pre-assignment
    Screening details
    A total of 11 subjects were screened for participation in the safety lead-in, and 9 subjects were enrolled. A total of 1401 subjects were screened for entry into the main study. Of these subjects, 143 subjects were screen failures, and the remaining 1258 eligible subjects were randomized.

    Period 1
    Period 1 title
    Main Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CSL112 (2 g)
    Arm description
    CSL112 (low dose) is to be administered as an intravenous (IV) infusion once weekly for 4 consecutive weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    CSL112
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CSL112 (low or high dose) is to be administered as an intravenous (IV) infusion once weekly for 4 consecutive weeks.

    Arm title
    CSL112 (6 g)
    Arm description
    CSL112 (high dose) is to be administered as an IV infusion once weekly for 4 consecutive weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    CSL112
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CSL112 (low or high dose) is to be administered as an intravenous (IV) infusion once weekly for 4 consecutive weeks.

    Arm title
    Placebo
    Arm description
    Placebo is to be administered as an IV infusion at the same frequency, volume and duration as either the low dose or high dose CSL112 infusion.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (0.9% weight/volume sodium chloride solution (ie, normal saline) is to be administered as an IV infusion at the same frequency, volume and duration as either the low dose or high dose CSL112 infusion.

    Number of subjects in period 1
    CSL112 (2 g) CSL112 (6 g) Placebo
    Started
    419
    421
    418
    Completed
    375
    379
    376
    Not completed
    44
    42
    42
         Adverse event, serious fatal
    2
    2
    1
         Physician decision
    -
    2
    -
         Patient did not want another infusion
    3
    3
    2
         Randomized by error/screen failure
    -
    1
    -
         Consent withdrawn by subject
    7
    3
    4
         Patient decision
    7
    9
    14
         Adverse event, non-fatal
    11
    6
    12
         Due to key hepatic values
    1
    -
    -
         Missed IV due to pharmacy error
    -
    1
    -
         Non-compliance
    2
    1
    1
         Vacation
    1
    -
    -
         Unable to contact patient
    3
    1
    2
         Patient unable to come to site/attend visit
    6
    11
    6
         Lost to follow-up
    -
    1
    -
         Distance to center
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CSL112 (2 g)
    Reporting group description
    CSL112 (low dose) is to be administered as an intravenous (IV) infusion once weekly for 4 consecutive weeks.

    Reporting group title
    CSL112 (6 g)
    Reporting group description
    CSL112 (high dose) is to be administered as an IV infusion once weekly for 4 consecutive weeks.

    Reporting group title
    Placebo
    Reporting group description
    Placebo is to be administered as an IV infusion at the same frequency, volume and duration as either the low dose or high dose CSL112 infusion.

    Reporting group values
    CSL112 (2 g) CSL112 (6 g) Placebo Total
    Number of subjects
    419 421 418 1258
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    306 296 301 903
        From 65-84 years
    111 124 115 350
        85 years and over
    2 1 2 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.7 ( 10.15 ) 59.2 ( 9.87 ) 58.1 ( 10.57 ) -
    Gender categorical
    Units: Subjects
        Female
    82 98 77 257
        Male
    337 323 341 1001
    Renal function from Interactive Web Response System (IWRS)
    Units: Subjects
        Normal renal function
    195 192 191 578
        Mild renal impairment
    224 229 227 680

    End points

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    End points reporting groups
    Reporting group title
    CSL112 (2 g)
    Reporting group description
    CSL112 (low dose) is to be administered as an intravenous (IV) infusion once weekly for 4 consecutive weeks.

    Reporting group title
    CSL112 (6 g)
    Reporting group description
    CSL112 (high dose) is to be administered as an IV infusion once weekly for 4 consecutive weeks.

    Reporting group title
    Placebo
    Reporting group description
    Placebo is to be administered as an IV infusion at the same frequency, volume and duration as either the low dose or high dose CSL112 infusion.

    Subject analysis set title
    Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety population comprised all subjects who were randomized into the main study or PK/PD substudy and received at least a partial infusion of the IP.

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population comprised all subjects who were randomized to one of the three treatment groups for the Main Study or PK/PD substudy.

    Subject analysis set title
    Pharmacokinetic (PK) population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The PK population comprised all subjects who received at least 1 infusion of IP and had at least 1 post baseline measurable plasma concentration of apoA-I or PC.

    Subject analysis set title
    Pharmacokinetic/Pharmacodynamic (PK/PD) population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The Pharmacokinetic/Pharmacodynamic (PK/PD) population was a subset of subjects from the main study who consented to participate in the PK/PD substudy.

    Subject analysis set title
    Serology population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    A random subset of subjects was selected and had their samples tested for the presence of parvovirus B19.

    Primary: Percent of subjects with clinically important change in drug-induced liver injury (Safety population)

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    End point title
    Percent of subjects with clinically important change in drug-induced liver injury (Safety population)
    End point description
    A clinically important change in drug-induced liver injury is defined as a change (from baseline) in alanine aminotransferase (ALT) greater than 3 times the upper limit of normal (ULN) or a change in total bilirubin greater than 2 times ULN, that is confirmed upon repeat measurement.
    End point type
    Primary
    End point timeframe
    From baseline (before 1st infusion) to Day 29
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    415
    416
    413
    Units: Percent of subjects
        number (not applicable)
    1
    0.5
    0
    Statistical analysis title
    Non-inferiority assessment CSL112 (2 g) vs Placebo
    Comparison groups
    CSL112 (2 g) v Placebo
    Number of subjects included in analysis
    828
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.1241
    Method
    Newcombe-Wilson score method
    Parameter type
    Difference in event rates (%)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    2.5
    Notes
    [1] - The upper limit of the confidence interval for the difference in rates (2.5%) is less than the non-inferiority limit of 4%. Therefore, the non-inferiority criterion was satisfied.
    Statistical analysis title
    Non-inferiority assessment CSL112 (6 g) vs Placebo
    Comparison groups
    CSL112 (6 g) v Placebo
    Number of subjects included in analysis
    829
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    = 0.4994
    Method
    Newcombe-Wilson score method
    Parameter type
    Difference in event rates (%)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    1.7
    Notes
    [2] - The upper limit of the confidence interval for the difference in rates (1.7%) is less than the non-inferiority limit of 4%. Therefore, the non-inferiority criterion was satisfied.

