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    Clinical Trial Results:
    A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Safety and Efficacy Trial of Multiple Dosing Regimens of ABT-719 for the Prevention of Acute Kidney Injury in Subjects Undergoing High Risk Cardiac Surgery

    Summary
    EudraCT number
    2012-003942-33
    Trial protocol
    DK  
    Global end of trial date
    07 Mar 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    18 May 2016
    First version publication date
    25 Jul 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    potential category issues

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-796
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01777165
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    Abbott House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire , United Kingdom, SL6 4XE
    Public contact
    Global Medical Information, AbbVie, 001 800-633-9110,
    Scientific contact
    Ann Eldred, MD, AbbVie, ann.eldred@abbvie.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
    07 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study objective is to compare the safety and efficacy of doses of 800 mcg/kg, 1600 mcg/kg and 2100 mcg/kg intravenous (IV) infusions of ABT-719 to placebo in subjects who are at risk of acute kidney injury (AKI) and undergoing pre-defined on-pump cardiac surgery.
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Feb 2013
    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
    Denmark: 49
    Country: Number of subjects enrolled
    United States: 191
    Worldwide total number of subjects
    240
    EEA total number of subjects
    49
    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)
    66
    From 65 to 84 years
    162
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled at 39 investigative sites in Denmark and the United States.

    Pre-assignment
    Screening details
    Screening visit occurred between Day -28 and Day -5 prior to surgery.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    A total of 6, 10-minute infusions administered 1) prior to skin incision; 2) before clamp release but at least 1 hour after the first dose 3) 6 hours (± 30 minutes) after clamp release; 4) 12 hours (± 30 minutes) after clamp release; 5) 24 hours (± 60 minutes) after clamp release; and 6) 48 hours (± 60 minutes) after clamp release.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo administered by intravenous infusion

    Arm title
    ABT-719 800 mcg/kg
    Arm description
    Six 10-minute infusions with a total dose of 800 mcg/kg ABT-719, administered 1) prior to skin incision (200 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (400 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (200 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (0 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (0 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (0 mcg/kg).
    Arm type
    Experimental

    Investigational medicinal product name
    ABT-719
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    ABT-719 administered by intravenous infusion

    Arm title
    ABT-719 1600 mcg/kg
    Arm description
    Six 10-minute infusions with a total dose of 1600 mcg/kg ABT-719, administered 1) prior to skin incision (300 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (600 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (200 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (200 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (200 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (0 mcg/kg).
    Arm type
    Experimental

    Investigational medicinal product name
    ABT-719
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    ABT-719 administered by intravenous infusion

    Arm title
    ABT-719 2100 mcg/kg
    Arm description
    Six 10-minute infusions with a total dose of 2100 mcg/kg ABT-719, administered 1) prior to skin incision (300 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (600 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (300 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (300 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (300 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (300 mcg/kg).
    Arm type
    Experimental

    Investigational medicinal product name
    ABT-719
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    ABT-719 administered by intravenous infusion

    Number of subjects in period 1 [1]
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Started
    59
    57
    59
    56
    Completed
    51
    54
    55
    49
    Not completed
    8
    3
    4
    7
         Other, not specified
    8
    3
    4
    7
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 240 subjects were enrolled; 9 subjects discontinued before receiving any study drug; and 231 subjects are included in the full analysis set (FAS).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    A total of 6, 10-minute infusions administered 1) prior to skin incision; 2) before clamp release but at least 1 hour after the first dose 3) 6 hours (± 30 minutes) after clamp release; 4) 12 hours (± 30 minutes) after clamp release; 5) 24 hours (± 60 minutes) after clamp release; and 6) 48 hours (± 60 minutes) after clamp release.

    Reporting group title
    ABT-719 800 mcg/kg
    Reporting group description
    Six 10-minute infusions with a total dose of 800 mcg/kg ABT-719, administered 1) prior to skin incision (200 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (400 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (200 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (0 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (0 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (0 mcg/kg).

    Reporting group title
    ABT-719 1600 mcg/kg
    Reporting group description
    Six 10-minute infusions with a total dose of 1600 mcg/kg ABT-719, administered 1) prior to skin incision (300 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (600 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (200 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (200 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (200 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (0 mcg/kg).

    Reporting group title
    ABT-719 2100 mcg/kg
    Reporting group description
    Six 10-minute infusions with a total dose of 2100 mcg/kg ABT-719, administered 1) prior to skin incision (300 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (600 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (300 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (300 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (300 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (300 mcg/kg).

    Reporting group values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg Total
    Number of subjects
    59 57 59 56 231
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71.1 ( 9.39 ) 68.9 ( 10.23 ) 67.7 ( 12.54 ) 68.6 ( 10.6 ) -
    Gender categorical
    Units: Subjects
        Female
    13 17 16 20 66
        Male
    46 40 43 36 165

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    A total of 6, 10-minute infusions administered 1) prior to skin incision; 2) before clamp release but at least 1 hour after the first dose 3) 6 hours (± 30 minutes) after clamp release; 4) 12 hours (± 30 minutes) after clamp release; 5) 24 hours (± 60 minutes) after clamp release; and 6) 48 hours (± 60 minutes) after clamp release.

    Reporting group title
    ABT-719 800 mcg/kg
    Reporting group description
    Six 10-minute infusions with a total dose of 800 mcg/kg ABT-719, administered 1) prior to skin incision (200 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (400 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (200 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (0 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (0 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (0 mcg/kg).

