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    Clinical Trial Results:
    A Phase 2, Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group, Study to Investigate the Safety and Tolerability of Multiple Dose Administration of CSL112 in Subjects with Moderate Renal Impairment and Acute Myocardial Infarction

    Summary
    EudraCT number
    2015-003017-26
    Trial protocol
    DE   HU   NL  
    Global end of trial date
    19 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Jul 2018
    First version publication date
    01 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL112_2001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02742103
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CSL Behring LLC
    Sponsor organisation address
    1020 First Avenue, King of Prussia, United States, 19406
    Public contact
    Trial Registration Coordinator, CSL Behring, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Registration Coordinator, CSL Behring, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the renal safety of CSL112 in subjects with moderate renal impairment and acute myocardial infarction after up to 4 weekly administrations of CSL112
    Protection of trial subjects
    This study will be conducted in accordance with standards of Good Clinical Practice (as defined by the International Conference on Harmonisation), ethical principles that have their origin in the Declaration of Helsinki and all applicable national and local regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Netherlands: 10
    Worldwide total number of subjects
    83
    EEA total number of subjects
    54
    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)
    15
    From 65 to 84 years
    65
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    To ensure that at least 1/3 of the study population had an estimated glomerular filtration (eGFR) in the chronic kidney disease (CKD) Stage 3b range, no more than 2/3 of the study population were to have an eGFR in the CKD Stage 3a range. Randomization was stratified by eGFR and by medical history of diabetes.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CSL112
    Arm description
    CSL112 (6 g) will be administered as a 2-hour intravenous (IV) infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total).
    Arm type
    Experimental

    Investigational medicinal product name
    CSL112
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CSL112 contains apolipoprotein A-I (apoA-I), phosphatidylcholine (PC), cholate, and sucrose as a stabilizer. CSL112 (6 g) will be administered as a 2-hour IV infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total).

    Arm title
    Placebo
    Arm description
    Placebo control (0.9% weight/volume sodium chloride solution, i.e., normal saline) administered as a 2-hour IV infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total) in a volume matched to the CSL112 infusion.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo control (0.9% weight/volume sodium chloride solution, i.e., normal saline) administered as a 2-hour IV infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total) in a volume matched to the CSL112 infusion.

    Number of subjects in period 1
    CSL112 Placebo
    Started
    55
    28
    Completed
    46
    23
    Not completed
    9
    5
         Protocol deviation
    1
    -
         Adverse event, serious fatal
    2
    2
         Adverse event, non-fatal
    1
    -
         Moved to another town
    -
    1
         Consent withdrawn by subject
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CSL112
    Reporting group description
    CSL112 (6 g) will be administered as a 2-hour intravenous (IV) infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total).

    Reporting group title
    Placebo
    Reporting group description
    Placebo control (0.9% weight/volume sodium chloride solution, i.e., normal saline) administered as a 2-hour IV infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total) in a volume matched to the CSL112 infusion.

    Reporting group values
    CSL112 Placebo Total
    Number of subjects
    55 28 83
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    11 4 15
        From 65-84 years
    42 23 65
        85 years and over
    2 1 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    70.6 ± 10.95 71.9 ± 10.12 -
    Gender categorical
    Units: Subjects
        Female
    18 10 28
        Male
    37 18 55

    End points

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    End points reporting groups
    Reporting group title
    CSL112
    Reporting group description
    CSL112 (6 g) will be administered as a 2-hour intravenous (IV) infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total).

    Reporting group title
    Placebo
    Reporting group description
    Placebo control (0.9% weight/volume sodium chloride solution, i.e., normal saline) administered as a 2-hour IV infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total) in a volume matched to the CSL112 infusion.

    Subject analysis set title
    Safety Population (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety (SAF) Population consisted of all subjects who received at least a partial dose of investigational product.

    Subject analysis set title
    Pharmacokinetic Population (PK)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All subjects in the SAF who had at least 1 measurable plasma concentration of either apoA-I or PC.