    Primary: Percent of subjects with clinically important change in renal status (Safety population)

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    End point title
    Percent of subjects with clinically important change in renal status (Safety population)
    End point description
    A clinically important change in renal status is defined as a serum creatinine (Cr) increase to ≥ 1.5 x the baseline value that is confirmed upon repeat measurement.
    End point type
    Primary
    End point timeframe
    From baseline (before 1st infusion) to Day 29
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    415
    416
    413
    Units: Percent of subjects
        number (not applicable)
    0
    0.7
    0.2
    Statistical analysis title
    Non-inferiority assessment CSL112 (2 g) vs Placebo
    Comparison groups
    CSL112 (2 g) v Placebo
    Number of subjects included in analysis
    828
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    P-value
    = 0.4988
    Method
    Newcombe-Wilson score method
    Parameter type
    Difference in event rates (%)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    0.7
    Notes
    [3] - The upper limit of the confidence interval for the difference in rates (0.7%) is less than the non-inferiority limit of 5%. Therefore, the non-inferiority criterion was satisfied.
    Statistical analysis title
    Non-inferiority assessment CSL112 (6 g) vs Placebo
    Comparison groups
    CSL112 (6 g) v Placebo
    Number of subjects included in analysis
    829
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    P-value
    = 0.6241
    Method
    Newcombe-Wilson score method
    Parameter type
    Difference in event rates (%)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    1.9
    Notes
    [4] - The upper limit of the confidence interval for the difference in rates (1.9%) is less than the non-inferiority limit of 5%. Therefore, the non-inferiority criterion was satisfied.

    Secondary: Time-to-first occurrence of a major adverse cardiovascular event (MACE) (ITT population)

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    End point title
    Time-to-first occurrence of a major adverse cardiovascular event (MACE) (ITT population)
    End point description
    The MACE composite secondary endpoint was a 4-component composite comprised of the time to the first of the following events: CV death, nonfatal myocardial infarction, ischemic stroke (non-hemorrhagic), and hospitalization for unstable angina. The percentage of subjects with time-to-first occurrence of a major adverse cardiovascular event (MACE) are presented.
    End point type
    Secondary
    End point timeframe
    From the start of the first infusion up to approximately 382 days
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    419
    421
    418
    Units: Percent of subjects
        number (not applicable)
    6.4
    5.7
    5.5
    Statistical analysis title
    CSL112 (2 g)
    Comparison groups
    CSL112 (2 g) v Placebo
    Number of subjects included in analysis
    837
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5733 [5]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    2.05
    Notes
    [5] - Stratified log-rank p-value
    Statistical analysis title
    CSL112 (6 g)
    Comparison groups
    CSL112 (6 g) v Placebo
    Number of subjects included in analysis
    839
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9717 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.8
    Notes
    [6] - Stratified log-rank p-value

    Secondary: Baseline-Corrected Plasma Concentrations of Apolipoprotein A-I (apoA-I) and Phosphatidylcholine (PC) at End of Infusion 1 for all subjects (PK population)

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    End point title
    Baseline-Corrected Plasma Concentrations of Apolipoprotein A-I (apoA-I) and Phosphatidylcholine (PC) at End of Infusion 1 for all subjects (PK population)
    End point description
    Apolipoprotein A-I (apoA-I) and Phosphatidylcholine (PC) are analytes of CSL112
    End point type
    Secondary
    End point timeframe
    Before infusion 1 and end of Infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    396
    404
    403
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    35.9 ( 22.13 )
    136.1 ( 54.37 )
    -4.7 ( 13.46 )
        PC
    57.7 ( 31.12 )
    180.4 ( 74.4 )
    -1.2 ( 20.43 )
    No statistical analyses for this end point

    Secondary: Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 4 for all subjects (PK population)

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    End point title
    Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 4 for all subjects (PK population)
    End point description
    apoA-I and PC are analytes of CSL112
    End point type
    Secondary
    End point timeframe
    Before infusion 1 and end of Infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    366
    370
    370
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    52.1 ( 55.03 )
    158 ( 55.07 )
    5.4 ( 26.47 )
        PC
    48.7 ( 55.75 )
    186.8 ( 79.39 )
    -12.9 ( 42.05 )
    No statistical analyses for this end point

    Secondary: Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 1 for subjects with normal renal function (PK population)

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    End point title
    Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 1 for subjects with normal renal function (PK population)
    End point description
    apoA-I and PC are analytes of CSL112
    End point type
    Secondary
    End point timeframe
    Before infusion 1 and end of Infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    185
    175
    183
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    36 ( 25.35 )
    134.5 ( 48.25 )
    -4 ( 16.95 )
        PC
    58 ( 37.06 )
    177.4 ( 67.93 )
    -1.3 ( 25.74 )
    No statistical analyses for this end point

    Secondary: Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 4 for subjects with normal renal function (PK population)

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    End point title
    Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 4 for subjects with normal renal function (PK population)
    End point description
    apoA-I and PC are analytes of CSL112
    End point type
    Secondary
    End point timeframe
    Before infusion 1 and end of Infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    173
    160
    171
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    54.7 ( 74.94 )
    154.3 ( 53.64 )
    4.8 ( 28.19 )
        PC
    47.6 ( 64.67 )
    182 ( 80.74 )
    -12.3 ( 44.89 )
    No statistical analyses for this end point

    Secondary: Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 1 for subjects with mild renal impairment (PK population)

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    End point title
    Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 1 for subjects with mild renal impairment (PK population)
    End point description
    apoA-I and PC are analytes of CSL112
    End point type
    Secondary
    End point timeframe
    Before infusion 1 and end of Infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    189
    212
    203
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    35.9 ( 19.05 )
    135.5 ( 59.05 )
    -5.3 ( 9.7 )
        PC
    57.8 ( 24.71 )
    180.6 ( 79.5 )
    -0.8 ( 14.95 )
    No statistical analyses for this end point

    Secondary: Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 4 for subjects with mild renal impairment (PK population)