    Reporting group title
    ABT-719 1600 mcg/kg
    Reporting group description
    Six 10-minute infusions with a total dose of 1600 mcg/kg ABT-719, administered 1) prior to skin incision (300 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (600 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (200 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (200 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (200 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (0 mcg/kg).

    Reporting group title
    ABT-719 2100 mcg/kg
    Reporting group description
    Six 10-minute infusions with a total dose of 2100 mcg/kg ABT-719, administered 1) prior to skin incision (300 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (600 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (300 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (300 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (300 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (300 mcg/kg).

    Subject analysis set title
    Placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomized subjects who received all 6 infusions of study drug and underwent the pre-defined on-pump cardiac surgery.

    Subject analysis set title
    ABT-719 800 mcg/kg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomized subjects who received all 6 infusions of study drug and underwent the pre-defined on-pump cardiac surgery.

    Subject analysis set title
    ABT-719 1600 mcg/kg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomized subjects who received all 6 infusions of study drug and underwent the pre-defined on-pump cardiac surgery.

    Subject analysis set title
    ABT-719 2100 mcg/kg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomized subjects who received all 6 infusions of study drug and underwent the pre-defined on-pump cardiac surgery.

    Primary: Percentage of Subjects Developing Acute Kidney Injury (AKI) as Defined by the Acute Kidney Injury Network (AKIN) Scoring Criteria

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    End point title
    Percentage of Subjects Developing Acute Kidney Injury (AKI) as Defined by the Acute Kidney Injury Network (AKIN) Scoring Criteria
    End point description
    The AKIN is an evidence-based definition for AKI based on changes to serum creatinine (SCr), urine output (UO), and renal replacement therapy (RRT). The 3 severity grades are defined on the basis of the changes in SCr or UO where the worst of each criterion is used: Stage 1 (increased Cr x 1.5 or ≥ 0.3 mg/dL; UO < 0.5 mL/kg/hr x 6 hr), Stage 2 (increased Cr x 2; UO < 0.5 mL/kg/hr x 12 hr), and Stage 3 (increased Cr x 3 Cr ≥ 4 mg/dL with acute rise of ≥ 0.5 mg/dL; UO < 0.3 mL/kg/hr x 24 hr or anuria x 12 hr). A change in SCr of ≥ 26.2 µmol/L) defines the presence of AKI. The AKIN scoring criteria includes a time limit of 48 hours for diagnosis of AKI, and any patients receiving RRT are classified as Stage 3 AKI, regardless of the stage that the patient is in at the time of commencement of RRT. The number of subjects analyzed = all subjects in the full analysis set with available data.
    End point type
    Primary
    End point timeframe
    Day 0 (Surgery) to Day 7
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    58
    55
    59
    56
    Units: percentage of subjects
    number (not applicable)
        No
    29.31
    27.27
    35.59
    28.57
        Stage 1
    10.34
    18.18
    6.78
    14.29
        Stage 2
    48.28
    49.09
    50.85
    51.79
        Stage 3
    12.07
    5.45
    6.78
    5.36
        Any stage
    70.69
    72.73
    64.41
    71.43
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    P-value from pairwise comparisons between each ABT-719 dose group and placebo using 2-sided Cochran-Mantel-Haenszel test after adjustment for type of surgery and SCr-based estimated glomerular filtration rate (eGFR).
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.848
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    P-value from pairwise comparisons between each ABT-719 dose group and placebo using 2-sided Cochran-Mantel-Haenszel test after adjustment for type of surgery and SCr-based estimated glomerular filtration rate (eGFR).
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.469
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    P-value from pairwise comparisons between each ABT-719 dose group and placebo using 2-sided Cochran-Mantel-Haenszel test after adjustment for type of surgery and SCr-based estimated glomerular filtration rate (eGFR).
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.906
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of Subjects Developing a Composite Event (Death, Renal Replacement Therapy [RRT], or 25% Reduction in Serum Creatinine Based Estimated Glomerular Filtration Rate [SCr eGFR]) – Day 90

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    End point title
    Percentage of Subjects Developing a Composite Event (Death, Renal Replacement Therapy [RRT], or 25% Reduction in Serum Creatinine Based Estimated Glomerular Filtration Rate [SCr eGFR]) – Day 90
    End point description
    The percentage of subjects developing at least 1 of the composite events: death, needing RRT during the 90 day post-operative period, or having a ≥25% reduction in SCr eGFR at the Day 90 post-surgery visit. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    52
    54
    55
    42
    Units: percentage of subjects
        number (not applicable)
    19.23
    12.96
    10.91
    20.41
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Developing a Composite Event (Death, Renal Replacement Therapy [RRT], or 50% Reduction in Serum Creatinine Based Estimated Glomerular Filtration Rate [SCr eGFR]) – Day 90

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    End point title
    Percentage of Subjects Developing a Composite Event (Death, Renal Replacement Therapy [RRT], or 50% Reduction in Serum Creatinine Based Estimated Glomerular Filtration Rate [SCr eGFR]) – Day 90
    End point description
    The percentage of subjects developing at least 1 of the composite events: death, needing RRT during the 90 day post-operative period, or having a ≥50% reduction in SCr eGFR at the Day 90 post-surgery visit. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    52
    54
    55
    49
    Units: percentage of subjects
        number (not applicable)
    11.54
    5.56
    3.64
    8.16
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Developing a Composite Event (Death, Renal Replacement Therapy [RRT], or 25% Reduction in S-Cystatin C Based Estimated Glomerular Filtration Rate [SCr eGFR]) – Day 90