    Primary: Percent of subjects with at least one occurrence of treatment-emergent renal Serious Adverse Events (SAEs) (SAF)

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    End point title
    Percent of subjects with at least one occurrence of treatment-emergent renal Serious Adverse Events (SAEs) (SAF)
    End point description
    A renal SAE is defined as any SAE with a MedDRA preferred term included in the Acute Renal Failure narrow Standard MedDRA Query or a preferred term of renal tubular necrosis, renal cortical necrosis, renal necrosis, or renal papillary necrosis.
    End point type
    Primary
    End point timeframe
    Up to 9 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Percent of subjects
        number (not applicable)
    1.9
    14.3
    Statistical analysis title
    Rate difference between treatment groups
    Comparison groups
    CSL112 v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Newcombe-Wilson
    Parameter type
    Rate difference (CSL112 - placebo)
    Point estimate
    -0.124
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.296
         upper limit
    -0.005

    Primary: Percent of subjects with treatment-emergent Acute Kidney Injury (AKI ) (SAF)

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    End point title
    Percent of subjects with treatment-emergent Acute Kidney Injury (AKI ) (SAF)
    End point description
    Acute kidney injury is defined as an absolute increase in serum creatinine from baseline ≥ 0.3 mg/dL during the Active Treatment Period that is sustained upon repeat measurement by the central laboratory no earlier than 24 hours after the elevated value. If no repeat value is obtained, a single serum creatinine value that is increased from baseline ≥ 0.3 mg/dL (26.5 μmol/L) during the Active Treatment Period would also fulfil the definition of AKI.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Percent of subjects
        number (not applicable)
    4.0
    14.3
    Statistical analysis title
    Rate difference between treatment groups
    Comparison groups
    CSL112 v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Newcombe-Wilson
    Parameter type
    Rate difference (CSL112 - placebo)
    Point estimate
    -0.103
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.277
         upper limit
    0.025

    Secondary: Number of subjects with any treatment-emergent adverse event (TEAE) (SAF)

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    End point title
    Number of subjects with any treatment-emergent adverse event (TEAE) (SAF)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Number of subjects
        number (not applicable)
    38
    20
    No statistical analyses for this end point

    Secondary: Percent of subjects with any TEAE (SAF)

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    End point title
    Percent of subjects with any TEAE (SAF)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Percent of subjects
        number (not applicable)
    73.1
    71.4
    No statistical analyses for this end point

    Secondary: Total number of TEAEs (SAF)

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    End point title
    Total number of TEAEs (SAF)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Number
        number (not applicable)
    111
    61
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent adverse drug reaction (ADR) or suspected ADR (SAF)

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    End point title
    Number of subjects with treatment-emergent adverse drug reaction (ADR) or suspected ADR (SAF)
    End point description
    Adverse drug reactions or suspected adverse drug reactions are defined as: 1.All TEAEs, including local tolerability events, that begin during or within 1 hour after the end of an infusion; or 2.Those TEAEs that the investigator or sponsor indicate may be causally related to product administration; or 3.All TEAEs for which the Investigator's causality assessment is missing or indeterminate; or 4.All TEAEs for which the incidence in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more
    End point type
    Secondary
    End point timeframe
    Up to 9 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Number of subjects
        number (not applicable)
    30
    4
    No statistical analyses for this end point

    Secondary: Percentage of subjects with treatment-emergent ADR or suspected ADR (SAF)

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    End point title
    Percentage of subjects with treatment-emergent ADR or suspected ADR (SAF)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Percent of subjects
        number (not applicable)
    57.7
    14.3
    No statistical analyses for this end point

    Secondary: Number of subjects with change in renal status with central laboratory (SAF)