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    End point title
    Baseline-Corrected Plasma Concentrations of apoA-I and PC at End of Infusion 4 for subjects with mild renal impairment (PK population)
    End point description
    apoA-I and PC are analytes of CSL112
    End point type
    Secondary
    End point timeframe
    Before infusion 1 and end of Infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    171
    195
    183
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    49.3 ( 26.73 )
    158.4 ( 56.19 )
    6 ( 25.68 )
        PC
    50.6 ( 47.17 )
    188.3 ( 79.39 )
    -13.2 ( 40.08 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)
    End point description
    Cmax is the maximal plasma concentration.
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    24
    21
    18
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    42.6 ( 11.2 )
    147.4 ( 31.9 )
    7.1 ( 7.9 )
        PC
    67.7 ( 19.2 )
    196.4 ( 36.2 )
    11.1 ( 15.2 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)
    End point description
    Cmax is the maximal plasma concentration.
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    22
    19
    17
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    57.6 ( 19.5 )
    164.3 ( 33.4 )
    12.7 ( 19.5 )
        PC
    59 ( 34.2 )
    187.4 ( 49.9 )
    9.1 ( 43.1 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)

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    End point title
    Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)
    End point description
    Cmax is the maximal plasma concentration.
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    13
    10
    13
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    40.9 ( 12 )
    135.1 ( 22.8 )
    7.8 ( 8.3 )
        PC
    61.9 ( 21 )
    184.9 ( 31.5 )
    13 ( 16.5 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)

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    End point title
    Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)
    End point description
    Cmax is the maximal plasma concentration.
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    12
    8
    12
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    60.8 ( 19.2 )
    149 ( 26.9 )
    17.5 ( 20.3 )
        PC
    45.8 ( 26.4 )
    176.1 ( 54 )
    20.1 ( 44.2 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)
    End point description
    Cmax is the maximal plasma concentration.
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    11
    10
    5
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    44.6 ( 10.2 )
    160.7 ( 37 )
    5.2 ( 7.3 )
        PC
    74.6 ( 14.7 )
    211.3 ( 37.5 )
    6 ( 10.8 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Baseline-corrected plasma Cmax for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)
    End point description
    Cmax is the maximal plasma concentration.
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    10
    10
    5
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    53.7 ( 20.1 )
    169.7 ( 29.3 )
    1 ( 12.1 )
        PC
    74.8 ( 37 )
    190.4 ( 46.7 )
    -17.4 ( 28.9 )
    No statistical analyses for this end point

    Secondary: Plasma Tmax for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)

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    End point title
    Plasma Tmax for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)
    End point description
    Tmax is time to maximal plasma concentration
    End point type
    Secondary
    End point timeframe
    Before and for 7 days after the first infusion
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    24
    21
    18
    Units: hours
    median (full range (min-max))
        apoA-I
    2.23 (1.7 to 236.9)
    2.17 (2 to 4)
    46.8 (0 to 216.3)
        PC
    2.23 (1.7 to 8.4)
    2.17 (2 to 4)
    5.29 (0 to 188.9)
    No statistical analyses for this end point

    Secondary: Plasma Tmax for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)

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    End point title
    Plasma Tmax for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)
    End point description
    Tmax is time to maximal plasma concentration
    End point type
    Secondary
    End point timeframe
    Before and for 7 days after the fourth infusion
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    22
    19
    17
    Units: hours
    median (full range (min-max))
        apoA-I
    2.13 (2 to 23.5)
    2.25 (2 to 4.2)
    119 (0 to 332.9)
        PC
    2.17 (2 to 53.1)
    2.25 (2 to 4.2)
    46.93 (0 to 187.3)
    No statistical analyses for this end point

    Secondary: Plasma Tmax for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)

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    End point title
    Plasma Tmax for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)
    End point description
    Tmax is time to maximal plasma concentration
    End point type
    Secondary
    End point timeframe
    Before and for 7 days after the first infusion
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    13
    10
    13
    Units: hours
    median (full range (min-max))
        apoA-I
    2.25 (1.7 to 236.9)
    2.17 (2 to 3.4)
    96.1 (0 to 216.3)
        PC
    2.22 (1.7 to 8.4)
    2.17 (2 to 3.4)
    8.1 (0 to 188.9)
    No statistical analyses for this end point

    Secondary: Plasma Tmax for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)

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    End point title
    Plasma Tmax for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)
    End point description
    Tmax is time to maximal plasma concentration
    End point type
    Secondary
    End point timeframe
    Before and for 7 days after the fourth infusion
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    12
    8
    12
    Units: hours
    median (full range (min-max))
        apoA-I
    2.13 (2.1 to 3.5)
    2.17 (2 to 2.4)
    119.3 (0 to 332.9)
        PC
    2.17 (2.1 to 53.1)
    2.17 (2 to 2.4)
    29 (0 to 187.3)
    No statistical analyses for this end point

    Secondary: Plasma Tmax for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Plasma Tmax for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)
    End point description
    Tmax is time to maximal plasma concentration
    End point type
    Secondary
    End point timeframe
    Before and for 7 days after the first infusion
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    11
    10
    5
    Units: hours
    median (full range (min-max))
        apoA-I
    2.18 (2.1 to 3.4)
    2.22 (2.1 to 4)
    0 (0 to 117.9)
        PC
    2.28 (2.1 to 5)
    2.22 (2.1 to 4)
    0 (0 to 5.3)
    No statistical analyses for this end point