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    End point title
    Percentage of Subjects Developing a Composite Event (Death, Renal Replacement Therapy [RRT], or 25% Reduction in S-Cystatin C Based Estimated Glomerular Filtration Rate [SCr eGFR]) – Day 90
    End point description
    The percentage of subjects developing at least 1 of the composite events: death, needing RRT during the 90 day post-operative period, or having a ≥25% reduction in S-Cystatin C eGFR at the Day 90 post-surgery visit. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    52
    54
    55
    49
    Units: percentage of subjects
        number (not applicable)
    13.46
    7.41
    7.27
    10.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Developing a Composite Event (Death, Renal Replacement Therapy [RRT], or 50% Reduction in S-Cystatin C Based Estimated Glomerular Filtration Rate [SCr eGFR]) – Day 90

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    End point title
    Percentage of Subjects Developing a Composite Event (Death, Renal Replacement Therapy [RRT], or 50% Reduction in S-Cystatin C Based Estimated Glomerular Filtration Rate [SCr eGFR]) – Day 90
    End point description
    The percentage of subjects developing at least 1 of the composite events: death, needing RRT during the 90 day post-operative period, or having a ≥50% reduction in S-Cystatin C eGFR at the Day 90 post-surgery visit. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    49
    52
    52
    46
    Units: percentage of subjects
        number (not applicable)
    11.54
    7.41
    1.82
    8.16
    No statistical analyses for this end point

    Secondary: Serum Neutrophil Gelatinase Associated Lipocalin (NGAL): Change from Baseline to Day 90

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    End point title
    Serum Neutrophil Gelatinase Associated Lipocalin (NGAL): Change from Baseline to Day 90
    End point description
    From repeated measures analysis. The least squares mean (LS mean) change from baseline to each visit in serum NGAL (ng/mL). Lower measures for NGAL are desirable. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    42
    47
    44
    36
    Units: ng/mL
        least squares mean (standard error)
    120.4 ( 38.6 )
    78.5 ( 36.7 )
    113.1 ( 37.8 )
    113.7 ( 41.6 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -41.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -146.3
         upper limit
    62.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    53.2
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    ABT-719 1600 mcg/kg v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -113.3
         upper limit
    62.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    54
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -118
         upper limit
    104.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    56.7

    Secondary: Urine Interleukin-18 (IL-18): Change from Baseline to Day 90

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    End point title
    Urine Interleukin-18 (IL-18): Change from Baseline to Day 90
    End point description
    From repeated measures analysis. The least squares mean (LS mean) change from baseline to each visit in urine IL-18 (pg/mL). Lower measures for IL-18 are desirable. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    43
    47
    44
    36
    Units: pg/mL
        least squares mean (standard error)
    1.7 ( 16.7 )
    1.1 ( 15.9 )
    6.3 ( 16.5 )
    -2.7 ( 18.2 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -45.9
         upper limit
    44.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    23.1
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    4.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -41.7
         upper limit
    50.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    23.6
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -4.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -53
         upper limit
    44.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    24.8

    Secondary: Urine Kidney Injury Molecule (KIM-1): Change from Baseline to Day 90

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    End point title
    Urine Kidney Injury Molecule (KIM-1): Change from Baseline to Day 90
    End point description
    From repeated measures analysis. The least squares mean (LS mean) change from baseline to each visit in urine KIM-1 (ng/mL). Lower measures for urine KIM-1 are desirable. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    43
    47
    44
    36
    Units: ng/mL
        least squares mean (standard error)
    0.17 ( 0.27 )
    0.2 ( 0.25 )
    -0.02 ( 0.26 )
    0.36 ( 0.29 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.69
         upper limit
    0.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.93
         upper limit
    0.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.58
         upper limit
    0.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: Urine Neutrophil Gelatinase Associated Lipocalin (NGAL): Change from Baseline to Day 90

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    End point title
    Urine Neutrophil Gelatinase Associated Lipocalin (NGAL): Change from Baseline to Day 90
    End point description
    From repeated measures analysis. The least squares mean (LS mean) change from baseline to each visit in NGAL (ng/mL). Lower measures for NGAL are desirable. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    43
    47
    44
    36
    Units: ng/mL
        least squares mean (standard error)
    399 ( 107.3 )
    47 ( 103.7 )
    18 ( 106.9 )
    1 ( 118.2 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -352.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -645
         upper limit
    -60
    Variability estimate
    Standard error of the mean
    Dispersion value
    149.1
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -381.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -679
         upper limit
    -84
    Variability estimate
    Standard error of the mean
    Dispersion value
    151.54
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; the autoregressive variance-covariance structure is used.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -389.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -711
         upper limit
    -86
    Variability estimate
    Standard error of the mean
    Dispersion value
    159.4

    Secondary: Hospitalization Days Within 90 Days after Surgery

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    End point title
    Hospitalization Days Within 90 Days after Surgery
    End point description
    From ANOVA model. The LS mean number of days that subjects spent hospitalized, up to 90 days after surgery. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    51
    54
    55
    49
    Units: days
        least squares mean (standard error)
    19 ( 3.4 )
    16.5 ( 3.3 )
    12.2 ( 3.3 )
    26.4 ( 3.5 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANOVA model with treatment as the factor.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.2
         upper limit
    5.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.7
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    ANOVA model with treatment as the factor.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.5
         upper limit
    0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.7
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    ANOVA model with treatment as the factor.
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    7.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    15.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.8