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    End point title
    Number of subjects with change in renal status with central laboratory (SAF)
    End point description
    Changes in renal status defined as: ◦Absolute increases from baseline in serum creatinine as follows: i. ≤ baseline value ii. > 0 to < 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. > 0.5 mg/dL ◦Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL ◦Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit
    End point type
    Secondary
    End point timeframe
    Baseline and up to 4 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Number of subjects
    number (not applicable)
        ≤ baseline value
    9
    3
        > 0 to < 0.3 mg/dL
    35
    18
        ≥ 0.3 to ≤ 0.5 mg/dL
    4
    4
        > 0.5 mg/dL
    2
    2
        ≥ 1.5 × Baseline
    1
    0
        ≥ 2 × Baseline
    0
    0
        ≥ 3 × Baseline
    0
    0
        ≥ 4.0 mg/dL
    0
    0
        Decrease in eGFR by ≥ 25%
    5
    4
    No statistical analyses for this end point

    Secondary: Percentage of subjects with change in renal status with central labortory (SAF)

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    End point title
    Percentage of subjects with change in renal status with central labortory (SAF)
    End point description
    Changes in renal status defined as: ◦Absolute increases from baseline in serum creatinine as follows: i. ≤ baseline value ii. > 0 to < 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. > 0.5 mg/dL ◦Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL ◦Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit
    End point type
    Secondary
    End point timeframe
    Baseline and up to 4 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Percent of subjects
    number (not applicable)
        ≤ Baseline Value
    17.3
    10.7
        > 0 to < 0.3 mg/dL
    67.3
    64.3
        ≥ 0.3 to ≤ 0.5 mg/dL
    7.7
    14.3
        > 0.5 mg/dL
    3.8
    7.1
        ≥ 1.5 × Baseline
    1.9
    0
        ≥ 2 × Baseline
    0
    0
        ≥ 3 × Baseline
    0
    0
        ≥ 4.0 mg/dL
    0
    0
        Decrease in eGFR by ≥ 25%
    9.6
    14.3
    No statistical analyses for this end point

    Secondary: Number of subjects with changes in hepatic status with central laboratory (SAF)

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    End point title
    Number of subjects with changes in hepatic status with central laboratory (SAF)
    End point description
    Change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement defined as: 1.Alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) 2.ALT > 5 x ULN 3.ALT > 10 x ULN 4.Serum total bilirubin > 1.5 x ULN 5.Serum total bilirubin > 2 x ULN
    End point type
    Secondary
    End point timeframe
    Baseline and up to 4 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Number of subjects
    number (not applicable)
        total bilirubin > 1.5 x ULN
    4
    1
        total bilirubin > 2 x ULN
    1
    0
        ALT > 3 x ULN
    0
    0
        ALT > 5 x ULN
    0
    0
        ALT > 10 x ULN
    0
    0
    No statistical analyses for this end point

    Secondary: Percent of subjects with changes in hepatic status with central laboratory (SAF)

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    End point title
    Percent of subjects with changes in hepatic status with central laboratory (SAF)
    End point description
    Change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement defined as: 1.ALT > 3 x upper limit of normal (ULN) 2.ALT > 5 x ULN 3.ALT > 10 x ULN 4.Serum total bilirubin > 1.5 x ULN 5.Serum total bilirubin > 2 x ULN
    End point type
    Secondary
    End point timeframe
    Baseline and up to 4 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Percent of subjects
    number (not applicable)
        total bilirubin > 1.5 x ULN
    7.7
    3.7
        total bilirubin > 2 x ULN
    1.9
    0
        ALT > 3 x ULN
    0
    0
        ALT > 5 x ULN
    0
    0
        ALT > 10 x ULN
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent bleeding events (SAF)

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    End point title
    Number of subjects with treatment-emergent bleeding events (SAF)
    End point description
    Bleeding events are as defined by the Bleeding Academic Research Consortium criteria (Mehran et al., 2011).
    End point type
    Secondary
    End point timeframe
    Up to 9 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Number of subjects
        number (not applicable)
    7
    5
    No statistical analyses for this end point

    Secondary: Percent of subjects with treatment-emergent bleeding events (SAF)

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    End point title
    Percent of subjects with treatment-emergent bleeding events (SAF)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: Percent of subjects
        number (not applicable)
    13.5
    17.9
    No statistical analyses for this end point