    Secondary: Plasma Tmax for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Plasma Tmax for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)
    End point description
    Tmax is time to maximal plasma concentration
    End point type
    Secondary
    End point timeframe
    Before and for 7 days after the fourth infusion
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    10
    10
    5
    Units: hours
    median (full range (min-max))
        apoA-I
    2.17 (2 to 23.5)
    2.25 (2.1 to 4.2)
    72.5 (0 to 166.5)
        PC
    2.17 (2 to 8)
    2.25 (2.1 to 4.2)
    48.3 (9 to 166.5)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma area under the curve (AUC) AUC0 - last for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma area under the curve (AUC) AUC0 - last for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)
    End point description
    Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last]
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    24
    21
    18
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    1703 ( 2149 )
    4819 ( 2580 )
    -766 ( 2248 )
        PC
    -66.12 ( 3653 )
    869 ( 3796 )
    -2096 ( 3372 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)
    End point description
    Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last]
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    22
    19
    17
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    4579 ( 2705 )
    8985 ( 4263 )
    747 ( 3226 )
        PC
    70.7 ( 5327 )
    2499 ( 7662 )
    -2185 ( 5189 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)
    End point description
    Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last]
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    13
    10
    13
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    1278 ( 1742 )
    3762 ( 2367 )
    -516 ( 2091 )
        PC
    -1382 ( 2853 )
    -137 ( 4057 )
    -1337 ( 2590 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)
    End point description
    Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last]
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    12
    8
    12
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    4513 ( 2701 )
    8609 ( 4500 )
    1632 ( 3235 )
        PC
    -2130 ( 4691 )
    3609 ( 10232 )
    -542 ( 4480 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)
    End point description
    Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last]
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    11
    10
    5
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    2205 ( 2543 )
    5917 ( 2568 )
    -1416 ( 2763 )
        PC
    1489 ( 4003 )
    1828 ( 3661 )
    -4068 ( 4634 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0 - last for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)
    End point description
    Area under the plasma concentration time curve (AUC) from time point zero (baseline) to the last quantifiable time-point before the analyte first returns to baseline [AUC0 - last]
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    10
    10
    5
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    4659 ( 2854 )
    8786 ( 4201 )
    -1376 ( 2205 )
        PC
    2712 ( 5010 )
    1541 ( 5815 )
    -6128 ( 4998 )
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)
    End point description
    AUC from baseline to time point t (AUC0-t)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    24 [7]
    21 [8]
    18 [9]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I (0-24h)
    496 ( 212 )
    1929 ( 557 )
    -168 ( 158 )
        apoA-I (0-48h)
    731 ( 447 )
    2903 ( 944 )
    -331 ( 375 )
        apoA-I (0-72h)
    880 ( 726 )
    3516 ( 1248 )
    -439 ( 632 )
        apoA-I (0-96h)
    1006 ( 1104 )
    3943 ( 1581 )
    -541 ( 940 )
        apoA-I (0-168h)
    1009 ( 1761 )
    4734 ( 2382 )
    -452 ( 1498 )
        PC (0-24h)
    508 ( 349 )
    1545 ( 552 )
    -92 ( 229 )
        PC (0-48h)
    466 ( 744 )
    1627 ( 872 )
    -315 ( 522 )
        PC (0-72h)
    418 ( 1251 )
    1713 ( 1209 )
    -549 ( 886 )
        PC (0-96h)
    389 ( 1841 )
    1712 ( 1694 )
    -780 ( 1346 )
        PC (0-168h)
    -405 ( 3636 )
    1273 ( 2764 )
    -1494 ( 2501 )
    Notes
    [7] - apoA-I (0-168h, n=16); PC (0-96h, n=23); PC (0-168h, n=16)
    [8] - apoA-I (0-96h, n=20); apoA-I (0-168h, n=20); PC (0-168h, n=15)
    [9] - apoA-I (0-168h, n=10); PC (0-168h, n=11)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)
    End point description
    AUC from baseline to time point t (AUC0-t)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    22 [10]
    19 [11]
    17 [12]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I (0-24h)
    881 ( 422 )
    2392 ( 655 )
    -57 ( 377 )
        apoA-I (0-48h)
    1593 ( 798 )
    3913 ( 1235 )
    -55 ( 759 )
        apoA-I (0-72h)
    2195 ( 1177 )
    5050 ( 1794 )
    -6 ( 1160 )
        apoA-I (0-96h)
    2741 ( 1526 )
    6000 ( 2292 )
    90 ( 1590 )
        apoA-I (0-168h)
    3997 ( 2655 )
    8865 ( 3200 )
    1635 ( 3540 )
        PC (0-24h)
    462 ( 681 )
    1564 ( 1051 )
    -488 ( 772 )
        PC (0-48h)
    472 ( 1293 )
    1765 ( 1948 )
    -902 ( 1433 )
        PC (0-72h)
    509 ( 1989 )
    1899 ( 2823 )
    -1173 ( 2168 )
        PC (0-96h)
    518 ( 2679 )
    1951 ( 3681 )
    -1417 ( 2894 )
        PC (0-168h)
    -625 ( 4963 )
    2655 ( 6024 )
    -442 ( 6319 )
    Notes
    [10] - apoA-I (0-168h, n=18); PC (0-168h, n=16)
    [11] - apoA-I (0-168h, n=16); PC (0-168h, n=16)