    Secondary: Percentage of Subjects Developing Acute Kidney Injury (AKI) as Defined by the Risk, Injury and Failure (RIFLE) Scoring Criteria

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    End point title
    Percentage of Subjects Developing Acute Kidney Injury (AKI) as Defined by the Risk, Injury and Failure (RIFLE) Scoring Criteria
    End point description
    The RIFLE is an evidence-based definition for AKI based on changes to serum creatinine (SCr), urine output (UO), and two clinical outcomes (Loss [acute kidney failure for > 4 weeks] and End-stage renal disease). The 3 severity grades are defined on the basis of the changes in SCr or UO where the worst of each criterion is used: Risk (increased Cr x 1.5 or GFR decreased < 25%; UO < 0.5 mL/kg/hr x 6 hr), Injury (increased Cr x 2 or GFR decreased < 50%; UO < 0.5 mL/kg/hr x 12 hr), and Failure (increased Cr x 3 or GFR decreased < 25% or Cr ≥ 4 mg/dL with acute rise of ≥ 0.5 mg/dL; UO < 0.3 mL/kg/hr x 24 hr or anuria x 12 hr). The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 7
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    52
    54
    55
    49
    Units: percentage of subjects
    number (not applicable)
        No
    26.92
    25.93
    32.73
    22.45
        Risk
    11.54
    14.81
    9.09
    18.37
        Injury
    51.92
    53.7
    52.73
    53.06
        Failure
    9.62
    5.56
    5.45
    6.12
        Any stage
    73.08
    74.07
    67.27
    77.55
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Developing Acute Kidney Injury (AKI) as Defined by the Kidney Disease: Improving Global Outcomes (KDIGO) Scoring Criteria

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    End point title
    Percentage of Subjects Developing Acute Kidney Injury (AKI) as Defined by the Kidney Disease: Improving Global Outcomes (KDIGO) Scoring Criteria
    End point description
    The KDIGO is based on the RIFLE and the AKIN criteria and risk relationships. AKI is defined as increase in SCr by ≥ 3 mg/dl (≥ 26.5 µmol/L) within 48 hours; increase in SCr to ≥ 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or urine volume < 0.5 mL/kg/h for 6 hours. The 3 severity grades are defined as: Stage 1 (increased Cr x 1.5-1.9 x baseline or ≥ 3 mg/dl [≥ 26.5 µmol/L] UO < 0.5 mL/kg/hr x 6-12 hr), Stage 2 (increased Cr x 2.0-2.9; UO < 0.5 mL/kg/hr x 12 hr), and Stage 3 (increased Cr x 3.0 OR increase Cr to ≥ 4.0 mg/dL (≥ 353.6 μmol/L) OR initiation of renal replacement therapy OR, in patients < 18 years, decrease in eGFR to < 35 mL/min per 1.73 m^2; UO < 0.3 mL/kg/hr for ≥ 24 hr or anuria for ≥ 12 hr). The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 7
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    52
    54
    55
    49
    Units: percentage of subjects
    number (not applicable)
        No
    26.92
    25.93
    34.55
    26.53
        Stage 1
    11.54
    18.52
    7.27
    14.29
        Stage 2
    51.92
    50
    52.73
    53.06
        Stage 3
    9.62
    5.56
    5.45
    6.12
        Any stage
    73.08
    74.07
    65.45
    73.47
    No statistical analyses for this end point

    Secondary: Serum Creatinine (SCr): Change from Baseline to Day 90

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    End point title
    Serum Creatinine (SCr): Change from Baseline to Day 90
    End point description
    From repeated measures analysis. The least squares mean (LS mean) change from baseline to each visit in SCr (µmol/L). Lower measures for SCr are desirable. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) through Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    42
    47
    48
    35
    Units: µmol/L
        least squares mean (standard error)
    10.9 ( 3.54 )
    9.3 ( 3.37 )
    3.4 ( 3.38 )
    6.5 ( 3.85 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.2
         upper limit
    8
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.89
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -7.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.2
         upper limit
    2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.9
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -4.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.6
         upper limit
    6
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.25

    Secondary: Serum Creatinine (SCr): Maximal Change from Baseline Over All Study Visits up to Day 7 (or Hospital Discharge)

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    End point title
    Serum Creatinine (SCr): Maximal Change from Baseline Over All Study Visits up to Day 7 (or Hospital Discharge)
    End point description
    From ANCOVA model. The least squares mean (LS mean) maximal change from baseline to each visit up to Day 7 in SCr (µmol/L). Lower measures for SCr are desirable. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) through Day 7
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    51
    54
    50
    48
    Units: µmol/L
        least squares mean (standard error)
    30.2 ( 6.08 )
    32.8 ( 5.9 )
    26.3 ( 6.14 )
    28.4 ( 6.26 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANCOVA model with treatment group as the factor and baseline as a covariate.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    2.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14
         upper limit
    19.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.47
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    ANCOVA model with treatment group as the factor and baseline as a covariate.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.9
         upper limit
    13.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.64
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    ANCOVA model with treatment group as the factor and baseline as a covariate.
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19
         upper limit
    15.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.73

    Secondary: S-Cystatin C: Change from Baseline to Day 90

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    End point title
    S-Cystatin C: Change from Baseline to Day 90
    End point description
    From repeated measures analysis. The least squares mean (LS mean) change from baseline to each visit in S-Cystatin C (nmol/L). Lower measures for S-Cystatin C are desirable. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    40
    47
    46
    35
    Units: nmol/L
        least squares mean (standard error)
    16.1 ( 3.13 )
    11.3 ( 2.96 )
    11.6 ( 3.03 )
    12.8 ( 3.34 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.2
         upper limit
    3.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.31
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.1
         upper limit
    4.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.36
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.3
         upper limit
    5.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.58