    Secondary: Percentage of subjects with binding antibodies specific to apolipoprotein A-I (apo-A1) and CSL112 (SAF)

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    End point title
    Percentage of subjects with binding antibodies specific to apolipoprotein A-I (apo-A1) and CSL112 (SAF)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 weeks
    End point values
    CSL112 Placebo
    Number of subjects analysed
    46
    22
    Units: Percent of subjects
    number (not applicable)
        CSL112 antibody
    0
    0
        apoA-I antibody
    0
    0
    No statistical analyses for this end point

    Secondary: Plasma apoA-I and phosphatidylcholine (PC) accumulation ratio after infusion 4 (PK)

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    End point title
    Plasma apoA-I and phosphatidylcholine (PC) accumulation ratio after infusion 4 (PK) [1]
    End point description
    End point type
    Secondary
    End point timeframe
    Immediately after end of infusion
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Accumulation ratio is not calculated for subjects in the Placebo group.
    End point values
    CSL112
    Number of subjects analysed
    38
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    1.2 ± 0.32
        PC
    1.0 ± 0.36
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma concentration maximum (Cmax) after infusion 1 for apoA-I and PC (PK)

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    End point title
    Baseline-corrected plasma concentration maximum (Cmax) after infusion 1 for apoA-I and PC (PK)
    End point description
    End point type
    Secondary
    End point timeframe
    Immediately after end of infusion
    End point values
    CSL112 Placebo
    Number of subjects analysed
    52
    28
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    124.6 ± 25.38
    -4.5 ± 9.46
        PC
    198.4 ± 43.56
    -4.9 ± 15.04
    No statistical analyses for this end point

    Secondary: Baseline-corrected plasma concentration maximum (Cmax) after infusion 4 for apoA-I and PC (PK)

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    End point title
    Baseline-corrected plasma concentration maximum (Cmax) after infusion 4 for apoA-I and PC (PK)
    End point description
    End point type
    Secondary
    End point timeframe
    Immediately after end of infusion
    End point values
    CSL112 Placebo
    Number of subjects analysed
    38
    21
    Units: mg/dL
    arithmetic mean (standard deviation)
        apoA-I
    141.5 ± 41.11
    1.4 ± 23.57
        PC
    200.0 ± 71.78
    -13.2 ± 27.96
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    67 days for each subject
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    CSL112
    Reporting group description
    CSL112 (6 g) will be administered as a 2-hour IV infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total).

    Reporting group title
    Placebo
    Reporting group description
    Placebo control (0.9% weight/volume sodium chloride solution, i.e., normal saline) administered as a 2-hour IV infusion into a suitable vein (peripheral or central) once weekly for 4 consecutive weeks (four infusions total) in a volume matched to the CSL112 infusion.

    Serious adverse events
    CSL112 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 52 (23.08%)
    10 / 28 (35.71%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    2
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post concussion syndrome
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal erosion
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephropathy toxic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    CSL112 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 52 (34.62%)
    12 / 28 (42.86%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 52 (9.62%)
    1 / 28 (3.57%)
         occurrences all number
    5
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 28 (0.00%)
         occurrences all number
    5
    0
    Haemoglobin decreased
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    5 / 52 (9.62%)
    2 / 28 (7.14%)
         occurrences all number
    5
    2
    Hypotension
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 28 (3.57%)
         occurrences all number
    4
    1
    Nausea
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jun 2016
    -Revised the AKI definition -Added the evaluations that would be conducted for comparing AKI rates -Revised exclusion criterion 6 to clarify the definition of nephrotic range proteinuria at screening -Revised the secondary endpoints 2 and 3 regarding 1) the timing for capturing the occurrence of adverse drug reactions or suspected adverse drug reactions relative to investigational product infusion and 2) serum creatinine parameters -Revised the definition of study completion, to make the definition more conservative and easier to operationalize -Clarify the timing and number of repeat serum creatinine measurements for subsequent infusion eligibility -Defined “high grade proteinuria” on the locally performed urine dipstick at screening that would trigger the need for a central laboratory urinalysis assessment

    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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