    [12] - apoA-I (0-168h, n=8); PC (0-168h, n=8)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)
    End point description
    AUC from baseline to time point t (AUC0-t)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    13 [13]
    10 [14]
    13 [15]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I (0-24h)
    418 ( 117 )
    1653 ( 496 )
    -149 ( 123 )
        apoA-I (0-48h)
    547 ( 204 )
    2521 ( 955 )
    -316 ( 332 )
        apoA-I (0-72h)
    628 ( 337 )
    3064 ( 1280 )
    -435 ( 579 )
        apoA-I (0-96h)
    692 ( 554 )
    3342 ( 1642 )
    -528 ( 883 )
        apoA-I (0-168h)
    821 ( 1387 )
    3780 ( 2353 )
    -275 ( 1461 )
        PC (0-24h)
    364 ( 245 )
    1347 ( 661 )
    -46 ( 160 )
        PC (0-48h)
    145 ( 536 )
    1294 ( 1025 )
    -235 ( 441 )
        PC (0-72h)
    -38 ( 946 )
    1325 ( 1421 )
    -426 ( 759 )
        PC (0-96h)
    -256 ( 1415 )
    1218 ( 2005 )
    -569 ( 1162 )
        PC (0-168h)
    -1511 ( 3053 )
    437 ( 2061 )
    -1089 ( 2188 )
    Notes
    [13] - apoA-I (0-168h, n=8); PC (0-168h, n=9)
    [14] - apoA-I (0-96h, n=9); apoA-I (0-168h, n=9); PC (0-168h, n=7)
    [15] - apoA-I (0-168h, n=7); PC (0-168h, n=7)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)
    End point description
    AUC from baseline to time point t (AUC0-t)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    12 [16]
    8 [17]
    12 [18]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I (0-24h)
    929 ( 396 )
    2098 ( 463 )
    20 ( 417 )
        apoA-I (0-48h)
    1668 ( 753 )
    3459 ( 1001 )
    105 ( 820 )
        apoA-I (0-72h)
    2252 ( 1116 )
    4497 ( 1478 )
    249 ( 1232 )
        apoA-I (0-96h)
    2769 ( 1473 )
    5360 ( 1909 )
    459 ( 1666 )
        apoA-I (0-168h)
    3811 ( 2706 )
    8342 ( 2549 )
    2486 ( 2804 )
        PC (0-24h)
    189 ( 483 )
    1524 ( 1388 )
    -295 ( 819 )
        PC (0-48h)
    -59 ( 952 )
    1796 ( 2613 )
    -523 ( 1446 )
        PC (0-72h)
    -306 ( 1544 )
    2000 ( 3773 )
    -605 ( 2133 )
        PC (0-96h)
    -573 ( 2204 )
    2078 ( 4905 )
    -633 ( 2772 )
        PC (0-168h)
    -3853 ( 3242 )
    4584 ( 7822 )
    1253 ( 4446 )
    Notes
    [16] - apoA-I (0-168h, n=10); PC (0-168h, n=8)
    [17] - apoA-I (0-168h, n=6); PC (0-168h, n=6)
    [18] - apoA-I (0-168h, n=7); PC (0-168h, n=7)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)
    End point description
    AUC from baseline to time point t (AUC0-t)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    11 [19]
    10 [20]
    5 [21]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I (0-24h)
    589 ( 263 )
    2219 ( 515 )
    -218 ( 238 )
        apoA-I (0-48h)
    949 ( 560 )
    3308 ( 847 )
    -370 ( 514 )
        apoA-I (0-72h)
    1179 ( 946 )
    3998 ( 1152 )
    -451 ( 834 )
        apoA-I (0-96h)
    1376 ( 1468 )
    4517 ( 1465 )
    -576 ( 1188 )
        apoA-I (0-168h)
    1196 ( 2155 )
    5624 ( 2293 )
    -865 ( 1824 )
        PC (0-24h)
    678 ( 386 )
    1777 ( 353 )
    -212 ( 348 )
        PC (0-48h)
    845 ( 797 )
    1968 ( 623 )
    -523 ( 705 )
        PC (0-72h)
    956 ( 1393 )
    2093 ( 950 )
    -871 ( 1196 )
        PC (0-96h)
    1227 ( 2058 )
    2194 ( 1351 )
    -1329 ( 1769 )
        PC (0-168h)
    1018 ( 4052 )
    2004 ( 3214 )
    2203 ( 3197 )
    Notes
    [19] - apoA-I (0-168h, n=8); PC (0-96h, n=10); PC (0-168h, n=7)
    [20] - PC (0-168h, n=8)
    [21] - apoA-I (0-168h, n=3); PC (0-168h, n=4)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0-t for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)
    End point description
    AUC from baseline to time point t (AUC0-t)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    10 [22]
    10 [23]
    5 [24]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I (0-24h)
    823 ( 466 )
    2469 ( 573 )
    -243 ( 170 )
        apoA-I (0-48h)
    1503 ( 881 )
    4049 ( 1221 )
    -440 ( 436 )
        apoA-I (0-72h)
    2128 ( 1304 )
    5226 ( 1910 )
    -617 ( 741 )
        apoA-I (0-96h)
    2707 ( 1669 )
    6212 ( 2503 )
    -796 ( 1045 )
        apoA-I (0-168h)
    4229 ( 2754 )
    8840 ( 3678 )
    -4322 ( 0 )
        PC (0-24h)
    789 ( 760 )
    1518 ( 799 )
    -950 ( 405 )
        PC (0-48h)
    1110 ( 1402 )
    1650 ( 1474 )
    -1810 ( 1001 )
        PC (0-72h)
    1487 ( 2090 )
    1726 ( 2176 )
    -2536 ( 1731 )
        PC (0-96h)
    1826 ( 2706 )
    1751 ( 2867 )
    -3297 ( 2471 )
        PC (0-168h)
    2603 ( 4295 )
    1316 ( 4998 )
    -12308 ( 0 )
    Notes
    [22] - apoA-I (0-168h, n=8); PC (0-168h, n=8)
    [23] - apoA-I (0-168h, n=9); PC (0-168h, n=9)
    [24] - apoA-I (0-168h, n=1); PC (0-168h, n=1)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)
    End point description
    AUC0-∞ is plasma area under the curve (AUC0-infinity)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    6
    16 [25]
    1 [26]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    1425 ( 1297 )
    6090 ( 3642 )
    0 ( 0 )
        PC
    1850 ( 3120 )
    1678 ( 651 )
    6979 ( 0 )
    Notes
    [25] - PC (n=10)
    [26] - apoA-I (n=0)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)
    End point description
    AUC0-∞ is plasma area under the curve (AUC0-infinity)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    10 [27]
    15 [28]
    1 [29]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    15540 ( 19437 )
    13570 ( 6965 )
    4615 ( 0 )
        PC
    2015 ( 2855 )
    12863 ( 16731 )
    0 ( 0 )
    Notes
    [27] - PC (n=6)
    [28] - PC (n=11)
    [29] - PC (n=0)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)