    Secondary: S-Cystatin C: Maximal Change from Baseline Over All Study Visits up to Day 7 (or Hospital Discharge)

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    End point title
    S-Cystatin C: Maximal Change from Baseline Over All Study Visits up to Day 7 (or Hospital Discharge)
    End point description
    From ANCOVA model. The least squares mean (LS mean) maximal change from baseline to each visit up to Day 7 in S-Cystatin C (nmol/L). Lower measures for S-Cystatin C are desirable. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) through Day 7
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    51
    54
    50
    48
    Units: µmol/L
        least squares mean (standard error)
    22.6 ( 4.04 )
    23 ( 3.92 )
    18.4 ( 4.08 )
    20.6 ( 4.16 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANCOVA model with treatment group as the factor and baseline as a covariate.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.6
         upper limit
    11.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.63
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    ANCOVA model with treatment group as the factor and baseline as a covariate.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -4.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.4
         upper limit
    7.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.74
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    ANCOVA model with treatment group as the factor and baseline as a covariate.
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.4
         upper limit
    9.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.8

    Secondary: Measured Glomerular Filtration Rate (GFR): Change from Baseline to Day 90

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    End point title
    Measured Glomerular Filtration Rate (GFR): Change from Baseline to Day 90
    End point description
    From repeated measures analysis. The least squares mean (LS mean) change from baseline to each visit in GFR (L/min/1.73m^2). Higher measures for GFR are desirable. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) through Day 7
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    42
    45
    48
    35
    Units: mL/min/1.73m^2
        least squares mean (standard error)
    -4 ( 1.72 )
    -4.9 ( 1.67 )
    -1.2 ( 1.67 )
    -5.9 ( 1.86 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.6
         upper limit
    3.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.41
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    7.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.9
         upper limit
    3.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.54

    Secondary: Estimated Glomerular Filtration Rate (eGFR): Change from Baseline to Day 90

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    End point title
    Estimated Glomerular Filtration Rate (eGFR): Change from Baseline to Day 90
    End point description
    From repeated measures analysis. The least squares mean (LS mean) change from baseline to each visit in eGFR (L/min/1.73m^2). Higher measures for eGFR are desirable. All subjects in the per protocol analysis set with available data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) through Day 7
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    7
    6
    7
    4
    Units: mL/min/1.73m^2
        least squares mean (standard error)
    -11.1 ( 5.04 )
    -6.6 ( 5.13 )
    2.3 ( 4.9 )
    2.7 ( 6.46 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.2
         upper limit
    19.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.27
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    13.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    27.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.11
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    A mixed effects, repeated measures model including fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as fixed, continuous effects of baseline measurements and subject effects; covariance structure is unstructured.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    13.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.7
         upper limit
    30.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.15

    Secondary: Intensive Care Unit (ICU) Days Within 90 Days after Surgery

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    End point title
    Intensive Care Unit (ICU) Days Within 90 Days after Surgery
    End point description
    From ANOVA model. The LS mean number of days that subjects spent in ICU, up to 90 days after surgery. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Secondary
    End point timeframe
    Day 0 (Surgery) to Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    49
    51
    54
    49
    Units: days
        least squares mean (standard error)
    5.4 ( 0.8 )
    4.6 ( 0.8 )
    3.5 ( 0.8 )
    6.3 ( 0.8 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANOVA model with treatment as the factor.
    Comparison groups
    Placebo v ABT-719 800 mcg/kg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    ANOVA model with treatment as the factor.
    Comparison groups
    Placebo v ABT-719 1600 mcg/kg
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    ANOVA model with treatment as the factor.
    Comparison groups
    Placebo v ABT-719 2100 mcg/kg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean of difference
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2

    Other pre-specified: Euroqol 5 Dimensions Questionnaire (EQ-5D) Index: Change from Baseline to Day 90

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    End point title
    Euroqol 5 Dimensions Questionnaire (EQ-5D) Index: Change from Baseline to Day 90
    End point description
    The EQ-5D-3L consists of 5 dimensions: 1) mobility, 2) self-care, 3) usual activities, 4) pain/discomfort, and 5) anxiety/depression. There are 3 levels to each dimension; Level 1 = no problem, Level 2 = some problem, and Level 3 = extreme problem. The scores of the 5 dimensions were converted into a single summary index by utilizing country specific value sets. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Other pre-specified
    End point timeframe
    Day 0 (Surgery) and Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    46
    49
    52
    38
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.034 ( 0.092 )
    0.072 ( 0.1 )
    0.017 ( 0.093 )
    0.017 ( 0.102 )
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects Who Experienced "No Problem" (Level 1) and "Problems" (Levels 2 and 3) in the 5 Dimensions of the Euroqol 5 Dimensions (EQ-5D) Questionnaire on Day 90

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    End point title
    Percentage of Subjects Who Experienced "No Problem" (Level 1) and "Problems" (Levels 2 and 3) in the 5 Dimensions of the Euroqol 5 Dimensions (EQ-5D) Questionnaire on Day 90
    End point description
    The EQ-5D-3L consists of 5 dimensions: 1) mobility, 2) self-care, 3) usual activities, 4) pain/discomfort, and 5) anxiety/depression. There are 3 levels to each dimension; Level 1 = no problem, Level 2 = some problem, and Level 3 = extreme problem. All subjects in the per protocol analysis set with available data are included in the analysis. The number of subjects analyzed = all subjects in the per protocol analysis set with available data.
    End point type
    Other pre-specified
    End point timeframe
    Day 90
    End point values
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Number of subjects analysed
    46
    49
    53
    38
    Units: percentage of subjects
    number (not applicable)
        Mobility - no problem
    73.91
    85.71
    69.81
    76.32
        Mobility - some problem
    26.09
    14.29
    30.19
    23.68
        Mobility - extreme problem
    0
    0
    0
    0
        Self-care - no problem
    93.48
    95.92
    90.57
    94.74
        Self-care - some problem
    6.52
    4.08
    9.43
    5.26
        Self-care - extreme problem
    0
    0
    0
    0
        Usual activities - no problem
    63.04
    83.67
    60.38
    71.05
        Usual activities - some problem
    34.78
    16.33
    35.85
    28.95
        Usual activities - extreme problem
    2.17
    0
    3.77
    0
        Pain/discomfort - no problem
    71.74
    77.55
    67.92
    73.68
        Pain/discomfort - some problem
    23.91
    22.45
    26.42
    26.32
        Pain/discomfort - extreme problem
    4.35
    0
    5.66
    0
        Anxiety/depression - no problem
    84.78
    91.84
    77.36
    84.21
        Anxiety/depression - some problem
    15.22
    8.16
    22.64
    10.53
        Anxiety/depression - extreme problem
    0
    0
    0
    5.26
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from study drug administration until 30 days after last dose (32 days); serious adverse events (SAEs) were collected from the time that informed consent was obtained (60 days).
    Adverse event reporting additional description
    AEs were collected whether solicited or spontaneously reported by the subject until 30 days after last dose; after 30 days, only AEs that were spontaneously reported were collected.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    A total of 6, 10-minute infusions administered 1) prior to skin incision; 2) before clamp release but at least 1 hour after the first dose 3) 6 hours (± 30 minutes) after clamp release; 4) 12 hours (± 30 minutes) after clamp release; 5) 24 hours (± 60 minutes) after clamp release; and 6) 48 hours (± 60 minutes) after clamp release.

    Reporting group title
    ABT-719 800 mcg/kg
    Reporting group description
    Six 10-minute infusions with a total dose of 800 mcg/kg ABT-719, administered 1) prior to skin incision (200 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (400 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (200 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (0 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (0 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (0 mcg/kg).

    Reporting group title
    ABT-719 1600 mcg/kg
    Reporting group description
    Six 10-minute infusions with a total dose of 1600 mcg/kg ABT-719, administered 1) prior to skin incision (300 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (600 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (200 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (200 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (200 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (0 mcg/kg).

    Reporting group title
    ABT-719 2100 mcg/kg
    Reporting group description
    Six 10-minute infusions with a total dose of 2100 mcg/kg ABT-719, administered 1) prior to skin incision (300 mcg/kg); 2) before clamp release but at least 1 hour after the first dose (600 mcg/kg); 3) 6 hours (± 30 minutes) after clamp release (300 mcg/kg); 4) 12 hours (± 30 minutes) after clamp release (300 mcg/kg); 5) 24 hours (± 60 minutes) after clamp release (300 mcg/kg); and 6) 48 hours (± 60 minutes) after clamp release (300 mcg/kg).