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    End point title
    Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)
    End point description
    AUC0-∞ is plasma area under the curve (AUC0-infinity)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    3 [30]
    8 [31]
    0 [32]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    589 ( 17 )
    4505 ( 2528 )
    ( )
        PC
    490 ( 1540 )
    1596 ( 785 )
    ( )
    Notes
    [30] - apoA-I (n=2)
    [31] - PC (n=5)
    [32] - No values collected for this point.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)
    End point description
    AUC0-∞ is plasma area under the curve (AUC0-infinity)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    7 [33]
    5 [34]
    1 [35]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    17079 ( 23224 )
    12422 ( 7399 )
    4615 ( 0 )
        PC
    638 ( 566 )
    16142 ( 17777 )
    0 ( 0 )
    Notes
    [33] - PC (n=4)
    [34] - PC (n=3)
    [35] - PC (n=0)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)
    End point description
    AUC0-∞ is plasma area under the curve (AUC0-infinity)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    4 [36]
    7 [37]
    1 [38]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    1842 ( 1451 )
    8032 ( 4220 )
    0 ( 0 )
        PC
    3210 ( 4052 )
    1761 ( 566 )
    6979 ( 0 )
    Notes
    [36] - PC (n=3)
    [37] - PC (n=5)
    [38] - apoA-I (n=0)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma AUC0-∞ for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)
    End point description
    AUC0-∞ is plasma area under the curve (AUC0-infinity)
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    3 [39]
    9 [40]
    0 [41]
    Units: mg•h/dL
    arithmetic mean (standard deviation)
        apoA-I
    11951 ( 7374 )
    13157 ( 6734 )
    ( )
        PC
    4769 ( 4128 )
    12827 ( 18453 )
    ( )
    Notes
    [39] - PC (n=2)
    [40] - PC (n=7)
    [41] - Values were not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    6
    16 [42]
    1 [43]
    Units: hours
    arithmetic mean (standard deviation)
        apoA-I
    46.4 ( 33.1 )
    53.9 ( 38.7 )
    0 ( 0 )
        PC
    32.9 ( 29.6 )
    9.7 ( 7.2 )
    241.2 ( 0 )
    Notes
    [42] - PC (n=10)
    [43] - apoA-I (n=0)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    10 [44]
    15 [45]
    1 [46]
    Units: hours
    arithmetic mean (standard deviation)
        apoA-I
    269.1 ( 292 )
    103.6 ( 61.1 )
    145 ( 0 )
        PC
    21.5 ( 20.6 )
    156.3 ( 245.8 )
    0 ( 0 )
    Notes
    [44] - PC (n=6)
    [45] - PC (n=11)
    [46] - PC (n=0)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    3 [47]
    8 [48]
    0 [49]
    Units: hours
    arithmetic mean (standard deviation)
        apoA-I
    7.5 ( 1.7 )
    41.4 ( 24.1 )
    ( )
        PC
    34 ( 27.7 )
    12.3 ( 8.9 )
    ( )
    Notes
    [47] - apoA-I (n=2)
    [48] - PC (n=5)
    [49] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    7 [50]
    5 [51]
    1 [52]
    Units: hours
    arithmetic mean (standard deviation)
        apoA-I
    271.6 ( 317.4 )
    96.5 ( 47.3 )
    145 ( 0 )
        PC
    9.1 ( 9.3 )
    121.1 ( 102.7 )
    0 ( 0 )
    Notes
    [50] - PC (n=4)
    [51] - PC (n=3)
    [52] - PC (n=0)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    4 [53]
    7 [54]
    1 [55]
    Units: hours
    arithmetic mean (standard deviation)
        apoA-I
    65.9 ( 17.5 )
    66.4 ( 51.4 )
    0 ( 0 )
        PC
    31.8 ( 37.7 )
    7.1 ( 4.4 )
    241.2 ( 0 )
    Notes
    [53] - PC (n=3)
    [54] - PC (n=5)
    [55] - apoA-I (n=0)
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Terminal Half-life (t1/2) for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    3 [56]
    9 [57]
    0 [58]
    Units: hours
    arithmetic mean (standard deviation)
        apoA-I
    263.1 ( 285.4 )
    99.2 ( 68.2 )
    ( )
        PC
    46.3 ( 2.2 )
    185.6 ( 306.5 )
    ( )
    Notes
    [56] - PC (n=2)
    [57] - PC (n=7)
    [58] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    6 [59]
    16 [60]
    0 [61]
    Units: L/h
    arithmetic mean (standard deviation)
        apoA-I
    0.29 ( 0.27 )
    0.15 ( 0.13 )
    ( )
        PC
    0.32 ( 0.26 )
    0.61 ( 0.26 )
    ( )
    Notes
    [59] - PC (n=5)
    [60] - PC (n=10)
    [61] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    17 [62]
    16 [63]
    0 [64]
    Units: L/h
    arithmetic mean (standard deviation)
        apoA-I
    0.09 ( 0.1 )
    0.07 ( 0.02 )
    ( )
        PC
    0.11 ( 0.09 )
    0.57 ( 1.12 )
    ( )
    Notes
    [62] - PC (n=6)
    [63] - PC (n=11)
    [64] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    2
    8 [65]
    0 [66]
    Units: L/h
    arithmetic mean (standard deviation)
        apoA-I
    0.33 ( 0.01 )
    0.19 ( 0.17 )
    ( )
        PC
    0.41 ( 0.38 )
    0.68 ( 0.35 )
    ( )
    Notes
    [65] - PC (n=5)
    [66] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    10 [67]
    6 [68]
    0 [69]
    Units: L/h
    arithmetic mean (standard deviation)
        apoA-I
    0.11 ( 0.12 )
    0.08 ( 0.02 )
    ( )
        PC
    0.24 ( 0 )
    0.19 ( 0.12 )
    ( )
    Notes
    [67] - PC (n=1)
    [68] - PC (n=5)
    [69] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    4 [70]
    7 [71]
    0 [72]
    Units: L/h
    arithmetic mean (standard deviation)
        apoA-I
    0.27 ( 0.35 )
    0.09 ( 0.05 )
    ( )
        PC
    0.26 ( 0.23 )
    0.54 ( 0.13 )
    ( )
    Notes
    [70] - PC (n=3)
    [71] - PC (n=5)
    [72] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Clearance (CL) for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    7 [73]
    9 [74]
    0 [75]
    Units: L/h
    arithmetic mean (standard deviation)
        apoA-I
    0.05 ( 0.02 )
    0.08 ( 0.03 )
    ( )
        PC
    0.08 ( 0.07 )
    1.01 ( 1.63 )
    ( )
    Notes
    [73] - PC (n=5)
    [74] - PC (n=5)
    [75] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma volume of distribution at steady state (Vss) for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma volume of distribution at steady state (Vss) for apoA-I and PC after Infusion 1 for all subjects (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    6 [76]
    16 [77]
    0 [78]
    Units: Liters
    arithmetic mean (standard deviation)
        apoA-I
    33.4 ( 64.7 )
    7.4 ( 3.1 )
    ( )
        PC
    6.1 ( 4.4 )
    14.4 ( 33.3 )
    ( )
    Notes
    [76] - PC (n=5)
    [77] - PC (n=10)
    [78] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Vss for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)