    Serious adverse events
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 59 (44.07%)
    12 / 57 (21.05%)
    13 / 59 (22.03%)
    27 / 56 (48.21%)
         number of deaths (all causes)
    3
    1
    0
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Haemorrhage
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypoperfusion
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (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
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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 / 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea paroxysmal nocturnal
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Pneumothorax
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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 hypertension
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Respiratory arrest
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    5 / 56 (8.93%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Investigations
    Escherichia test positive
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Heart rate decreased
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Pulse absent
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Cardiac valve rupture
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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 / 1
    Fall
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative thoracic procedure complication
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Venous injury
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Wound dehiscence
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (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
    Arrhythmia
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         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
    Atrial fibrillation
         subjects affected / exposed
    5 / 59 (8.47%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    4 / 56 (7.14%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         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
    Atrioventricular block
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Atrioventricular block complete
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 57 (1.75%)
    1 / 59 (1.69%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Atrioventricular dissociation
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Bradycardia
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 59 (3.39%)
    2 / 57 (3.51%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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 congestive
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial haemorrhage
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (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
    Pericardial effusion
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Pericardial haemorrhage
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Pulseless electrical activity
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    2 / 56 (3.57%)
         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 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         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
    Ventricle rupture
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Cerebrovascular accident
         subjects affected / exposed
    2 / 59 (3.39%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Dizziness
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Loss of consciousness
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal compartment syndrome
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (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
    Hepatobiliary disorders
    Hepatic ischaemia
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Decubitus ulcer
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Renal and urinary disorders
    Renal disorder
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Critical illness myopathy
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Rhabdomyolysis
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Pneumonia
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Wound infection
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Dehydration
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Fluid overload
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Hypercalcaemia
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 56 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo ABT-719 800 mcg/kg ABT-719 1600 mcg/kg ABT-719 2100 mcg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 59 (91.53%)
    42 / 57 (73.68%)
    54 / 59 (91.53%)
    49 / 56 (87.50%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 57 (5.26%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    3
    0
    1
    Hypertension
         subjects affected / exposed
    2 / 59 (3.39%)
    6 / 57 (10.53%)
    2 / 59 (3.39%)
    6 / 56 (10.71%)
         occurrences all number
    2
    6
    2
    6
    Hypotension
         subjects affected / exposed
    8 / 59 (13.56%)
    7 / 57 (12.28%)
    11 / 59 (18.64%)
    11 / 56 (19.64%)
         occurrences all number
    9
    8
    11
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    3 / 59 (5.08%)
    2 / 56 (3.57%)
         occurrences all number
    0
    1
    3
    2
    Oedema
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 57 (5.26%)
    2 / 59 (3.39%)
    3 / 56 (5.36%)
         occurrences all number
    2
    3
    2
    3
    Oedema peripheral
         subjects affected / exposed
    3 / 59 (5.08%)
    3 / 57 (5.26%)
    3 / 59 (5.08%)
    3 / 56 (5.36%)
         occurrences all number
    3
    3
    3
    3
    Pain
         subjects affected / exposed
    6 / 59 (10.17%)
    3 / 57 (5.26%)
    7 / 59 (11.86%)
    7 / 56 (12.50%)
         occurrences all number
    7
    3
    7
    7
    Pyrexia
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 57 (5.26%)
    5 / 59 (8.47%)
    4 / 56 (7.14%)
         occurrences all number
    2
    3
    6
    4
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 57 (5.26%)
    2 / 59 (3.39%)
    0 / 56 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Atelectasis
         subjects affected / exposed
    6 / 59 (10.17%)
    9 / 57 (15.79%)
    10 / 59 (16.95%)
    6 / 56 (10.71%)
         occurrences all number
    6
    9
    10
    8
    Dyspnoea
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 57 (3.51%)
    1 / 59 (1.69%)
    2 / 56 (3.57%)
         occurrences all number
    3
    2
    1
    2
    Pleural effusion
         subjects affected / exposed
    18 / 59 (30.51%)
    10 / 57 (17.54%)
    13 / 59 (22.03%)
    13 / 56 (23.21%)
         occurrences all number
    19
    11
    13
    15
    Pneumothorax
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 57 (5.26%)
    2 / 59 (3.39%)
    3 / 56 (5.36%)
         occurrences all number
    1
    3
    2
    3
    Respiratory failure
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 57 (5.26%)
    4 / 59 (6.78%)
    5 / 56 (8.93%)
         occurrences all number
    2
    3
    4
    5
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    4 / 56 (7.14%)
         occurrences all number
    0
    2
    3
    4
    Confusional state
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 57 (1.75%)
    2 / 59 (3.39%)
    3 / 56 (5.36%)
         occurrences all number
    3
    1
    2
    3
    Delirium
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 57 (5.26%)
    1 / 59 (1.69%)
    2 / 56 (3.57%)
         occurrences all number
    1
    3
    1
    2
    Insomnia
         subjects affected / exposed
    4 / 59 (6.78%)
    2 / 57 (3.51%)
    2 / 59 (3.39%)
    2 / 56 (3.57%)
         occurrences all number
    4
    2
    2
    2
    Mental status changes
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 57 (5.26%)
    0 / 59 (0.00%)
    2 / 56 (3.57%)
         occurrences all number
    1
    3
    0
    2
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 57 (0.00%)
    2 / 59 (3.39%)
    3 / 56 (5.36%)
         occurrences all number
    4
    0
    2
    3
    Cardiac index decreased
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 57 (5.26%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    1
    3
    0
    1
    Urine output decreased
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 57 (1.75%)
    7 / 59 (11.86%)
    4 / 56 (7.14%)
         occurrences all number
    3
    1
    7
    4
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 57 (1.75%)
    1 / 59 (1.69%)
    4 / 56 (7.14%)
         occurrences all number
    1
    1
    1
    4
    Incision site pain
         subjects affected / exposed
    6 / 59 (10.17%)
    5 / 57 (8.77%)
    5 / 59 (8.47%)
    5 / 56 (8.93%)
         occurrences all number
    7
    5
    5
    5
    Procedural haemorrhage
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    3 / 59 (5.08%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    3
    1
    Procedural nausea
         subjects affected / exposed
    6 / 59 (10.17%)
    8 / 57 (14.04%)
    6 / 59 (10.17%)
    9 / 56 (16.07%)
         occurrences all number
    6
    8
    6
    9
    Procedural pain
         subjects affected / exposed
    22 / 59 (37.29%)
    19 / 57 (33.33%)
    20 / 59 (33.90%)
    23 / 56 (41.07%)
         occurrences all number
    22
    19
    20
    23
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    25 / 59 (42.37%)
    17 / 57 (29.82%)
    13 / 59 (22.03%)
    21 / 56 (37.50%)
         occurrences all number
    27
    17
    14
    21
    Atrial flutter
         subjects affected / exposed
    2 / 59 (3.39%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    4 / 56 (7.14%)
         occurrences all number
    2
    1
    0
    4
    Sinus tachycardia
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    4 / 59 (6.78%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Tachycardia
         subjects affected / exposed
    1 / 59 (1.69%)
    2 / 57 (3.51%)
    1 / 59 (1.69%)
    3 / 56 (5.36%)
         occurrences all number
    1
    2
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 59 (27.12%)
    12 / 57 (21.05%)
    20 / 59 (33.90%)
    12 / 56 (21.43%)
         occurrences all number
    16
    12
    20
    12
    Haemorrhagic anaemia
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 57 (0.00%)
    8 / 59 (13.56%)
    0 / 56 (0.00%)
         occurrences all number
    2
    0
    8
    0
    Leukocytosis
         subjects affected / exposed
    4 / 59 (6.78%)
    3 / 57 (5.26%)
    2 / 59 (3.39%)
    5 / 56 (8.93%)
         occurrences all number
    4
    3
    3
    5
    Thrombocytopenia
         subjects affected / exposed
    6 / 59 (10.17%)
    8 / 57 (14.04%)
    9 / 59 (15.25%)
    4 / 56 (7.14%)
         occurrences all number
    6
    8
    9
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    16 / 59 (27.12%)
    10 / 57 (17.54%)
    14 / 59 (23.73%)
    15 / 56 (26.79%)
         occurrences all number
    17
    10
    14
    15
    Diarrhoea
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 57 (0.00%)
    2 / 59 (3.39%)
    3 / 56 (5.36%)
         occurrences all number
    0
    0
    2
    3
    Dysphagia
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 57 (5.26%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         occurrences all number
    1
    3
    1
    1
    Nausea
         subjects affected / exposed
    19 / 59 (32.20%)
    13 / 57 (22.81%)
    22 / 59 (37.29%)
    19 / 56 (33.93%)
         occurrences all number
    21
    13
    23
    19
    Vomiting
         subjects affected / exposed
    3 / 59 (5.08%)
    3 / 57 (5.26%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         occurrences all number
    4
    3
    1
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 57 (1.75%)
    1 / 59 (1.69%)
    3 / 56 (5.36%)
         occurrences all number
    1
    1
    1
    3
    Renal failure acute
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 57 (3.51%)
    2 / 59 (3.39%)
    3 / 56 (5.36%)
         occurrences all number
    3
    2
    2
    3
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 57 (1.75%)
    1 / 59 (1.69%)
    1 / 56 (1.79%)
         occurrences all number
    3
    1
    1
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 57 (3.51%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    3
    2
    0
    1
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 57 (3.51%)
    5 / 59 (8.47%)
    3 / 56 (5.36%)
         occurrences all number
    3
    2
    5
    3
    Electrolyte imbalance
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 57 (0.00%)
    3 / 59 (5.08%)
    3 / 56 (5.36%)
         occurrences all number
    2
    0
    3
    3
    Fluid overload
         subjects affected / exposed
    10 / 59 (16.95%)
    10 / 57 (17.54%)
    19 / 59 (32.20%)
    9 / 56 (16.07%)
         occurrences all number
    10
    10
    20
    9
    Fluid retention
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 57 (5.26%)
    2 / 59 (3.39%)
    1 / 56 (1.79%)
         occurrences all number
    2
    3
    2
    1
    Hyperglycaemia
         subjects affected / exposed
    15 / 59 (25.42%)
    10 / 57 (17.54%)
    15 / 59 (25.42%)
    17 / 56 (30.36%)
         occurrences all number
    15
    10
    15
    17
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 57 (1.75%)
    2 / 59 (3.39%)
    3 / 56 (5.36%)
         occurrences all number
    0
    1
    2
    3
    Hypocalcaemia
         subjects affected / exposed
    6 / 59 (10.17%)
    5 / 57 (8.77%)
    12 / 59 (20.34%)
    9 / 56 (16.07%)
         occurrences all number
    6
    5
    12
    10
    Hypokalaemia
         subjects affected / exposed
    14 / 59 (23.73%)
    14 / 57 (24.56%)
    16 / 59 (27.12%)
    14 / 56 (25.00%)
         occurrences all number
    16
    14
    16
    14
    Hypomagnesaemia
         subjects affected / exposed
    6 / 59 (10.17%)
    4 / 57 (7.02%)
    9 / 59 (15.25%)
    5 / 56 (8.93%)
         occurrences all number
    6
    4
    9
    5
    Hyponatraemia
         subjects affected / exposed
    2 / 59 (3.39%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    2 / 56 (3.57%)
         occurrences all number
    2
    2
    3
    2
    Hypovolaemia
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    3 / 56 (5.36%)
         occurrences all number
    3
    2
    3
    3
    Metabolic acidosis
         subjects affected / exposed
    5 / 59 (8.47%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    0 / 56 (0.00%)
         occurrences all number
    5
    2
    3
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2012
    To remove both 1200 mcg/kg groups and add the 1600 mcg/kg and 2100 mcg/kg groups and update procedures and statistical analyses; for doses given outside the operating room, allow principal investigator to write an order for study drug to be administered by hospital personnel; permit an additional 20 subjects per treatment group if appropriate based on results from interim analysis; add that some of the study visits may be conducted in the home or in a non-hospital setting and that subjects may use a home trial support service with agreement of the investigatory; modify inclusion criteria to clarify the definition of stable renal function, that patients with intravascular iodinated contrast within 48 hours of the day of surgery could be included if no known serum creatinine change ≥0.3 mg; modify exclusion criteria to clarify definition of active peptic ulcer, exclude patients with known or document RIFLE ‘R’ or AKIN ‘Stage 1’ results within the previous 4 weeks; specify timing of urine output collection; add must specify need for RRT; clarify measurements and procedures; add secondary endpoints to evaluate composite events utilizing cystatin-C based eGFR in addition to SCr based eGFR; change number of infusions from 5 to 6 and, if study drug is administered through a central line, then it should be administered through a separate port; add 2 interim analyses; revise total of number of subjects to up to 240.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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