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    End point title
    Baseline-corrected plasma Vss for apoA-I and PC after Infusion 4 for all subjects (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    10 [79]
    15 [80]
    0 [81]
    Units: Liters
    arithmetic mean (standard deviation)
        apoA-I
    18.7 ( 16.6 )
    9.4 ( 4.7 )
    ( )
        PC
    10.7 ( 7.5 )
    58.3 ( 94.9 )
    ( )
    Notes
    [79] - PC (n=6)
    [80] - PC (n=11)
    [81] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Vss for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Vss for apoA-I and PC after Infusion 1 for subjects with normal renal function (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    2
    8 [82]
    0 [83]
    Units: Liters
    arithmetic mean (standard deviation)
        apoA-I
    3.8 ( 0.9 )
    8.1 ( 3.8 )
    ( )
        PC
    8.3 ( 7.7 )
    24.7 ( 47.2 )
    ( )
    Notes
    [82] - PC (n=5)
    [83] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Vss for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)

    Close Top of page
    End point title
    Baseline-corrected plasma Vss for apoA-I and PC after Infusion 4 for subjects with normal renal function (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    7 [84]
    5 [85]
    0 [86]
    Units: Liters
    arithmetic mean (standard deviation)
        apoA-I
    18.7 ( 16.1 )
    9.4 ( 2.5 )
    ( )
        PC
    11.4 ( 8.3 )
    17 ( 10.3 )
    ( )
    Notes
    [84] - PC (n=4)
    [85] - PC (n=3)
    [86] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Vss for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Baseline-corrected plasma Vss for apoA-I and PC after Infusion 1 for subjects with mild renal impairment (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 1
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    4 [87]
    7 [88]
    0 [89]
    Units: Liters
    arithmetic mean (standard deviation)
        apoA-I
    48.2 ( 78.1 )
    6.4 ( 2.3 )
    ( )
        PC
    4.7 ( 1.3 )
    4 ( 1.5 )
    ( )
    Notes
    [87] - PC (n=3)
    [88] - PC (n=5)
    [89] - Values not collected.
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma Vss for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)

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    End point title
    Baseline-corrected plasma Vss for apoA-I and PC after Infusion 4 for subjects with mild renal impairment (PK/PD population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1 (baseline) and for up to approximately 7 days after infusion 4
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    3 [90]
    9 [91]
    0 [92]
    Units: Liters
    arithmetic mean (standard deviation)
        apoA-I
    18.7 ( 21.3 )
    9.4 ( 5.9 )
    ( )
        PC
    9.3 ( 8.2 )
    83.1 ( 114 )
    ( )
    Notes
    [90] - PC (n=2)
    [91] - PC (n=7)
    [92] - Values not collected.
    No statistical analyses for this end point

    Secondary: Percent of subjects with the occurrence of adverse drug reactions (Safety population)

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    End point title
    Percent of subjects with the occurrence of adverse drug reactions (Safety population)
    End point description
    The overall percentage of subjects: ◦with adverse events (AEs), including local tolerability events, that begin during or within 1 hour of an infusion; or ◦with AEs considered to be causally related to the test product; or ◦who experience an AE for which the incidence rate in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more
    End point type
    Secondary
    End point timeframe
    From the start of infusion 1, up to approximately Day 382
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    415
    416
    413
    Units: percent of subjects
        number (not applicable)
    31.8
    28.4
    23.5
    No statistical analyses for this end point

    Secondary: Percent of subjects with any AE (Safety population)

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    End point title
    Percent of subjects with any AE (Safety population)
    End point description
    End point type
    Secondary
    End point timeframe
    From the start of infusion 1, up to approximately Day 382
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    415
    416
    413
    Units: Percent of subjects
        number (not applicable)
    50.6
    51.4
    49.6
    No statistical analyses for this end point

    Secondary: Percent of subjects who experience bleeding events (Safety population)

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    End point title
    Percent of subjects who experience bleeding events (Safety population)
    End point description
    Percent of subjects who experience bleeding events as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al, 2011)
    End point type
    Secondary
    End point timeframe
    From the start of infusion 1, up to approximately Day 112
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    415
    416
    413
    Units: Percent of subjects
        number (not applicable)
    9.2
    9.1
    12.3
    No statistical analyses for this end point

    Secondary: Change from baseline to end of study in serum antibodies to CSL112 and apoA-I (Safety population)

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    End point title
    Change from baseline to end of study in serum antibodies to CSL112 and apoA-I (Safety population)
    End point description
    End point type
    Secondary
    End point timeframe
    Before infusion 1, up to approximately Day 112
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    377
    389
    380
    Units: Titer
    arithmetic mean (standard deviation)
        Anti-CSL112 antibody
    0 ( 0.14 )
    0 ( 0.2 )
    0 ( 0.2 )
        Anti-apoA-I antibody
    0 ( 0.09 )
    0 ( 0.14 )
    0 ( 0.1 )
    No statistical analyses for this end point

    Secondary: Number of subjects with positive serology results for IgG and IgM antibodies to parvovirus B19 (Serology population)

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    End point title
    Number of subjects with positive serology results for IgG and IgM antibodies to parvovirus B19 (Serology population)
    End point description
    Assessments (i.e., evidence of seroconversion or infection) will be conducted for parvovirus B19.
    End point type
    Secondary
    End point timeframe
    Study Day 112
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    60
    60
    60
    Units: Number of subjects
    number (not applicable)
        IgG
    40
    48
    44
        IgM
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with parvovirus B19 DNA in serum (Serology population)

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    End point title
    Number of subjects with parvovirus B19 DNA in serum (Serology population)
    End point description
    Assessments (i.e., evidence of seroconversion or infection) will be conducted for parvovirus B19
    End point type
    Secondary
    End point timeframe
    Study Day 112
    End point values
    CSL112 (2 g) CSL112 (6 g) Placebo
    Number of subjects analysed
    60
    60
    60
    Units: Number of subjects
    number (not applicable)
        Not detected
    57
    60
    59
        < 101 IU/mL
    1
    0
    1
        Missing
    2
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 year, 10 months
    Adverse event reporting additional description
    The Serious Adverse Events include both treatment-emergent and non-treatment emergent events.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Safety Lead-in [CSL112 (2 g)]
    Reporting group description
    In the safety lead-in, a small number of subjects (evenly stratified between subjects with normal renal function or mild renal impairment) were administered a single, 2 g infusion of CSL112.

    Reporting group title
    CSL112 (2 g)
    Reporting group description
    CSL112 (low dose) was administered as an intravenous (IV) infusion once weekly for 4 consecutive weeks.

    Reporting group title
    CSL112 (6 g)
    Reporting group description
    CSL112 (high dose) was administered as an IV infusion once weekly for 4 consecutive weeks.

    Reporting group title
    Placebo
    Reporting group description
    Placebo was administered as an IV infusion at the same frequency, volume and duration as either the low dose or high dose CSL112 infusion.

    Serious adverse events
    Safety Lead-in [CSL112 (2 g)] CSL112 (2 g) CSL112 (6 g) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    66 / 415 (15.90%)
    54 / 416 (12.98%)
    55 / 413 (13.32%)
         number of deaths (all causes)
    1
    5
    4
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal neoplasm
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    2 / 413 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    9 / 415 (2.17%)
    4 / 416 (0.96%)
    5 / 413 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 415 (0.48%)
    4 / 416 (0.96%)
    4 / 413 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular stent restenosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    2 / 413 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular stent thrombosis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 415 (0.48%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    1 / 416 (0.24%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 415 (0.48%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery restenosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arteriovenous malformation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 415 (1.20%)
    6 / 416 (1.44%)
    5 / 413 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 9 (0.00%)
    6 / 415 (1.45%)
    3 / 416 (0.72%)
    4 / 413 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 415 (0.72%)
    1 / 416 (0.24%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 415 (0.72%)
    1 / 416 (0.24%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    3 / 416 (0.72%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 415 (0.72%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 415 (0.48%)
    0 / 416 (0.00%)
    2 / 413 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac aneurysm
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac asthma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular septal defect acquired
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery dissection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 415 (0.72%)
    3 / 416 (0.72%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 415 (0.48%)
    2 / 416 (0.48%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 415 (0.72%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal ganglia haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Carotid artery disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cluster headache
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 415 (0.48%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    2 / 416 (0.48%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 415 (0.48%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postrenal failure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fasciitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    1 / 416 (0.24%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral fungal infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    2 / 413 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 415 (0.24%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    1 / 413 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 415 (0.00%)
    1 / 416 (0.24%)
    0 / 413 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety Lead-in [CSL112 (2 g)] CSL112 (2 g) CSL112 (6 g) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 9 (22.22%)
    15 / 415 (3.61%)
    23 / 416 (5.53%)
    9 / 413 (2.18%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Extrasystoles
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    15 / 415 (3.61%)
    23 / 416 (5.53%)
    9 / 413 (2.18%)
         occurrences all number
    0
    19
    24
    10
    Skin and subcutaneous tissue disorders
    Skin exfoliation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 415 (0.00%)
    0 / 416 (0.00%)
    0 / 413 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2013
    1. A safety lead-in period was added to assess the safety and tolerability of CSL112 compared to placebo in subjects with acute myocardial infarction, with the requirement of safety data review by the Data Safety Monitoring Board from this lead-in period prior to enrolment of subjects into the main study. The safety lead-in period was added to this study to fulfill a request from FDA. 2. A pharmacokinetic (PK)/pharmacodynamics (PD) substudy was added to the protocol with intense sampling to occur in approximately 48 subjects after doses 1 and 4, with only sparse PK/PD sampling of subjects to be included in the main study. 3. New assessments were added to schedules for monitoring safety: i. presence of hypovolemia ii. determination and review of serum creatinine and ALT values prior to dosing iii. drug hypersensitivity reactions iv. urinalysis v. exploratory renal biomarkers (limited to PK/PD substudy only). 4. The objectives of the study were modified and changes were made to the corresponding endpoints. The secondary objectives now include characterization of the safety and tolerability and the pharmacokinetics of CSL112 in subjects with acute myocardial infarction. 5. The inclusion criterion defining eligibility restrictions for subjects who undergo angiography were modified, reducing the magnitude of allowable increases in serum creatinine post contrast agent administration. Further definition was also provided regarding the meaning of “significant” ST/T wave changes. 6. Modifications/clarifications of and additional dose delay/dose stopping rules were added to the protocol with respect to confirming subject eligibility for initial and subsequent investigational product treatment based on serum creatinine values.
    01 Oct 2014
    1. Assessment of bilirubin was included in criteria for determining stable hepatic function and levels were defined for dose delay/stopping rules in the main study. 2. Serology and nucleic acid testing was revised to test only for the presence of parvovirus B19 instead of testing for 5 pathogens (ie, HIV 1/2, hepatitis A virus, hepatitis B virus, hepatitis C virus, and parvovirus B19) as originally planned. 3. Inclusion of a new methods section and requirement of additional measurements (repeat assessment of hemoglobin level, serum haptoglobin levels, lactate dehydrogenase, total and direct bilirubin levels, including the calculation of indirect bilirubin, and urine hemosiderin) for assessment of hemolysis for any ≥ 2 g/dL decrease in hemoglobin not explained by overt blood loss. 4. Parameters were set for the maximum duration between infusions (at least 7 days and no more than 10 days) and allowance for fewer than 4 infusions to be administered if the total duration from Study Day 1 would exceed 30 days (ie, discussed in text as “missed infusions”). 5. Drug-related adverse events (adverse reactions), changing the time window relative to infusion from within 72 hours to within 1 hour for classification and reporting requirements of adverse drug reactions that occur with an incidence > 30% of that of the placebo rate and that occur in at least 1% of subjects is redefined.
    14 Jul 2015
    1. Allowed for screening and randomization to occur on the same day if specific criteria are met. 2. For screening and randomization occurring on the same day, allowed for a single blood draw to be performed at screening to collect two samples, one for local and one for central laboratory testing. 3. Decreased retention time for virology samples to 1 year from 5 years. 4. Further defined adverse events of special interest and added potential Hy's law and drug hypersensitivity reactions to the adverse event of special interest section. 5. Further defined the drug hypersensitivity reaction assessment. 6. Added collection of a standard of care serum creatinine value prior to administration of contrast agent. 7. Modified the secondary endpoint language for evaluation of adverse drug reactions. 8. Added the definition of first medical contact 9. In reviewing the available study data and the FDA-suggested guidelines and analyses for early dosing of investigational product following contrast administration, the DSMB assessed the safety of the investigational product when administered within 48 h from contrast administration and determined that earlier treatment could be initiated in the US cohort of patients. The recommendation harmonized the US with all other sites and allowed the study to be conducted under a single global harmonized protocol (allowing administration of investigational product to be as early as 12 h after the index event or 12 h after the administration of IV contrast media once renal function is determined to be stable).

    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.
    This study was not designed to test for efficacy and was underpowered to assess efficacy. The overall number of MACE was low and the number of subjects with complete follow-up through 1 year was also low (89 of 1258 subjects; 7.1%).
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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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